Eurogene

Genetic testing and potential harm: DTC or trust me I’m a doctor?

2011-06-12T15:30:00.002+02:00

Recently at a couple of conferences (European Human Genetics conference and Consumer Genetics Conf) there have been various speakers questioning DTC genetics and calling for all health related personal genetics to be delivered through medical practitioners. I argued in the past that unregulated tests delivered through practitioners actually have the potential for more harm, not less. By coincidence last week some discrepancies in a DTC and a via MD test were pointed out to me – and they seem topical.

Breast feeding has many benefits one of which appears to be increased IQ scores – however not all studies agree, some indicating that results may be confounded by maternal intelligence (see Wikipedia). Sometimes inconsistencies in associating an action with an outcome can be resolved by looking at genetic variation (which tends to increase the error bars when not accounted for).

So in 2007 some headlines were made when a study was published by Caspi’s group (PNAS, open access) reporting that there is an increase in IQ but only in infants who were not GG for the FADS2 rs174575 SNP. It seemed like a good study, 2 cohorts whose location could not have been farther apart and nearly 3,000 children tested. The numbers begin to get much smaller though when they are dissected as only approx 8% were homozygous GG:

Interesting results – but just one study and there were some doubts expressed at the time (e.g. “they have a measure of maternal IQ but don't directly include it in the published multiple regression suggests that they tried it, but didn't like the results”)

These are preliminary results but a genetic test is being offered to medical practitioners to enable “informed decisions” to be made (they don’t cite the study but it must be Caspi). They say:

Genetic testing performed by Existence Genetics enables parents to have access to this extremely useful information about their newborn. Although it may be ideal for most mothers to breastfeed, many are in situations that make the decision not so simple. For example, some women take medications that prevent them from breastfeeding, and others experience pain, poor milk production, and other difficulties.

If the baby doesn’t have this gene then breastfeeding appears to have no effect upon IQ.

Empowered by this groundbreaking research, Existence Genetics now provides women, pediatricians, wet nurses, and lactation consultants with exclusive genetic testing services that will allow them to make a more informed decision about breastfeeding.

Infants who have a specific version of the FADS2 gene will have an increase of approximately 7 IQ points, whereas infants without the variant won’t experience any IQ boost from breastfeeding.

Clearly the only influence that this result could have would be to make it easier for mothers not to breastfeed if there is no IQ benefit. Mothers of FADS2 GG babies will be told that breastfeeding will not increase IQ, there is no difference.

Rule No.1: do not base a genetic test on one study, even if it does look compelling. Break this rule at your peril.

Heres why:

Steer CD, Davey Smith G, Emmett PM, Hibbeln JR, Golding J (2010) FADS2 Polymorphisms Modify the Effect of Breastfeeding on Child IQ. PLoS ONE 5(7): e11570.

In a larger study Steer et al attempted replication in 5,394 children. They were not able to reproduce the results, in fact they reported that breastfed GG children performed better by 5.8 IQ points. GG children actually showed the greatest difference.

And another study:

Martin NW, Benyamin B, Hansell NK, Montgomery GW, Martin NG, Wright MJ, Bates TC. Cognitive function in adolescence: testing for interactions between breast-feeding and FADS2 polymorphisms. J Am Acad Child Adolesc Psychiatry. 2011 Jan;50(1):55-62.e4. Epub 2010 Dec 3.

They also were unable to repeat the Caspi study – unadjusted data showed a benefit if breastfeeding across all genotypes although they also say that when adjusted for sex, SES, paternal and maternal education, and birth weight the significance disappeared – they support the hypothesis that the breastfeeding/IQ association “reﬂects variation in parental cognitive ability” – in any case there was no FADS2 GG effect.

Based on the follow-up studies there is no support for any personalised advice based on the FADS2 gene – it cannot be used as a reason not to breastfeed and the largest study actually showed increased benefits for IQ in the group that would be advised that not breastfeeding makes no difference

This same doubtful information is also delivered by 23andme: just one study and no mention of the two larger studies. It is though announced as a “preliminary research report”.

I am disappointed that 23andme have not caught the other 2 papers – do they not have an army of researchers keeping up to date? It’s an enormously emotive subject and thus very important, it suggests that they need to improve their literature update methods and I hope they will – try using the “alert me when this article is cited” feature common to almost all journals.

This is does not particularly look good for either of the companies, but there is a big difference – one is delivered by the healthcare practitioner as “useful information” to help you decide to not breastfeed, the other is presented as results of a study. Neither are justified but I would say that the potential for a harmful impact is increased in one of the situations rather than the other. Which has the potential for more harm? Even if you are of the opinion that both are equally harmful, it certainly does not support the claims that because DTC could be harmful it should be banned and all delivered through medical practitioners because that would protect the patient. My view is that DTC or MD is not the problem – transparency is.

I suppose FADS2 is an appropriate name at least

Caspi A, Williams B, Kim-Cohen J, Craig IW, Milne BJ, Poulton R, Schalkwyk LC, Taylor A, Werts H, & Moffitt TE (2007). Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism. Proceedings of the National Academy of Sciences of the United States of America, 104 (47), 18860-5 PMID: 17984066

If You Want to Practice Evidence Based Medicine then… Use the Evidence

2011-04-25T15:00:00.003+02:00

Travelling on a train to Scotland, all for the first time:

Clinical researcher says: "Look the cows in Scotland are black!".
Physicist replies: "No. Some of the cows in Scotland are black"
Mathematician says: "No, actually in Scotland there is at least one cow black on one side"

I’ve written about folic acid, homocysteine and various clinical trials of nutrients in the past. I just want to revisit it briefly because I think there are some seriously wrong messages emerging from the conclusions. For an excellent comment on evidence based recommendations see Colby Vorland.

Homocysteine (Hcy) is associated with CVD, may or may not be causal but the evidence is good (Wald et al, BMJ, 2002). Folic acid (Vitamin B9) in reasonable amounts will lower homocysteine but clinical trials have been carried out, mostly showing not much benefit as far a CVD is concerned. A recent meta-analysis of 8 trials (total 37,485 individuals) seems to confirm this: “Dietary supplementation with folic acid to lower homocysteine levels had no significant effects within 5 years on cardiovascular events”.

BUT… all the studies were in ill people (mean age 65yrs), 7/8 with heart disease or stroke and 1 study on patients with kidney disease:

So a fair conclusion is that people who have already had a heart attack, stroke or some other sort of vascular disease may not benefit from homocysteine lowering – e.g. there was no reduction in second heart attacks, at least over the short term (mean 5 yrs).

Pity, but not so unexpected, after all vitamins are not medicines to be used when one becomes ill at 65 years old – vitamins are for life.

There are also several possibilities why Hcy lowering had apparently no effect on the patients, and also Wald et al point out that aspirin use may mask the effect of homocysteine lowering – it was interesting to see that they felt the need to underline what should be obvious:

“The fact that most of the trials included patients with pre-existing cardiovascular disease leaves open the possibility that folic acid has a useful role in the primary prevention of ischaemic heart disease, where aspirin is generally not used, but not in secondary prevention, where it is routine.”

So what do Clarke et al conclude? It’s starts off OK:

“The present meta-analysis has demonstrated that lowering homocysteine levels by an average of 25% (about 3 µmol/L) for an average of 5 years has no significant effect on the incidence of major vascular events during the scheduled treatment period.”
(They just missed out the aged ill patients bit)

They go on to discuss how observational and epidemiological studies associate homocysteine with cardiovascular disease and stroke (but do not point out that these studies were in the general population, not a diseased subset) and finally:

“One-third of adults in the United States and one-quarter of those in the United Kingdom report taking daily multivitamin supplements containing folic acid. The present meta-analysis, however, found no evidence that routine use of folic acid for 5 years has any material effect on cardiovascular or non cardiovascular events in the North American and European populations studied.”

These are two sentences from different contexts entirely – the results of the meta-analysis apply only to the study group and have NO bearing on the folic acid and homocysteine as far as primary prevention is concerned. The reviewers really should not have let that pass.

There is also a commentary on this article in the same issue which goes even further in the wrong direction. It begins discussing the role of vitamins in health and prevention then discusses the impact of the meta-analysis:

Clarke and colleagues definitively answers most of the questions about the efficacy of B-vitamin therapy.
There were no trends toward benefit in any of the primary outcomes overall or in the prespecified subgroups
This is a cautionary tale for all who are searching for therapies to prevent disease in the general population.

But as the commentary says there is a “strong scientific rationale” for Hcy lowering and “consistent observational data from high quality cohort studies with more than 10 years of prospective follow-up confirmed the outcomes suggested by hypotheses arising from laboratory and animal data.”

This all remains true and has not been touched by any of the clinical trials but the author goes on:

“However, randomized trials of vitamin therapy with folate, vitamin B6, vitamin B12…demonstrated that none of these therapies are effective for preventing cardiovascular disease…in the general population.”

This is simply not true, the trials did not study the general population and have NO relevance at all for primary prevention. There’s more:

“As trusted counselors with an ethical mandate to first do no harm, we physicians should keep this history in mind as we advise our patients about the risks and benefits of dietary supplements… Vitamins taken in excess of the dose required to prevent deficiency states have not improved not improved our patients’ health and may harm them. We should recommend therapies to prevent disease in healthy patients only when randomized trials unequivocally demonstrate that net benefits outweigh net harms, and we should continue to emphasize the importance of a nutritious diet, regular physical activity, and no smoking as the best ways to optimize health.”

Couple of things: a) to not recommend is also a recommendation and b) how does the author know about the benefits of physical activity & nutritious diet and possible harms of smoking? All the evidence is from epidemiology and observation – they have not been confirmed by randomized trials!

Maybe the cows in Scotland are black.

Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R, & B-Vitamin Treatment Trialists' Collaboration (2010). Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Archives of internal medicine, 170 (18), 1622-31 PMID: 20937919

Breast feeding: Personal genetics is in it’s infancy…

2011-01-17T10:08:00.001+01:00

There is a lot in the new today about breast feeding – should it be exclusive for at least 6 months (WHO) or should it include some earlier introduction of solid foods (BMJ article)? A lot of the reporting is confusing the issue, claiming or implying that the BMJ authors are saying the 6 months is too long (and pointing out that they have been consultants to the baby food industry). The BMJ authors are not saying that, they simply say that it might be prudent to introduce gradually some solid foods, while still breast feeding before 6 months.

There is a useful account at the Marion Nestle blog and I left a comment there which I have expanded upon here. This could be an area where genetic testing can help – blanket advice is never the best for all but confusion (as we have now) is even worse. I blogged about celiac disease and genetic testing a while ago and part of the post addressed exactly the issue of breastfeeding and weaning.

...babies differ! Probably, very likely, one type of advice is not applicable to every situation, but we don't yet have much idea of how to select.

The choice here is not breastfeeding vs. infant formula, it should be made very clear that the evidence suggesting adding solid foods before 6 months does NOT also suggest stopping breastfeeding. Precisely the opposite. The ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) issued some precise advice targeted especially at infants with possible celiac disease risk (i.e. a genetic predisposition): For further details see http://bit.ly/9xo8lt)

It is prudent to avoid both early (<4 months) and late (>or=7 months) introduction of gluten, and to introduce gluten gradually while the infant is still breast-fed, inasmuch as this may reduce the risk of celiac disease, type 1 diabetes mellitus, and wheat allergy.

Using genetics to give targeted advice is in it's infancy (excuse me!) - but could be useful in this case. If the universal advice were to suggest introducing solid foods between 4-6 months, there is a danger that it could lead to more frequent introduction actually before 4 months, which according to the evidence is even more risky for allergies and autoimmune diseases. So in this perspective the WHO advice could be considered to be wise, but there are exceptions.

I’m not so sure I understand the SACN logic though:

Currently available evidence on the timing of introduction of gluten into the infant diet and subsequent risk of coeliac disease and T1DM is insufficient to support recommendations about the appropriate timing of introduction of gluten into the infant diet for either the general population or high-risk sub-populations. However, there is evidence suggesting that not being breastfed at the time when gluten is introduced into the diet is associated with an increased risk of subsequently developing coeliac disease.

Source: Draft SACN/COT Statement on the Timing of Introduction of Gluten into the Infant’s Diet

I understand why earlier introduction of gluten may not be the best advice for the general population, but for high-risk sub-populations, I’m not so sure. The evidence is not water tight but that which does exist has been reproducible and indicates that 4-6 month introduction of gluten (while still breastfeeding) is the lower risk option. There are no studies that contradict this and none that suggest that there are more benefits than risks by waiting until after 6 months in high risk subpopulations. There are some clinical trials underway (e.g. PreventCD) which may help, but until then, the benefits and risks calculation suggests following the ESPGHAN advice, see above.

The Great Health Data Deficit: Are Environmental causes for Disease a Mirage?

2010-12-16T10:15:00.001+01:00

Ever since I was a child the message has been eat your greens (we got caned at primary school if we didn’t), you need to exercise, carrots will make you see in the dark, an apple a day keeps the doctor away. It continues today with the “5 a day”, all the healthy food pyramids, anti-junk foods, and so on. Yes the environment can be dangerous, it can kill us.

There are some indisputable examples, a bullet in the head for example, or getting hit by a car is an environmental impact that almost always results in injury and death. There are others on which we more or less agree, like smoking is harmful (evidence is very strong, although it has never actually been proven, who knows, it could be the regular movement of hand to mouth that causes all the damage, we need to do the proper controlled trial…)

For the rest we have always sort of somehow known that eating badly can cause disease – it seemed so obvious, and all the little research studies just confirmed what we knew and lead to the rise of the “big” health and big-organic industries.

But a strange thing has been happening, now that the results of the very large scale experiments are arriving, we are seeing something unexpected. Just a few examples:

Saturated fats do not cause heart disease (bad news for “big-marg”)
Fruit & veg do not protect us from cancer
Vitamins B do not work
Antioxidants are useless

What’s going on? – the scientists are now starting to argue with each other about where this “missing causality” must be.

[insert here a few hundred lines of sciency reasonable arguments. Make some valid points about the extremist denialists who say things like junk food is nutritionally useless – show the nutritional value of the Big Mac: protein and important essential fats, lycopene (in the ketchup), fibre (in the carton). Point out that despite all the doom and gloom life expectancy in all the “Western diet” countries is actually the highest it has ever been… and so on]

Then come to the clincher: Just recently the “health bandwagon” scientists have finally admitted that the last 50 years of their research has been useless and new research models are required if we are ever going to find the “missing causality” and the “missing prevention”.

But I say it is time to stop this waste of resources, their call is just an excuse to keep that bandwagon rollin’ along – the conclusion is obvious to anyone who does not have a vested interest:

It all means that genes must be the entire cause of ill health, i.e. junk food, pollution, lack of exercise, etc. do not have any impact whatsoever. We believe that if people live right, agriculture and therefore the planet will be more or less irrelevant and our genes will get us in the end, whatever we do

Some may disagree with this, in fact they might find it to be a rather silly conclusion

I do

PS I anyone is wondering what I am going on about please see http://bit.ly/hZEmHH AND http://bit.ly/gOVsm2

Personal Genetics & Utility: Round 2 – Mind the EGAPP

2010-11-28T12:36:00.001+01:00

Yesterday I wrote about the false Family History vs. Personal Genetics battle, today I look at the old chestnut of traditional risk factors. There seems to be a lot of fear among some professions that personal genetics is attempting to take over their jobs – it’s been like this from the beginning mainly due to misunderstanding (wilful or otherwise) exactly what personal genetics is and what it’s role in healthcare can be.

The latest salvo is from the EGAPP Working group who published their assessment of genetics vs. traditional risk factors (TRF) in cardiovascular disease risk. They looked at the 9p21 variant as well as 57 other variants in 28 genes associated with CVD and they sought to document

“the extent to which genomic profiling alters CVD risk estimation, alone and in combination with traditional risk factors, and the extent to which risk reclassification improves health outcomes”.

Some conclusions from EGAPP:

The magnitude of net health benefit from use of any of these tests alone or in combination is negligible.
The EWG discourages clinical use unless further evidence supports improved clinical outcomes.
the overall certainty of net health benefit is deemed “Low.”
the estimated additional benefit from adding genomic markers to traditional risk factors was found to be negligible.
Traditional risk factors such as those used in the Framingham Risk Scores have an advantage in clinical screening and risk assessment strategies because they measure the actual targets for therapy
To add value, genomic testing should lead to better outcomes than those achievable by assessment and treatment of traditional risk factors alone.
To be useful, genomic testing should provide demonstrable improvement on the predictive value of TRFs.

Fine, fine, fine, all correct and proven, but all missing the point completely. It does not matter that the genetics did not add anything, even with the legendary 9p21 variant. Why should personal genetics be thought of as a replacement for traditional risk factors? EGAPP in it’s narrow scope is correct, but as usual the “negligible benefits” etc. will be, actually are being, quoted widely to trivialise personal genetics, just as the family history study was used to consign genetics to irrelevance.

The world moves on and nothing changes. In the early days, almost 10 years ago, it was the same, the genetic risk had to be “over and above” traditional risk factors. But why? What is expected of genes, are they supposed to possess some transcendent quality so that some sort of independent risk factor emerges from a genetic profile? Or is it that genes code for proteins that function in the various pathways, the perturbation of which can lead to metabolic problems (the traditional risk factors) and eventually disease?

I get told off for car metaphors but here goes. Driving along in the rain, hit the brakes, skid, crash. Skidding is a risk factor for crashing, I can try to reverse the skid, it might work, but I would rather avoid it in the first place by driving better in the rain (at least until pharma comes up with the anti-lock brakes pill).

The aim of personal genetics is to prolong health. High blood pressure, low bone mineral density, arterial plaques, etc., are not present in healthy people. They might be useful indicators in predicting disease, they might be useful values to put into the Framingham calculator, but they are best avoided in the first place.

All this is obvious – so why is it that genetics is compared so frequently to classical risk factors? It’s not a surprise that they don’t contribute more, why should they? Genetic variation does not have this magic “over and above” quality. But it is there from birth, it is there even in healthy people. This was mentioned in an earlier influential paper comparing SNPs & risk factors in type 2 diabetes, the authors claimed that the genetics added little to nothing but did add as a by the way:

“Although genetic information appeared to be useful when only factors known in youth were considered, genetic information in the context of risk factors measured in adulthood did not help to refine the prediction of diabetes risk” (Meigs et al)

So it was only useful in youth, in healthy people. Dammit. When people are actually ill the traditional risk factors win hands down. Of course. So the contribution of genetics is “negligible”. No use for genetics in healthcare yet.
But what about the poor healthy people who want to stay that way? No family history for anything I particular. Normal BMI, fat mass, lipids, blood pressure, glucose, insulin, HbA1c, and so on… Will regular medicine and TRF testing still win? No, it can’t. I’m not saying that genetics will definitely win, but it’s certainly favourite, at least it has the possibility of scoring where regular medicine does not.

EGAPP is probably correct, not ready for use in the clinic – at least not in the clinics that most of us are familiar with. But this is not the same as not ready for use. Most doctors I have spoken to (many) want genetics to be a simple test that classifies risk; high, medium or low, and tells them what to do. This is a reasonable desire and fits in with the way most of them work – a few minutes per patient, clear decision making advice required. They have no time for a long interpretation and explanation of small risk changes, up or down, how to ameliorate raised risks in the long term through diet & lifestyle, etc. It’s not their job, mostly. But if “CVD is a public health care concern” (EGAPP) it needs a public health care approach and if genetics is going to be involved it will not be as a replacement for conventional risk factors but will be incorporated into healthcare long before conventional risk factors even begin to raise their ugly heads.

This is where the research should be going: proper assessments of personal genetics vs. standard health information with healthy people. Is genetics better than classical risk factors in healthy people? (of course this is just the same as asking “is genetics better than NOTHING” – which is exactly the right question). I’m expecting that 23andme will be exploring just this – they have the money, the skills, the database and the experience, and of course some business interest (as everybody does, including MDs and clinical geneticists). But I hope EGAPP will do it too.

It’s not genetics vs. regular healthcare, it’s when, where and how to use genetics in healthcare.

PS – The PHG foundation has a nice report on the Genetics and Public Policy Centre survey.

“A random sample of 1,048 US customers of the three major companies offering personal genomics DTC (23andMe, deCODEme and Navigenics) were surveyed online between June 2009 and March 2010…58% said they learned information that would help improve their health, and as a result of testing, 34% said they were being more careful about their diet and 14% were exercising more…This study provides long-overdue evidence that consumers are satisfied with DTC genetic testing services, and are generally able to interpret their results. It also indicates that there may be direct health benefits resulting from the tests in terms of behaviour modification…this survey indicates not only the absence of harm caused by DTC genetic testing services, but also the possibility of benefits.”

Early days, these were early adopters driven by some reason to take the tests, but a promising start.

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2010). Recommendations from the EGAPP Working Group: Genomic profiling to assess cardiovascular risk to improve cardiovascular health. Genetics in medicine : official journal of the American College of Medical Genetics PMID: 21042222

Personal Genetics has a Family History of getting beaten up

2010-11-11T15:12:00.001+01:00

Over the last few days personal genetics has come in for a bit of a bashing, first it was knocked out by family history then it was clearly nailed into the coffin by traditional risk factors.

Also have a look at Genesherpa’s blog for some more putting the boot in here and here.

Update: Nov 12th, here is the 23andMe blog on the subject

But what is behind the hype and the headlines? In this post I will look at family history and deal with EGAPP in the next.

The latest attack was sparked by a press release of some work presented at the ASHG. We don’t know too much because all we have is an abstract and a video but we have enough. FH was compared to the Navigenics genetic profile (PGS). From the abstract

“None of the 3 hereditary prostate cancer subjects were assessed as high risk on PGS. Based on FHRA, 10 subjects had hereditary breast cancer risk and PGS only identified 1 as high risk (K=0.12). None of the 9 hereditary colon cancer subjects were high risk on PGS.”

Sounds awful and this was the general message in the press, but it was not really so bad, not bad at all in fact. Why? Beacause Navigenics do not include the rare highly penetrant mutations that cause hereditary cancer, it concentrates on the common versions (no BRCA and no MMR genes), e.g. hereditary no polyposis colorectal cancer (HNPCC) makes up only about 3-5% of colorectal cancers. These are the cancers that FH picked up but which Navigenics missed, maybe because it was not looking for them?? (Maybe Navi should include them, maybe they don’t for regulatory/FDA reasons, but that’s a different issue).

What would really be much more informative would be to compare FH and genetics for the remaining 95-97% of cancers.

To be fair to Dr Eng, although I believe the study is flawed, she did say that “used in concert with family health history assessments, those tests could become more effective and accurate”

We can only really conclude that FH was better than Navigenics at finding something that FH was looking for but Navi was not. If Navi included the BRCA and MMR genes then maybe they would have at least been on the same playing field and playing the same game. (This BTW is not a correct conclusion from ABC News: Family History Better at Predicting Disease Risk Than Screening)

In any case it’s a false battle, why choose one over the other? Although proper FH is not so straightforward, it requires a lot of effort on the part of the patient, maybe weeks to contact and collect info from all the relatives – it’s not a 20 min questionnaire, there is no doubt that it is useful when available.

Family history measures genetics to a certain extent and it measures environment as well, but it’s not a full genetic analysis and of course will not detect all genetic risks, it cannot. Genetic profiles say nothing about environment. So what does this tell us? Don’t go looking for 100% concordance because you won’t find it, but while there is overlap there are also independent contributions to be made by both – they are complementary…

The Eng study was not helpful at all in comparing FH and genetics for the vast majority of the common complex diseases, it could not be with only 44 subjects. It would be interesting and useful to do a similar but much wider study on CVD or diabetes, not to see which is best but to show how and where they are complementary and how to get the best out of both.

Nutrigenetics–a little bit of history, but no miracles

2010-11-04T15:32:00.001+01:00

Reading The $1,000 Genome by Kevin Davies, as expected it’s a fascinating story and right at the beginning in Chapter 1 there was something that I liked. The first personal genome to be sequenced and interpreted was that of Jim Watson (Craig Venter was first but no interpretation). Davies describes the presentation of Watson’s genome to the man himself and reports that the sequencing was performed by 454 and the interpretation was handled by the team directed by Richard Gibbs of the Baylor Genome Center.

Watson’s genome inventory, for example, revealed 310 genes with likely mutations and 23 with known disease causing mutations, increasing his risk for cancer and heart disease. The Baylor team recommended that he should take folic acid and other vitamins and minimize his exposure to sunlight, particularly during his daily tennis matches. p19

So there you have it, the first advice based on the first interpretation of a human genome sequence was nutrigenetic!

But then I read later in the book about Davies’ experiences with Sciona (actually I read this first, I started reading from the index expecting to see Sciona there, remembering that several years previously the author had contacted me about trying out our test - his review is here http://www.bio-itworld.com/BioIT_Content.aspx?id=43364) and in the book (p. 141):

The report soberly recommended that I should cut back on alcohol and caffeine, eat more cruciferous vegetables, and exercise more. "Brilliant, I thought, I've known that for years!"

Still the ensuing dietary recommendations – increase my intake of folic acid and omega-3 fatty acids – would be standard medical advice from any family physician. In a few cases, specific gene variants prompted more personalized dietary advice in the form of recommended vitamin and antioxidant supplements. This couldn’t hurt, but would they actually do a body good? A Newsweek cover story on the nutrigenomics fad said it best: “Some people will be advised to eat broccoli, while others will be told to eat…even more broccoli”.

Later in the book on page 204 Davies quotes John Sulston

British HGP leader and Nobel prize winner Sir John Sulston said “Nutrigenomics is a very easy scam. Not only is the advice useless…worse, some companies are associated with the companies that will sell you the dietary supplements”. Sulston’s advice was simply to grow your own vegetables.

So Baylor what did you tell Jim???

Well it’s easy to understand the contrasting reactions, from Baylor actually giving Jim Watson nutrigenetic advice, through Kevin Davies’ reasonable but slightly sceptical review to the outright condemnation of Sulston. In my opinion Sulston is right, wrong and impractical all in one go. It is unfortunately an easy scam and there have been many scammers, many still exist, many more are on the way. I would estimate that about 90% of the offerings then and now are rubbish, either scams or just through ignorance. Genetic based nutritional advice is not necessarily useless though, not all of it, the Baylor group presumably would agree with that. Grow your own vegetables is good advice but maybe not so practical for many…

Nutrition has a big problem – it’s the home of many scams, false promises, snake oil, disreputable companies, poisonous ingredients, no standardisation, poor research, overblown claims, and on and on and on. It’s a problem for us all though because inside all the mess of exploitation there is the serious side, the only key we really have for preventative healthcare. There is constant talk about how we need to change the current situation from curing disease to prevention otherwise society will collapse under the burden of obesity and diabetes, heart disease, cancer, etc. But what is preventative healthcare? Is it prescribing statins, aspirin, metformin? No, of course not, it’s boring nutrition and lifestyle where personal genetics really do have a role to play

The Kevin Davies reaction to nutrigenetics is quite common, the advice seems the same as normal healthy eating advice, and it’s broccoli or more broccoli, etc, etc, etc,. But what do you expect? Really, what do you expect? Of course it’s going to be similar to the usual advice – it’s not going to tell you that you should live on a diet of beetroot juice and walnuts while another person needs to eat rabbit and pears. It’s going to say a bit more of this and a bit less of that – there is no magic. It’s looks very similar to what your doctor would say. Yes it does, similar, not the same. Little differences make big differences in the long term. A size 8.5 shoe looks very similar to a size 9 and may feel OK in the morning, but will be hurting by the afternoon. A few calories too many per day will not make a difference except that 30 years later 14 kg have appeared.

That’s nutrition for you and you need to accept it. It’s boring but it’s the best tool we have for preventative healthcare. If you expect more from nutrigenetics, if you expect a load of zing in the advice unfortunately there are many companies out there who will satisfy your need. Why are there so many scammers? Because there are so many miracle addicts desperate for a fix.

Unfortunately the hype around genetics, the great promises made in 2000 around the human genome (although I must say that these were mainly from the politicians) lead to great expectations, so some unexciting nutritional advice is seen as worthless and a waste of money. Ironically this is the sort of expectation that drives the sales of the genetic tests which offer nutritional miracles in a bag of pills and herbs – it’s not a surprise that the company which was labelled fraudulent by the GAO earlier this year, the one selling the bag of herbal panacea, is the company that is making the most money. Boring nutritional advice is not enough is it, surely there must be more than that… yes there is, but don’t rely on it to really work…

Maybe one day there will be harmless pills for preventing all known diseases whatever we do to ourselves, for now though all that nutrigenetics can offer you is a slightly better fitting shoe – anyone offering more is not to be trusted.

The murky side of physician prescribed LDTs

2010-09-06T20:49:00.001+02:00

Apparently the LDT community are not too happy with DTC genomics for having stirred up the regulatory hornets nest, well maybe that’s not such a bad thing. I have argued previously that physician prescribed tests can be more dangerous and more necessary of regulation than DTC and below is a good case for the argument.

First a huge huge thanks to @laikas for a) her excellent beautifully detailed and analytical posts on the CFS virus story (XMRV & MRV: here, here and here) and b) for specifically asking me and others to comment. I had been aware of the controversy but no more than that so Laika’s request made me read more – my first inclination was that it reminded me of the helicobacter story, scepticism followed by acceptance, cures and nobel prizes, but reading further it unfortunately looks more like the MMR / Autism debacle which was Laika’s comparison.

I’m not going to discuss the various findings here, no point as Laika has done that far better – what I do want to talk about is the commercial test that was put on the market as soon as the paper was published – it’s not a pretty story.

1. Lombardi et al of the Whittemore Peterson Institute (WPI) published in Science. They report the detection of a retrovirus, XMRV, in 68 of 101 CFS patients (67%) and 8 of 218 (3.7%) healthy controls - http://www.ncbi.nlm.nih.gov/pubmed/19815723

2. In the Science paper there is a “Note added in proof”: V.C.L. [Lombardi] is operations manager of Viral Immune Pathologies Laboratory, which is in negotiations with the Whittemore Peterson Institute to offer a dianostic test for XMRV.

3. In the same month www.vipdx.com began offering a $650 test for the XMRV – “essentially 100% accurate…”

4. Four independent follow-up studies failed to find the virus and a 5^th found a virus, not the XMRV but related MLV sequences were detected (all detailed here by Laika)

5. WPI group now say that they also find similar variants

6. Vipdx update their test so it now detects “other human MLV-related viruses” (so now essentially even more 100% accurate…)

7. Some things were missed out on the Science “note added in proof”, but they are in Laika’s blog posts, such as:

“Furthermore there is an intimate link between WPI and VIP Dx, both housed in Reno. Vip DX is licensed by WPI to provide the XMRV-test. Vipdx.com links to the same site as redlabsusa.com, for Vip Dx is the new name of the former RedLabs.

Interestingly Lombardi (the first author of the paper) co-founded Redlabs USA Inc. and served as the Director of Operations at Redlabs, Harvey Whittemore owns 100% of VIP Dx, and was the company President until this year and Mikovits is the Vice President of VIP Dx. (ME-forum). They didn’t disclose this in the Science paper.”

So that’s it – basically an unregulated clinical test is being offered to a very vulnerable and exploitable group based on 1 paper on a small isolated sample, with no independent confirmation…on the contrary…and some unfortunate conflicts of interest that were not reported when and where they should have been. They say all profits go back into research but that is irrelevant and meaningless (what are profits? What is left after paying everyone? Also the sales will increase the value of the company they own). But even without the COI – what would happen if 23andMe et al offered a “100% accurate” genetic test for CFS risk (or autism, yes, WPI are getting XMRV into that as well…ouch, just got hit by another bandwagon).

What exactly is wrong:

No independent confirmation
No demonstration of human-human infection
It’s a hypothesis that the viral presence is causal (it could be there, if it is, due to reduced immunity in CFS)
Test positive what do you do? Answer: of course some doctors are prescribing anti-retrovirals already
Some patients will naturally feel better even if by placebo, leading to testimonials of success
There will be alarms about infecting family members to drive sales (and fear). In fact this already goes on, by the senior author (Mikovitz) who says in an email to an individual: “To be clear..I do think even if you tested negative now that you are likely still infected with XMRV or its closest cousin..”

In retrospect this last sentence in the Science paper has an interesting tone:

“Finally, it is worth noting that 3.7% of the healthy donorsin our study tested positive for XMRV sequences. This suggeststhat several million Americans may be infected with a retrovirusof as yet unknown pathogenic potential”.

Updates:

Via Twitter: @Vansteenwinckel: yet another commercial test for #xmrv ? pfff http://bit.ly/bFJBlV #mecfs
Via Carlitos, who comments below: 1st International Workshop on XMRV. Tuesday and Wednesday, September 7 & 8, 2010, Bethesda, Washington, DC – please go to Carlitos’ blog for more details, it will also be partially videocast

FDA – Personal Genetics: Is it safe? It’s a marathon, man…

2010-08-09T19:55:00.001+02:00

It’s nearly 10 years now and still there is no clarity about the position of personal genetics in the regulatory framework. Maybe that’s going to change soon with the FDA activity and the recently published HGC Principles. It would be good to get it settled one way or another, the uncertainly doesn’t help anyone except those who exploit it to exploit the gullible.

Some elements:

DTC vs. DTMD (via physician) – I will argue that DTMD is actually higher risk and needs closer scrutiny
Is it medicine? I think this question is a waste of time, it will not be resolved, the definition is too broad, medicine is practised everywhere by everyone - if I take my son’s temperature, put a plaster on a cut or administer medication I am practising medicine.
What is the FDA duty bound to do and what will they decide?
- No regulation – more or less the current situation
- Tight regulation – medium/high risk requiring pre market approval (PMA)
- Somewhere in between – the “light touch”

The questions are what regulation, oversight and quality controls are necessary (and possible) to get the maximum benefit, for all

What is a medical device?

SEC. 201. [21 U.S.C. 321]
(h) The term "device" (except when used in paragraph (n) of this section and in sections 301(i), 403(f), 502(c), and 602(c)) means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is--

(1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,

(2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

(3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

This unfortunately is very broad, “prevention of disease”. That can apply to soap and a toothbrush and certainly applies to any publication that contains any form of health advice (if you stay healthy it is because you are preventing disease, right?). This is so broad that what it really boils down to is what the FDA decide. In 2007 they decided it was not, now they say it is. According to the definition it always has been – so this is very much a decision of the FDA, it is something they could, or could have avoided.

What are the FDA saying?

In their letters to 23andMe and others they said:

The 23andMe Personal Genome Service™ is a device under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h) because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body.

A few days ago Alberto Gutierrez and Elizabeth Mansfield of the FDA gave a revealing (taped!) interview to Mary Carmichael as part of her intriguing DNA Dilemma series in Newsweek here are some relevant snippets (whole interview – interview plus comments, see also Daniel MacArthur’s post on the subject):

AG (to Mary Carmichael): The law requires us to clear devices or approve devices before they go into the marketplace when they make medical claims…Now clearly the claims they are making are medical claims [re 23andMe]

AG: what is the risk of an undetected false result, what would be the medical action taken, and whether there’s high risk there or not… there might be some claims there that we may consider to be PMA-like [pre market approval]

EM: they have a variety of claims that span our normal risk classification. On a claim-by-claim basis, there are some that might be low, there are some that might be moderate, there are some that might be high

MC: So, would a company need to be approved just to provide a raw SNP list to people?
EM: They would if they made medical claims about that data. If they don’t make any medical claims about that data, then they’re free to provide information as far as we’re concerned.

So:

1. The “law requires”, they have no choice if a device makes medical claims.
2. FDA have decided that they are making medical claims and are to be regulated as devices
3. The type of regulation will depend on risk (class I, II or III)
4. Just providing genetic results is not a medical device

While many, including me, would prefer to have the FDA step back and allow a system of self-regulation, market forces and transparency (with mandatory genetic testing registry) to control the field it looks like the FDA have crossed the Rubicon with (1) and (2). This makes risk classification very important as it determines the regulation (see here) and whether expensive and time consuming pre-market approvals are required. Note that there is no distinction by the FDA on DTC vs. DTMD, a device is a device, but it would affect the risk.

The green light to the genotyping data is helpful because it means we can focus just on the actual interpretation and for this I am going to look at parts of three different services:

1. WebMD a medical website written for an audience that includes general public. It includes gene variant related information which would be relevant and personal to an individual who has already been genotyped.

2. 23andMe – DTC personal genetics service from genotyping to interpretation

3. Existence Genetics – DTMD personal genetics.

Note that like 23andMe “WebMD does not provide medical advice, diagnosis or treatment.” But they do say things like “Your 23andMe results can help you make more informed decisions about your health” or “Better information. Better Health”. So they do (both) expect you to make decisions based on the information presented on the website – is it safe?

Common diseases where current genetic knowledge is low impact, e.g. Heart Attack:

1. WebMD has a large section on Heart Disease including “Tips for Reducing Heart Disease Risk”. There is also an article on the SNP analysed by 23andMe - 9p21

2. 23andMe: “20.9 out of 100 men of European ethnicity who share Greg Mendel's genotype will get Heart Attack between the ages of 40 and 79 (average is 21.2 out of 100)” in the disease risk overview it says “your risk is 20.9%” and describes it as a typical risk (and is .99x lower risk). The advice is general, very much like webMD – plenty of background about the role of genetics and environment with advice on prevention and keeping healthy

3. Existence Genetics. Much less info available but some sample pages for heart attack among others:

a. Your lifetime risk = 61%,
b. General lifetime risk = 32%
c. Equal to 90% increased risk
d. It says that this disease is very important to my health and wellness and that preventative measures can be taken and lists some specific interventions, what to monitor and also how my genetics may affect medication.

All are services intended for the “prevention of disease”. In my opinion all are low risk (I would actually say no risk given current knowledge of gene impact) and would not merit any more than class I classification. Risk is classified, if I understand what AG was saying (not 100% here!) on

a) What action a person might take
b) What would be the consequence of a false positive result
c) What would be the consequence of a false negative result

Common disease - Potential Risks:

For WebMD false positive or false negative would be applied to the correctness of the advice. For the genetic companies there are additional possibilities of error: the genotyping, the software delivering the interpretation based on the genotype, the interpretation itself. It’s hard to see how an individual can come to any harm by following the advice on either of the consumer services and for EG the actions will be mediated via a medical professional (who though needs to be confident that the EG service itself is correct). For now a false result is not a risk, the predictive impact of genetics on heart disease is too low for any serious consequences. A false positive may lead to extra attention to diet & lifestyle and false negative will leave the situation unchanged – as long as it is clear that typical or reduced risk does not mean NO risk, and that in fact for these common diseases, with what we know now, the lifetime risk for anyone is always going to be significant. (If the impact of the genes is so low and uncertain, what’s the point of the service? Doesn’t matter, that’s for the buyer to decide and has no bearing on risk or FDA classification).

Serious diseases where genetics have v. high impact, e,g. cancer involving BRCA mutations:

WebMD: Having one first-degree relative with breast cancer approximately doubles a woman's risk, and having two first-degree relatives increases her risk 5-fold [this is DTC genetic risk information!]… An estimated one in 800 women carry the BRCA1 gene (the number of carriers of BRCA2 remain unknown). Women with inherited changes in either of these genes have up to an 80% chance of developing breast cancer in their lifetime.

23andMe: (it looks like you need to create a demo account and log in to get this info) “Carrier for the 185delAG BRCA1 mutation. Lifetime risk of breast cancer for women is increased from 13% to 81% and risk of ovarian cancer is increased from less than 2% to 54%. May significantly increase risk of prostate cancer in men. There is also an increased risk for breast cancer in men”. Of course it also tells me if I have the mutations or not. [Note that this section is “locked” the results are released only after reading some specific warnings and giving consent]. They also state “Please remember that the BRCA mutations covered by this report are only three of hundreds in the BRCA1 and BRCA2 genes that can cause cancer. Their absence does not rule out the possibility that you may carry another cancer-causing variation in one of those genes.”

EG: no info available

What are the risks? What action would be taken for each of the different possible results?

WebMD may make a person go and take the genetic test, especially if there is a first degree relative.

23andMe:

a. Positive: I don’t know what it says as I have not seen a positive result, but it should say something like “this service is for information only, go to your doctor and order an FDA approved clinical test for BRCA1 and BRCA2 mutations”. Even if it doesn’t the most likely outcome is a trip to the doctor who should then decide to order the approved clinical test. Would a doctor take action based on the 23andMe report? He/she should not and would not if competent – the FDA risk assessment does not take into consideration actions of incompetent professionals – there is nothing in the 23andMe report, as far as I can see, that would make the doctor think that this is an approved clinical test. Outcomes along the lines of demanding an immediate mastectomy and not stopping until finding a surgeon prepared to perform it are inconceivable, and anyway would still require the intervention of an incompetent or unscrupulous professional.

b. Negative: I think we have to base our assessment on the assumption that the customer does read the whole report so it should be clear that the customer realises that there is still a slight chance of having some other mutation and if worried should order full clinical test especially if family history. On the web page (need to log in) they say at the top: “Please remember that the BRCA mutations covered by this report are only three of hundreds in the BRCA1 and BRCA2 genes that can cause cancer. Their absence does not rule out the possibility that you may carry another cancer-causing variation in one of those genes”.

c. False positive: This would obviously cause a lot of anxiety until the result is revealed as false by the follow up clinical test. Do the FDA incorporate the likelihood of a false result, I don’t know? Genotyping is very accurate as far as we know - it would be helpful to have this controlled and published. The interpretation algorithm is very unlikely to be wrong. Overall there is a very low possibility of a false positive, and given that the benefits of detecting the mutation, when it is present, include saving lives, I would say that they outweigh the risks of a few weeks of extreme worry for some individuals.

d. False negative. This is tricky. A false negative could be catastrophic and much worse than a false positive. Negative is the most common result by far and it is not likely to be questioned (unless there is a lot of family history, in which case the clinical test should be taken anyway). A false negative for cancer is particularly bad because the disease is often not detected until it is too late for simple therapy. The consequences would be severe – this is the same for any provider of this test. What are the steps taken with Myriad to ensure that false negatives almost never occur?

For carrier status of other serious diseases (cystic fibrosis etc) I would describe the consequences more or less the same as for the BRCA mutations.

I would classify as low risk this part of the 23andMe service because I cannot see any serious consequences as happening more than very infrequently based on any of the outcomes (except (d), come to that in a minute) and one reason is precisely because it is a DTC test and clearly not to be used as the basis for clinical decisions, in my opinion, reduces the risk, not the opposite. I would definitely classify the Existence Genetics service as medium or high risk (as I would the Myriad test) – because these tests are giving information to clinicians that is designed influence serious clinical decisions, for this reason I would want to be very confident of the quality of the services (and paradoxically, until now, the physician only services have been far less transparent and far less subjected to scrutiny (see here).

Much has been said about the inclusion of BRCA mutations and other serious diseases being a game changer and that now they do need extra regulation. I don’t agree (we need confidence and transparency, but that’s a different issue). Not only are DTC services low risk, they will also be life savers. How often are BRCA mutations found in women after they have been diagnosed with cancer, i.e. too late? That’s the potential number that could be saved by encouraging screening – even though DTC would only be a “first draft” to be confirmed by clinical screening. If FDA involvement is any more than a “light touch”, if it involves anything that would reduce, restrict or remove DTC access then that action would have a high risk of having life threatening consequences for the public – the risks involved in over-regulating are much higher than those of proceeding slowly and with extreme caution. It’s not the other way around.

The false negative worries me somewhat, whether for BRCA or for carrier status of very serious genetic diseases like cystic fibrosis. However it needs putting in perspective. Genotyping as far as we seen so far, at least among the transparent companies, is very accurate. I would like to have a formal public measure of that though, an ongoing and public quality control on any genetics tests for serious mutations, this include Myriad, Counsyl etc. How accurate is Myriad, how many false negatives are they likely to have produced? Some FDA or other office should be set up that regularly sends blind control samples to all the companies (the companies can pay for it with an annual fee – wouldn’t cost much, 24 samples per year?)

Conclusions

DTC
Overall, with a few caveats, I think that the service offered by 23andMe is comparable to that of WedMD – I think it is very low risk and should not be more than Class I, there should be almost no time, effort or expense required to get it cleared by the FDA. Notification should be enough. The FDA may have bound themselves now by saying that they are medical devices, but they have not yet decided on things like Class, PMA etc, so there is still the opportunity to regulate this area in a sensible way, and even, ideally, to develop a novel future-proof framework for this new and disruptive field.

Caveats: The obvious differences are that the 23andMe services have more steps, compared to WebMD, where errors are possible (genotyping, software algorithms, and the actual interpretations). The FDA is not concerned with genotyping quality, that is CLIA’s domain (although the FDA, at the same time, are pressuring Illumina, and still at the same time are saying genotype data on it’s own is OK - contradictory). The quality control of the software is equally important – making sure that the data from the lab is not jumbled, that each result is assigned to the correct gene and the correct person. That each interpretation and each calculation based on each SNP, is working correctly. I don’t know what quality standards are required here, but some should be. In my opinion (and experience) there is more chance for error here than in the genotyping itself, much more. We also have to remember that here we are talking about 23andMe, deCODE, etc – they are transparent and have been scrutinised a lot by many experts. We have no idea who is going to come along next though. Companies will come along that will simply be bad, incompetent, unscrupulous or whatever. The regulatory net needs to be fine enough to catch them but without tangling up the good players. If all of the elements of the calls for transparency, the NIH GTR and the HGC Code of Practice were put together into an effective system then that would satisfy the needs to guarantee that DTC personal genetics services are at the lowest risk – basically do what at is proposed by Dan Vorhaus and stir in the HGC.

DTMD
The situation with Existence Genetics, Counsyl and may be Pathway & Navigenics, and all others who sell to medical practitioners is different. They are all selling a service to a medical professional. A genetic service delivered to clinicians who will take clinical action is something that has higher risk simply because decisions will be made and actions will be taken. The risks of serious consequences are higher, especially when results are in error. DTMD needs tighter controls than a DTC test that is clearly marked “for information only”. If a DTC service did appear that actually did claim that the results can be used to make clinical decisions then that would be need similar controls, in addition to the decision as to whether it should be available DTC or not.

I can get legal or financial information from a website, newspaper, journal etc, and also from lawyers and financial professionals. The difference is clear as are the differences in regulation and accountability.

The debate is the wrong way around – deal with the DTC via the transparency etc methods and deal with genetics services to clinicians as medical devices (I believe that the Roche Amplichip is class II). Once you allow genotyping you cannot block the information flow (SNPedia, Promethease, 23andMe, etc) and if the information is marked as “not for clinical” that has to be accepted.

Maybe not everyone will agree with these conclusions, maybe some of the analysis is mistaken – but regarding personal genetics, I think it is safe.

NB: I need to add something about pharmacogenetics:

The 23andMe result for Greg Mendel is Slightly increased warfarin sensitivity. May require decreased warfarin dose.

It does say at the top…”Only a medical professional can determine whether warfarin is the right medication for a particular patient. The information contained in this report should not be used to independently establish a warfarin regimen, or abolish or adjust an existing course of treatment”.

I bolded independently because I interpret it as meaning that the user should not make a decision alone but can make a decision after consulting a doctor.

I think this is or is close to saying that this information can be used for clinical decisions and I really think that 23andme need to modify the advice. They should say that it needs confirming via a class II regulated medical device and until then NO change in medication should be made.

I agree that the chances of the advice being wrong are small, but we have to think beyond 23andMe and the other high profile well managed companies.

Other recent comments on the FDA re personal genetics:

GeneticFuture: The FDA doesn't plan to regulate access to raw genetic data;

FDA Blog: FDA states cost 'not considered in any of our reviews' and In wake of FDA offensive, genomics entrepreneurs look overseas

DNA Dilemma, dissecting the FDA

2010-08-06T16:34:00.001+02:00

Mary Carmichael (General Editor, Newsweek) has this week been running a very interesting series of articles about the “dilemma” of whether or not to undergo a 23andMe type DTC genetic test. As part of that she interviewed the FDA and with journalistic cunning recorded the whole interview and published the full transcript (here). It was a very good thing too that she has the tapes because the interview was in some places quite revealing.

Mary asked me to comment/dissect the interview and I have done so below – I look forward to seeing the comments of others that Mary has asked on their blogs as well.

In a sentence the interview came over to me as unnecessarily vague and evasive (unless for some reason it was necessary!) – certainly lacking in clarity and not answering some of the questions asked but giving up some useful information.

DNA Dilemma: The Full Interview With the FDA on DTC Genetic Tests

NEWSWEEK: During the recent congressional hearing, 23andMe’s general counsel said that the FDA “encouraged them to proceed” freely in 2008. What specifically changed about their test panel between 2008 and now that caused the FDA to start to take some regulatory action? Alberto, I think you’ve touched on this a little with me before, that the concern was mutations with powerful effects on breast-cancer risk or drug metabolism—
tests that might influence medical decisions. Is that correct?
Alberto Gutierrez: They met with [former FDA commissioner Andrew von Eschenbach]. We were not there. We did meet with them on several occasions, but their claims of what they’re offering have been changing constantly. What was there in 2008 I’m sure looks very different from what is there now. The drug-metabolizing claims were not there previously, and even some of the claims that directly touch on disease states, cardiovascular disease, breast cancer were actually not originally—they’re much bigger now.

KG: “we were not there” – so what?! Is he really saying that anything that went on before has no relevance now he is in the seat? He can’t say “I’m sure it looks different”, it either does or it doesn’t and he should know. The cardio stuff was there, there has always been health related content. It’s true though that it has changed with the addition of the “locked” more serious disease associations like BRCA1 and the pharmacogenetics, which are significant additions

That’s interesting. I think before when we talked, the cardio and breast-cancer stuff was not brought up. So even some of the common disease claims—what is the specific concern with them? My understanding was that a lot of those genes really don’t nudge the risk up or down very much.
AG: The concern actually is with everything. The law requires us to clear devices or approve devices before they go into the marketplace when they make medical claims. The question with 23andMe has been whether their claims were medical claims or not. The original claims they were making really were very much on the edge. We actually told them that we thought they were medical claims, but it was at least possible that you could argue that they were not. Now clearly the claims they are making are medical claims. And to show you this is an issue we actually have been dealing with, we actually brought it up in SACGHS, that this was a point of discussion in 2009, because we kept hearing from 23andMe claiming that they were not making medical claims. We actually thought to have the Secretary’s Advisory Committee at least state whether they considered the claims that they were making medical claims or not.

KG: So confirmation that for the FDA the test IS a medical device that needs to be cleared or approved.

In our previous interview, and this is a direct quote, you said those health claims were “what we would consider to be moderate risk.” I’ve recently seen [the FDA’s director of the Center for Devices and Radiological Health] Jeffrey Shuren quoted as saying these claims are high risk, which I assume could mean stricter regulation. Which is it, moderate or high risk, and has something changed since our initial interview?
AG: It always depends on what medications they can have, how they’re offering it, we always look at what is the risk of an undetected false result, what would be the medical action taken, and whether there’s high risk there or not. I don’t think Dr. Shuren meant to imply that this would be [pre-market approval, or PMA], but that there might be some claims there that we may consider to be PMA-like, or PMA per encounter ...
Elizabeth Mansfield: In general, though, they have a variety of claims that span our normal risk classification. On a claim-by-claim basis, there are some that might be low, there are some that might be moderate, there are some that might be high. I think Dr. Shuren’s assessment that these were “high risk” was as opposed to “no risk.”

KG: Well that cleared that up then! I’m still totally confused about Shuren’s high risk and Manfield’s low, moderate and high. Why is AG talking about “medications they can have” etc? What’s the relevance? What exactly is an “undetected false result”? If it’s undetected a) how can it be false and b) how can any action be taken?!

Maybe I am being mean, let’s assume he means false negative or false positive, that I can understand is an issue worth evaluating - at least if they are actually referring to a false lab result, a miscalled SNP, rather than a false interpretation. (One point though, the FDA will need also include in the equation the likelihood of a false positive or negative – the analysis that Daniel MacArthur carried out on Mark Henderson’s DNA suggested and amazingly low error rate of “less than one in every 14,000 markers”):

For most of what 23andMe do (and the others) the false negative/positive is going to be low risk or no risk – this cannot be opposed by most critics who apart from saying that it should be heavily regulated also say that the risk predictions are small and imprecise. Yes, that’s accepted, which means a false result would be low risk or even no risk.
For the pharmacogenetics aspects this is different. If the false result is used to modify a drug prescription then it could be medium or high risk (I’m not qualified or knowledgeable enough about potential adverse consequences to choose which). A false positive would be the same. If the companies want to continue to claim that the information is for education only and is not intended for clinical use they need to make that very clear next to these results – they need to say that before any clinical decisions are made that these particular gene variants need to be retested by a lab that offers the test as a true regulated medical device. This I can agree with – the 23andMe pharmacogenetic interpretations are correct but that will not be the case with all companies in the future, and it applies to both physician prescribed and DTC tests.
For serious diseases, the “locked in” sections – where you need to give specific approval via the website before the results are revealed to you I would assume would be medium/high risk. To be wrongly informed of cystic fibrosis carrier status, high risk BRCA variants, etc, would be worrying for the customer. Not life threatening though, as long as explained correctly. I have not seen how they present a positive (as in carrier of risk allele) but again they would have caution that the result is provisional and any further action will require testing via a properly regulated device. Medium or High though, I am not sure, although I would say medium (but I realise a lot would say high) – If I got the information that I had a very high risk for prostate cancer I would be worried, I would straight away get retested by another lab, if that confirmed it, I would want to repeat it again (I have worked in both research and diagnostic labs for many years, I would repeat it!). If it was confirmed then it’s possible 23andEtc would have saved my life – if it was not confirmed, I would have gone through a week or two of anxiety, but I would not have thrown myself off a bridge.

Having just typed the above (“it’s possible 23andEtc would have saved my life”) – I am thinking now that it would be more risky than beneficial if the FDA took action which reduced access to these tests. They are potentially lifesaving and I am thinking that perhaps the “high risk of serious disease” tests are actually more important to go DTC (not as a free for all though, this does not mean NO regulation) and should be encouraged. Let people decide and pay for something if they want to.

If a medical decision is going to be made then I would want the interpretation to be as bullet proof as possible, therefore approved. I cannot see a serious (medium or high risk) medical decision being made without the use of a doctor though so I would only require approval of tests marketed to doctors as tests on which clinical decisions will be made. It’s a sort of paradox here, if it’s DTC it should be clear that it is not for medical use – a doctor should not make a clinical decision based on a 23andMe test. A customer can make a lifestyle decision, that’s different. A paradox because the decision of Pathway to go only via medical doctors should logically make it more liable for regulation. I would assess the 23andMe website as just like any other healthcare site, like WebMD, is that a medical device? WedMD has risk factor calculators, it makes medical interpretations of personal information, I really don’t see the difference as far as regulation is concerned. No doctor would make a clinical decision based on a patients interpretation of what he or she has read on WebMD, no reliable doctor that is.

So the FDA would actually be going through these panels test by test, and looking at each one and seeing, Is this one low risk or moderate risk or high risk, and approving them specifically?
AG: Yes, in a general sense we would go claim by claim. Whether each claim would require a different submission or not—we’d be looking at each of their claims and looking to see that they would have data to credibly back the claims they are making.

KG: good luck to them – Sisyphus

So if one of these companies wanted to add a new test to its panel, it would have to get that specifically approved?
AG: No. I want to make a distinction between what we would be doing now, and maybe what we would do in the future, and the reason here is that—Dr. Shuren put this on the table [unintelligible]—with these devices maybe it can collect a lot of data that may not be relevant at the moment. If later on data becomes available that shows that the company may be able to make a claim that doesn’t exist now, is there a way for us to do this that wouldn’t require necessarily a submission for each of them, or that we could bring together experts that could make the call that there is now enough evidence to make this kind of claim? That is something that we are discussing, that we are trying to figure out how we’re going to deal with devices that generate a lot of data for which there is no use now but may be in the future, like with whole-genome sequencing …

KG: Again very clear! It will be “claim by claim” (which is a specific thing, it can’t be a “general sense”) – or maybe it won’t be. All he should have said to the previous question is “that we are trying to figure out how”. Also Shuren in Congress seemed to recognise that this would be impossible and suggested a different way, something like overall approval of a company with regular reviews (like CLIA perhaps?)

[When we spoke last time], you had just sent five letters out and Illumina got one. Your concern in that letter, I believe, was that Illumina was selling a “research use only” chip and it was being used for nonresearch purposes by DTC firms. There were several reports I saw this morning indicating that the FDA has “requested” that Illumina stop selling chips to DTC genetic-test providers. Is that true in whole or in part?
EM: We have asked Illumina to work with us to bring their devices into compliance with our regulations. We have not specifically requested that they stop selling them to anybody.

KG: OK… can you “non-specifically” make such a request, with a nudge and a wink perhaps?

So they can continue supplying 23andMe and deCODEme with chips right now?
EM: We’re working with them on that …

KG: Ah yes, looks like you might be able to…

Illumina obviously isn’t the only chip maker out there. Why is it the only one that is getting these letters? Are the other ones going to be called in as well?
AG: You can bet that with the original set of letters in 2009, Illumina was not the only one to receive a letter.
I’m sorry, I’m not familiar with the 2009 letters. What were those?
AG: We sent letters to several companies with direct-to-consumer chip arrays to come in and discuss the issue.
And did those companies come in?
AG: Yes, and I think that’s part of what you saw with the public meeting on June 30 on the array issue and why several companies want to figure out a way to [unintelligible] …
[The chips are labeled “research use only.”] The DTC providers, when they sell these tests, aren’t [necessarily] doing research. Doesn’t that imply that Illumina does have to stop selling the chips to them?
EM: If they continue to label them that way, yes, that would be something that we would most likely take a little further action on. At the moment, they’re working with us and we will see what they can bring to us in a reasonable amount of time without completely blowing up their business or the market or anything …

KG: I really hope that is the case

So I guess if it’s not being used for research only it needs a different type of [label or] approval?
AG: That’s correct…

KG: Label OR approval, what do they want, what would Illumina have to do, how long, how much, what about when new SNPs are added, etc?

Until that happens, though, is it correct that the Illumina chips will remain on the market for direct-to-consumer companies to buy?
AG: [Pause] I think Illumina needs to figure out how they’re going to move forward.

KG: Oh dear, back to the “non-specific” – horses head in the bed?

Okay … I want to move on to whether the issue with direct-to-consumer is actually providing data to people, or is it the interpretation algorithms these companies are using? So, would a company need to be approved just to provide a raw SNP list to people?
EM: They would if they made medical claims about that data. If they don’t make any medical claims about that data, then they’re free to provide information as far as we’re concerned.

KG: Then the FDA need to give clear guidelines about what constitutes a medical claim. But one good thing – there will be NO obstruction to me getting my raw genotype data DTC. So then what happens if I go and read about my SNPs on www.snpedia.com, or pubmed, or OMIM or the excellent “HuGE Navigator”? What if I put my data through Promethease ? What about reading about SNPs and disease risk on WebMD and on and on

What exactly would constitute a “medical claim?” Would pointing people to medical research papers [qualify]?
AG: It depends. There are rules as to how one can do that … Those rules are actually worked out pretty well, and they just would need to make sure they’re staying within the rules.
Are those rules on the Web?
AG: I don’t know where the policy is. I would have to get it for you. It’s an agencywide policy. I would have to find it for you. And it won’t be that easy for people to follow it…

KG: The rules are worked out pretty well, now dammit, if only I could find them… What? “I don’t know”, “I wasn’t there” (see above), “it won’t be easy to follow” – terrible admissions to make

Alberto, I had heard a story, I believe it was in Rob Stein’s article in [The Washington Post], about these women who were having prophylactic oophorectomies on the basis of direct-to-consumer genetic results that were “questionable.”
AG: That’s a little bit taken out of context in the sense that it’s not based on the direct-to-consumer [model]. The cases we heard of were based on lab-developed tests that were not properly validated. What I did say was that even though 23andMe doesn’t make a direct claim as for ovarian cancer, they do provide information that links what they are giving the consumer to ovarian cancer.

KG: A little bit? It would have to be a lot out of context to have made such a shocking claim. It was shameful (actually it was also unbelievable, for good reason, it wasn’t true)

So that’s an example of where the interpretation is about pointing to a medical paper.
AG: It’s more than that. They interpret the medical paper for them … Ovarian cancer is called the “silent killer.” People actually don’t know they have it until it’s too late. And women that are high risk a lot of times choose to have their ovaries removed because they are afraid that it may not be caught in time. There’s no diagnostic test for it. So the tests that we have seen—there was one that was taken off the market because of FDA action … We knew that in those cases most women who were being operated on actually were likely to be negative for ovarian cancer … The one we heard most about originally, it was a test called OvaCheck that was going to go to the market, and we believed it was not well characterized and it was going to create problems. It never made it to the market, and then in 2008 another one made it to the market called OvaSure, and the FDA wrote LabCorp a warning letter …

KG: His answer is not at all relevant to your question but is interesting just the same. The “silent killer” – that makes me think, again, that anything that makes people more aware of their health, their possible risks, possible diseases, especially symptom free diseases, etc, should be encouraged, and should be DTC. I was not aware of this information about ovarian cancer, nor was my wife. If it silent then you are not going to go to a doctor about it until it is too late and of course AG knows very very very well that nobody would undergo serious surgery without medical guidance, I suppose it’s impossible unless you really want to do it in an illegal fashion, as in the days of the back street abortion.

Thank you, that’s very helpful to clarify. In general, when the FDA makes decisions about potentially fairly serious new regulation of a device or a test or a drug for that matter, does it do any sort of analysis and take into account the costs that regulation may impose on companies?
AG: This is a more complicated question than you actually think. We have rules we’re supposed to follow that we’re supposed to apply evenhandedly to everybody about what exactly is a new product. The law requires new medical devices to come into the FDA to get approval …That’s what the law is, so we don’t actually get to make a decision that’s based on the economic issues for that new device.

KG: It shouldn’t be complicated – surely they can say to a company “you will need PMA and you can expect it to cost $xyz”? Or do they just enjoy helping to proliferate the “FDA regulations consultant” industry?

I’m a little bit confused. Can we talk about that in the specific context of direct-to-consumer tests? What kind of thinking was there about the costs?
AG: [Direct-to-consumer tests] are a new medical device, and under the rules of the 1976 law, new medical devices require FDA clearance or approval before they go onto the market.

KG: No doubt again, they ARE a medical device

Right. But as part of that deliberation process, when you guys are considering whether to approve a device or not, do you take into account the cost that would impose on companies or the general impact on the industry?
AG: No. No. Our review does not, no, we don’t take into account cost.
EM: And Mary, that cuts agencywide. That is not considered in any of our reviews.
Okay. Thank you. I thought I had seen some obscure law saying there was a
requirement to take into [account] costs … Yes. Here it is. This is actually on the FDA Web site: “As part of its mission to supply economic analysis to decision makers, the Economics Staff in the Office of Planning conducts economic analyses of all important proposed and final regulations issued by the Food and Drug Administration. Each economic analysis includes an assessment of the costs, benefits, and cost-effectiveness of the action.” So this is right on the Web. How can you not take—
AG: So that is just, if you look at the first part, that is for all new guidances, for new rules and regulations.
EM: Which this is not.
AG: This is neither a rule nor a regulation.

KG: But once upon a time it was a new rule so an economic assessment should have been done, it should exist and can be adjusted for inflation – what’s the problem??

I see. You’re saying that because this is just like in 1976, these are medical devices, therefore they need approval— you don’t consider this new regulation, it’s just that the old regulations need to apply to these companies?
AG: That’s correct.

KG: Do they actually know what they are talking about?

Okay, thank you. One more question: … We’ve had the hearing and there were obviously some fairly troubling things that came out of the GAO report. I’m wondering what impact the hearing is having on the FDA right now. Are you guys taking those findings into account at all? Is that influencing your decisions?
AG: The findings of the GAO?
And other things that came out of the hearing.
AG: No, we believed that these devices [should be] under regulation. It hasn’t influenced us. Dr. Shuren did say that we should have been moving faster, and that we need to make these companies come in and get cleared for moving forward and selling their tests on the market. We will proceed with due diligence and try to help the companies come into compliance.
EM: The GAO report clearly did not undermine our feelings that these tests could present some risks to patients.

KG: I hope AG is right and that the GAO report is not used. EM’s answer though suggest it will be influential and I bet it will be. It should not be because as even the GAO admit, it was not scientific, the GAO did not make all of their information available for scrutiny, it was not independently reviewed, only selected sections and edited conversations were presented in a very theatrical way. I would bet that if all the information was made available it would show that overall the industry, as far as the reputable companies are concerned, is working very well and may even undermine EM’s feelings. It was very obvious that the GAO was making a “case for the prosecution” it was not an even handed survey, it was presented in a way to maximise the impression that the whole field is misleading and unethical.

[Given] Dr. Shuren’s comments that there should have been faster movement, are you guys feeling pressured to move fast right now?
AG: I think we are doing what we are supposed to be doing. We are obviously trying to get the companies to come into compliance and working with them to do so.

KG: OK we’ll see what’s next. Will it be like 2006 where the FDA got a similar rap on the knuckles by the Senate? If so then I suppose we will be back here after 4 more years of limbo to discuss the GAO/FDA/ETC findings on the DTC whole genome sequencing industry.

Overall the interview does nothing to clarify much at all, except that the FDA decided long ago that they are medical devices, even though they don’t know where the rules are (did he really say that? Thank goodness you got the tapes!). It’s all very murky – I was rather cynical in thinking that there are some murky politics behind it but after talking to Mary last night who had actually spoken to them, I think it is more that they simply do not know what to do yet, they don’t know how to regulate it. That is fine, it’s a very complex new situation, it’s not a simple laboratory test – the interpretation is a constantly changing river of information. There is no shame in not knowing what to do but the best response is not to pretend you are in control, it is better to consult widely (and openly, in public) and work closely with the industry you are trying to regulate. It is an opportunity to develop new innovative regulatory methods and not try to apply old rules, designed for simple tests, to this new, complex area.

One thing is clear though – if it makes a medical claim is it a medical device. I believe there should be clear guidelines for medical claims. Look – the nutrition and supplement industry are desperate to make health claims, they have to spend $millions to get them accepted and most of their applications are rejected. Here with DTC the situation seems to be the opposite, the FDA seem to have decided quite easily that these are valid medical claims. A medical claim should be something that would influence a clinical decision. Or a medical claim would be something like “if you take this test and follow our advice, or take our supplements, it will reduce your risk for disease” – if the DTC companies are quite clear that they are providing information that should not be used to make clinical decisions, and are not claiming to actually reduce your risk, are they really making health claims, are they really any different to any of the websites I have mentioned, including many run by the government?

Other recent comments on the FDA re personal genetics:

GeneticFuture: The FDA doesn't plan to regulate access to raw genetic data;

FDA Blog: FDA states cost 'not considered in any of our reviews' and In wake of FDA offensive, genomics entrepreneurs look overseas

DTC, FDA, GAO…2006 and all that

2010-07-22T10:41:00.000+02:00

I wrote a post below a few months ago but for various reasons got cold feet about posting it. Yesterday made me angry (like Daniel Macarthur), warmed them up and so after sleeping on it decided to go ahead. It is about events of 4 years ago but it needs hardly anything changed to make it perfect for today. I have made some slight modifications and added an introduction specifically about yesterdays US Congress Committee on Energy and Commerce hearing into the direct-to-consumer genetic testing industry.

The Congress hearing was eerily familiar. There were a few differences, in 2006 it in the Senate and was all out attack by a single senator (a committee of 1), yesterday at least there was balance and some sensible questions from some members of congress. I felt Henry Waxman was OK as was Burgess.
The whole hearing was based around the GAO investigation and this was just a mirror image of what happened in 2006. Just the same – selected evidence, highlight the most headline grabbing bits, even if they are false, uncover some truly bad practices and make it look like they apply to the whole industry – the tactics are clear in the title of the actual report (pdf download here):

DIRECT-TO-CONSUMER GENETIC TESTS
Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices

My title would be: Misleading Conclusions Further Complicated by Deceptive Investigation Techniques and Other Questionable Practices. What was really sleazy was the way it was presented. The highest profile companies were required to attend, they were identified during the hearing but none of the other companies were present and Kutz (GAO investogator) only semi-reluctantly revealed that the dodgy supplements company (he said this was fraud) was Genewize. For the rest of the hearing all we heard about was 23andME, deCODE, Pathway and Navigenics, they were in the dock and everything revealed in the report seemed to apply to them and therefore the whole DTC genetics industry must be rotten. This was the clear intention otherwise the other companies would have been identified and the worst practices would have been attributed correctly.

What we went through was rotten, what those present went through yesterday was rotten. Our reaction was to work quietly with FDA and FTC but keep a low media profile. In hindsight I think we should have had much more aggressive PR, to defend ourselves and expose the flaws in the GAO, but we didn’t and it festered.

There is no point in me going over yesterdays meeting because Dan Vorhaus in a a fantastic post yesterday has done the job (even more impressive as it was posted just after the hearing finished). Daniel Macarthur has a different type of description, very emotional - I share his anger and a lot of his pessimism. Mark Henderson of The Times also had a quick post (you will need to pay a sub, currently £1/30d – I know, I know, Murdoch and all that, but worth it just to read Mark who is by far the most balanced journalist on this subject that I have come across, no surprise that he is one of the few that are prominent on the twitter etc conversations on the subject).

Dan Vorhaus I felt was far too kind to the GAO – for me the GAO are the real problem. First of all though, just to be clear, at face value they did uncover some truly bad stuff – I am not surprised at that, it’s all over the internet. Disappointing that some was from Navigenics and Pathway – they need to sort out their sales / customer services people. There is no defence for the bad stuff the GAO found but there is also no defence for the way it was presented. The bad stuff can be fixed where possible and destroyed where necessary, but only if we know what we are dealing with, how bad, how extensive, who?

It is a tragedy that the GAO avoided the opportunity to produce a real balanced fair and USEFUL report, identifying clearly who did what, giving credit where it is due, calling expert help from both sides rather than relying on a clearly anti-DTC person. There is real rubbish out there, real harm being done. Kutz identified Genewize and actually accused them of fraud. Genewize claim to be making $millions per quarter (see Genelink, the parent company), that’s a lot of fraud, why is it kept quiet, why were they not in the dock? Apart from the 4 companies they tested (23andMe, deCODE, Navigenics, Pathway) they also investigated 11 others, who were they?

What now?

1) For me the most serious thing to fix is the difference in risk predictions for the same diseases. Sure, it happens with non-genetic algorithms for complex disease risk but genetics is supposed to be different. The consumer does not care about the explanations however valid they may be. The 4 above (23DNP!) need to get together and sort it out – maybe they should all agree on a standard chip, all do the same SNPs and differentiate themselves on their services, that’s more or less what they are doing now anyway. Pathway needs to get it’s act together and start being more open. It needs to publish full sample reports, details of risk calc, etc. It won’t even provide the raw DNA data to the paying customer for what I am reliably informed (Daniel MacArthur in Times comment) are absurd reasons – have you got something to hide? Would a standard panel be acceptable to them? Why not, soon we’ll be into whole genome sequencing anyway?

2) 23DNP should as soon as possible create an industry body and introduce principles of self-regulation – come on, you’ve been talking about it since the HGC banged your heads together in 2008, get a move on. Basing it on the HGC code of practice would be a good start. If and when FDA act they may find adopting what you develop to be simple and effective.

3) 23DNP should immediately create their own GTR, they know how to do it best so that it will be accessible to the consumer, maybe then when the NIH get ready (should I hold my breath?) they will operate as a joint venture. Hopefully the NIH GTR will be mandatory as well.

4) Call for transparency from the GAO. They investigated 15 companies. Who are they? What methods exactly did they use? How many calls did they make, how many were met with good responses and how many bad? Give us full transcripts of the calls, not just selected (and edited?) clips. They have done a lot of work, with all the data it should be possible to get a real picture of the actual state of the industry, separate the good from the bad, i.e. protect the consumer. Is it possible to demand this information be made public under freedom of information acts??

5) 23DNP should aggressively defend themselves in the media, criticize and expose the GAO methods, be public about the negative things found and what is being done about them.

OK that’s enough for now, here is the original post with my own GAO history:

The recent post by Linda Avey on the motives of the journalist apparently about to write a negative article on 23andme struck a chord. I have spent many years facing down the anti personal genetics brigade and bear the scars. I began way way back in 2002 (when a genome cost around $1 billion…) when I joined a little UK start up company called Sciona. The way I joined them was ironic – sitting in a pub in London reading a newspaper (The Guardian) I saw an attack dog article all about this unethical, misleading, scam job gene-diet company called Sciona. I sat up because one of the co-founders was a friend and former colleague at UCL, Rosalynn Gill (PGP #9!). I immediately got back in touch with “congratulations” on the press coverage, went down to see Sciona and was presented with a ton of publications that underpinned their work. I knew the reputation of the Sciona people and I was not surprised that they were easily able to prove to me that the Guardian article itself was misleading and based on ignorance (or just ignored most of the facts). Sciona had just won some funding and I joined the company, staying on the (very enjoyable, frustrating, eye-opening, teeth-grinding) roller-coaster until the end of 2008 when Lehman went bust, investment funds collapsed and along with it, a few months later, very sadly, also Sciona (by now located in Colorado).

Sciona was the first to offer this type of genetic testing DTC and boy did we get attacked, from so many sides, relentlessly. But with perseverance we did over the years make many friends in the academic world and managed to gain respect – among the informed. We won public research grants from the UK and EU and were very active in NuGO. We ended up with Jose Ordovas (who I am very happy to count as a good friend) on our scientific advisory board and a certain Wally Gilbert as well. The main investors were BASF, DSM, Burrill and Bioventures – companies whose chips are of the bluest hue and who certainly did not write cheques (or checks) without carrying out the most thorough due diligence. We all believed in personal genetics and we all still do.

Anyway, back to motives – the people who attack these new disruptive technologies, what are their motives? With personal genetics we are interested mainly about improving healthcare (NOT medicine, but healthcare, it’s different) so their motives should be a concern for the health of the consumer, concerns that they are not being mislead etc. But are these the real motives? I don’t think so. In the beginning there was Genewatch who ran a campaign against us from 2002 onwards. Lack of any real concern for the consumer is given away by their ideological and dogmatic attacks against every application of genetics? For them it’s all just an excuse for nasty companies to make money. They were so dogmatic and un-analytical that they became a broken record irrelevance.

Did the GAO really put the people first when it conducted it’s “investigation” into us and others in 2006? If so why was their embargoed report leaked to the press the day before the actual hearing (the press re-leaked it to us to get our comments and the articles were published on the morning of the hearing…I was a Brit staying in the Watergate hotel in DC, it was a surreal experience)? If they really cared and wanted a balanced report why did they include their press release, with their conclusions, in the press pack handed out to the audience and participants as they entered the room where the hearing was to take place? Why did the senator (there was only 1 at this “committee” hearing…OK another did appear, asked a question and left 10 minutes later, pity, I was looking forward to meeting Hillary Clinton and Elisabeth Dole) completely ignore all of the testimony from the participants (just about all of his questions were ably rebutted by Rosalynn Gill, one reply left the senator mumbling for words…)? Why did they allow inaccuracies in their report and in their press release to go ahead uncorrected? The most blatant, and headline grabbing, was the claim about one company offering personalised supplements based on the nutrigenetic test – the report stated that the ingredients in the supplements that had an annual cost of approx $1200 could actually be bought in a supermarket for only $35. My goodness, what a rip off, what a scam… But this was completely false – they had only considered the vitamin and mineral components and completely ignored the herbal and other components, which are much more costly (green tea extract, genistein, bioflavonoids, etc). Whatever you may think about the efficacy of the herbals etc, they cost a lot and to buy all of the components from elsewhere would have cost a lot more than $35 and indeed a lot more than $1200. Of course all this was made clear at the hearing, but it made no difference, that headline was just too good to drop so they continued with the press release and the conclusions remained unaltered. It may have been a mistake originally, maybe they were not so thorough in their investigation and they missed the fact the the supplements were more than just vitamins and minerals, but when they allowed the conclusions to stand it was no longer just a mistake. It caused economic damage to a particular company that was doing nothing wrong.

The press reports then and now are almost all just based on the press release and the conclusions therein – it is still trotted out that the GAO found that the products and services were misleading. Well they didn’t, certainly not ours anyway, I can’t speak for the other companies, although then, as now, there were some obvious rogues. The GAO tactics have been questioned by a couple of influential people at least.
One is David Castle, philosopher/ethicist, in a free academic article…

Although there are several methodological flaws in the report, the conclusion that at-home genetic tests offered to consumers are snake-oil was uncritically repeated. The flaws in the methodology and conclusions of the GAO report are serious and potentially damaging to private interests in nutrigenomics, as well as public confidence in the Food and Drug Administration (FDA).

Another is Ruth DeBusk in the Washintonian, April, 2010

While geneticist Ruth DeBusk concedes that there are “absolutely legitimate issues of concern” about nutritional genetic testing and many genetics labs, she calls the GAO report “irresponsible.”
“It’s clear the GAO investigators did not understand what nutritional genomics was all about,” DeBusk says. She says that some genetic-testing labs are doing solid research and offering legitimate genetic tests.

However in most articles the job done by the GAO PR is just lazily and uncritically repeated by just about all the journalists including…you guessed it…Andrew Pollack

I wish the GAO had carried out a proper review, along the lines of the HGC in the UK. The HGC were quite sceptical about Sciona and others, but they produced two balanced reports over the years and are still doing excellent work with their promotion of a Code of Practice. Here is a difference, the HGC is working on making things work, the GAO just made its headline then moved on to the next (hatchet?) job. The real pity is that there really are and were then, some highly dubious and really misleading scammers touting DNA tests with about zero evidence, they were, and are, the real villains. That’s it, I’ve got a lot off my chest and feel better for this rant. Good luck to 23andme, deCODE, Navigenics etc, bad luck to the scammers and real snake oil merchants.

The above paragraph I have emphasised because I wrote it back in March 2010 about the events in 2006 – and I don’t need to change a single word to make it perfectly relevant for yesterdays charade.

The situation in 2010 is a lot better than 2002 but there is still a way to go, investors please note, this is not a “5 year exit-strategy” business, if you just want to make money, go elsewhere, if you want to change the world, stay with us.

Mark Henderson cubed, comments here but go and read the article, it’s worth the £1 on it’s own

2010-07-20T12:57:00.001+02:00

I began this by commenting on Mark Henderson’s Blog about his genetic results, I had just had an espresso (and I live in Italy) & got carried away, it’s Mark’s fault as well, he invited comments via Twitter. The Times has become a subscription site for a few weeks – I really urge you to go and subscribe, it’s worth it for now at least (£1 for 30 days), the science coverage is the best in it’s class. Anyway, here are my comments on his excellent article, which you should go and read at: http://bit.ly/9H7iSP

Good stuff Mark and glad that others are climbing over the paywall to read it, it feels pretty lonely here! Just a few comments:

1) "Many of these, however, are based on preliminary, unreplicated findings [re 23andMe]" - this is OK and glad that Gutman agreed yesterday that prelim findings/information is OK as long as it is clearly labelled as such. I'm interested for professional and personal reasons in prelim findings, I can get them from the primary source but there is no reason why it should not be possible for anybody to access the same information in a more user friendly way (mostly from research that we have all paid for) - why should it only be accessible to "us". in fact the more public access the better, it could even improve journalism...I'm thinking Indy here, not the Times (well maybe Sunday Times)!

2) Yes interesting that Pathway are now docs only. I have always been disappointed by the lack of information on the Pathway site, what have they got to hide since their competitors have shown everything. They've always been the LibDems of the DTC world and just like with Clegg et al, recent events (Walgreens and following storm) have brought them to prominence. I wouldn't call them losers, and even if their attempt was an "ill-starred initiative" they are now definitely on the map, it brought them loads of publicity (the storm was interesting though, seems that selling through a pharmacy, with professional present, was considered worse than DTC via internet). Anyway, still do not like their opaque website and would not recommend them for that reason, I hope that the NIH Genetic Testing Registry will sort that out

3) On the NIH GTR - I hope that they learn from the DTC companies on how to present information, they will miss a big opportunity if they do not make it extremely user friendly for public and professionals alike

4) Not being able to see the Pathway results (by the way are they copyright protected or can you put them on the Times server for download, if you wanted of course? That would increase subs even more!) - I get the feeling that I agree with you. The "take action" stuff looks like they are presenting the risks as applying to YOU as an individual without making it clear enough that these are population risks. In fact, based on the genetics alone, you may not need to take action. Without the environmental, family history etc info the personal risk cannot be accurate. The gene for "dangerous driving" will only be relevant to you if you actually drive. I believe that 23andMe and Decode communicate this well enough, Pathway seem to be trying too hard to do "personalised" healthcare.

5) Re your glaucoma risk "I am now a confused customer!" Again I hope that the GTR will help (I am maybe hoping for far too much from the GTR) - if it has a forum area where anyone can post to (incl anonymous) then maybe you would get expert help in sorting out the confusion, we know from the blogs that the experts are out there and are happy to help

6) The apparent sampling errors could be due to typing complementary strands, so GG would be the same as CC? I don’t know if that would be the reason for AG → TG though (BTW do 23andme type rs6553078, according to dbSNP this is what rs10390924 has become?). However it would be very interesting to compare the full concordance for all the SNPs in the 3 sets of results, it’s important to know what the accuracies are, maybe you could get help from a friendly blogger (I would offer if I knew a good way to do it!)

7) “I'm still firmly of the view that individuals should be able to buy access to their genomes without medical supervision” – do you think though that they should be regulated in some way or is some sort of strong push for complete transparency enough (eg. GTR, again…)? If they are deemed Class II by FDA that would require premarket review, but of what? The details and interpretation are in continual flux – we’ll end up with a Zeno’s Paradox – if you pre-market review the service at a point in time you won’t see it moving and by the time you get the results it won’t be there anymore. If they want to make it Class II they will have to be innovative with the review process

Sorry, this became far too long, I should not write comments on genetics just after an espresso, but you asked!

If anybody is reading this (I have even fewer readers than The Times) please comment over at Mark’s blog (you can copy here as well, but I insist that you comment at Mark’s as well, please…I get NO commission, just want to help get discussion going at Eureka again)

Response to NIH regarding Genetic Testing Registry (GTR)

2010-07-16T14:15:00.001+02:00

The NIH is seeking input and advice on the following items:

Are there any types of genetic tests that should not be included in the GTR?
All tests that make some sort of utility claim should be included, also those that are not overtly connected to health (e.g. Child IQ, sports performance, baldness, etc). One aim of the GTR should be to create confidence in genetic testing and help protect against false or exaggerated claims. To have one single reliable (worldwide I hope) location where anyone, scientist, medic, consumer, journalist, business partner, etc can go to would be very helpful. If we end up with fragmented GTRs for different areas it will be less useful. Although run by NIH the criteria should include more than just strictly health applications

Further, the GTR should go beyond “testing” – it should cover all services, especially interpretation services which will become the main area of “personal genetics” as the testing part itself becomes routine.

What are the potential uses of the GTR for

Researchers – find collaborators and suppliers. ELSI researchers will benefit from a central mass of information
Patients/consumers – find reputable suppliers, education
Health care providers – find reputable suppliers, education
Clinical laboratory professionals – deposit information on own services, find suppliers / partners / customers, information on competitors(!)
Payers – education and information to help make decisions on utility and reimbursement. Maybe they will learn more about the opportunities for prevention and will be kept aware of specific ethical/legal problems regarding health insurance
Genetic testing entities/data submitters – information on available tests & services. Depending on how the database is structured it may offer the possibility of collaborative data sharing
Policy makers – education, awareness of services available, consumer attitudes (if consumer input is allowed)
Electronic health records – depends on the scope of the GTR and the database structure but there is a potentially very interesting opportunity to explore using standard language to enable genetic interpretation information to be incorporated into EHR.

What data elements are critical to include for use by (1) researchers, (2) patients/consumers, (3) health care providers, (4) clinical laboratory professionals, (5) payers, (6) genetic testing entities/data submitters, (7) policy makers, and (8) electronic health records?
Genes, SNPs, dbSNP rs numbers, claims that are made with clear links to how they arrived at the claims/advice/interpretations from the scientific literature. Full bibliography. It would be useful to have independent assessments of each service as well – either by professionals (like a journal editorial board and peer review) or via moderated comment, or both

What are the potential benefits and risks associated with facilitating public access to information about the:

Availability and accessibility of genetic tests?
Scientific basis and validity of genetic tests?
Utility of genetic tests?

Benefits:
A central reliable source of tests available, with some independent professional assessments of validity and utility will encourage consumer confidence, will allow the choice of relevant tests and will hopefully steer consumers away from untrustworthy services. The information will also help to decide whether healthcare professional involvement may be useful either before or after testing. Healthcare professionals also count as consumers, such a resource would be very helpful to determine what tests to use and how to integrate with clinical decision making.

Risks:
a) Depends on how the GTR is set up. If not presented well it could increase confusion and damage the uptake of genetics in health. If public access is to be given it will need to be pitched at the various levels expected to use it, from uninformed layperson to genetics expert. It has to be more consumer friendly than http://www.ncbi.nlm.nih.gov/ (not a criticism of NCBI, which is obviously excellent for professionals!).

b) The way the tests/services are presented, it has to be clear that simply being present on the registry is not an endorsement of the claims of the services offered.

c) A dedicated genetic testing resgistry is required but it should not foster so-called “genetic exceptionalism”. It should not encourage that idea that common genetic variations associated with traits are deterministic of disease independent of environmental variables

What is the best way to distinguish between data fields left blank because of an absence of data/evidence and those left blank for other reasons? How important is this distinction for enhancing transparency, including for the purpose of identifying research opportunities?
Best way is to state the reason for the absence of data. There may be no data, it may be restricted for personal or commercial confidentiality, it may be conditionally available, e.g. for research, etc.

To adequately and accurately describe a genetic test, which of the following data elements should be included in the GTR? Are there other data elements that should be added? What information is necessary to represent adequately each data element?

Contact information (e.g., location, name of the laboratory director, and contact information for the laboratory performing the test)
Laboratory certifications (e.g., Federal or State certification of the laboratory that performs the test)
Name of the test (e.g., common test name, commercial name, marketing materials about the test and/or genetic testing entity, standard identifier (e.g. CPT codes, LOINCⁱⁱ))
Regulatory clearances (e.g., for tests reviewed by the Food and Drug Administration, the 510(k) or premarket approval (PMA) number)
Intended use of the test (e.g., diagnosis, screening, drug response)
Recommended patient population
Limitations of the test (e.g., is the test validated only for certain subpopulations or limited to particular uses such as screening but not diagnostic testing?)
Test methodology
Analyte(s)—What is being measured in the test (e.g., genetic sequence)
Specimen requirements (e.g., blood, saliva, tissue samples, amniotic fluid)
Availability (e.g., is the submitter the sole provider of the test or are there multiple providers?)
Accessibility (e.g., accessible through a health provider, public health mandate, and/or direct-to-consumer)
Performance characteristicsⁱ
1. Analytical sensitivity
2. Analytical specificity
3. Accuracy
4. Precision
5. Reportable range of test results
6. Reference range
7. Method used for proficiency testing (e.g., formal PT program, alternative assessment) and score
Clinical validityⁱ
1. Clinical sensitivity
2. Clinical specificity
3. Positive and negative predictive value
4. Prevalence
5. Penetrance
6. Modifiers
Utility (e.g., clinical and/or personal utility) or outcomes
1. Benefits
2. Harms
3. Added value, compared with current management without genetic testing
Cost (e.g., price of the test, health insurance coverage)

All of the above. Accuracy of testing via historical data of control samples, allele frequencies stratified for population etc. Clinical validity to include odds ratios, relative risks, lifetime risks – in a way that is understandable by lay people. Modifiers are important, almost all risk assessments will be modified by environmental parameters and it is important that this is clear.

Clinical and personal utility is sometimes straightforward but often is hard to quantify. This section needs to be explanatory, figures and percentages will not be very helpful most of the time

Other info: most tests will involve the use of software in their interpretation. It will be important to give as much information as possible on this. For risk calculations the precise methods need to be supplied, for interpretations of gene x gene and gene x environment interactions and the advice generated, descriptions of the algorithms should be supplied. Also the validation procedures of the software should be detailed – how it is controlled to be sure that the correct advice/results are given for the various input results. What level of standard was used in the creation of the software and in the programming of the rules?

What types of information might be difficult for test providers to submit and why?
While some software details should be given it will clearly be difficult to submit full algorithms etc, and other commercial secrets.

What are the advantages and disadvantages of collecting and providing information on the molecular basis of genetic tests, such as detailed information about what the test detects and the specific methods employed?
No further comments

In addition to the data elements, would it be helpful to reference other resources, and if so, which ones (e.g., published studies, recommendations from expert panels such as the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children, U.S. Preventive Services Task Force, or Evaluation of Genomic Applications in Practice and Prevention Working Group)?
No comment

As the GTR is being designed, what are the important processes to consider to make the submission of data as easy as possible for the data provider (e.g., the capability of linking to information that has been submitted to other agencies, such as the Food and Drug Administration and the Centers for Medicare and Medicaid Services, or a master file of data common to particular tests)?
No comment

Which potential benefits and risks would be most likely to affect the decisions of researchers, test developers, and manufacturers on whether to submit data to the GTR, and what factors will best encourage submission of complete and accurate data?
Submission to the GTR should become a “required” step by any service provider. Not necessarily enforced but essential in the sense that if it is not there then it is suspect. Service providers would benefit from a GTR logo that they could use on their websites to link to their own submissions. It should become a commercial risk not to submit to the GTR. With the help of press, social media, conferences etc, the GTR should be widely publicised, easily accessible (and easy to understand/navigate, especially for journalists)

What are the most effective methods to ensure continued stakeholder input into the maintenance of the GTR?
Keep it up to date. Ensure an adequate budget, keep it publicised, regularly report on results, benefits, effects, etc of the GTR including in scientific papers

For what purpose(s) would you use the Registry to support your professional efforts?
Submitting tests and services, reviewing other tests and services, commenting on them (preferably on the GTR site itself).

Are there any other issues that NIH should consider in the development of the GTR?
As mentioned above, a review mechanism would be useful. A sort of peer review as used by scientific journals, with editorial board etc. There should be areas for comments by other users, maybe via comments or a wiki type system. Most service providers will have nothing to fear but there are already too many very dubious services and the GTR can help weed them out either via their absence from the registry or by critical analysis on the site. In addition it would be useful to have space for comment of tests which are available but which are not on the registry. Many of these will likely be dubious and are absent to avoid scrutiny – they should be scrutinised anyway. Others may well be valuable but have not been submitted fir various reasons (time & resources, ignorance of the registry, etc)

The most valuable thing that the GTR can achieve is clarity and transparency…many services will be direct to consumer but both healthcare professionals and consumers alike will suffer if the genetics/genomics service industry becomes as opaque and exploited as the supplement industry.

Technorati Tags: genetic testing registry,NIH GTR,personal genetics,DTC genetics,23andme,decodeme,navigenics

So vitamins fail again, this time it’s folate and B12. Really?

2010-06-24T13:41:00.002+02:00

Yet another clinical trial of folic acid and heart disease has been published – an extremely well designed trial where the results suggest true adherence to the vitamins vs. placebo regime. The conclusions are:

Taken together with the previous homocysteine-lowering trials, the results of SEARCH indicate that folic acid supplementation has no significant adverse effects on cancer or other major health outcomes, even if it also produces no beneficial effects on cardiovascular disease. In addition, these results highlight the importance of focusing on drug treatments (eg, aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid–based vitamin supplements, for the prevention of cardiovascular disease.

JAMA: Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors: A Randomized Trial, June 23/30, 2010, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group 303 (24): 2486 http://bit.ly/azza0X

First of all this is very good news regarding cancer especially as this would be considered a high risk group (where the majority were over 60 yrs old and therefore more likely to have precancerous lesions which excess folate could in theory accelerate the growth of see Ulrich, CEBP, 2008). This is important and the authors are right to highlight it – it is often used as a headline argument to oppose B vitamins but the details don’t support there being a real significant risk compared to the benefits, and this large study helps to confirm that.

Not so good news though for preventing heart disease, but what does it really tell us? They also mention osteoporosis, see below. This is a problem with trying to squeeze nutrition into a pharma type clinical research study. We are not dealing with a novel molecule with a precisely defined target but a common vitamin involved in complex biochemical pathways (inc. DNA synthesis and methylation) and it’s not surprising that perturbations to these pathways have multiple effects.

Homocysteine is a risk-marker for CVD, whether it is cause or effect is not established although there is reasonable evidence for it being involved (Wald et al, BMJ, 2002). It has been reported to have damaging effects on genome stability (Fenech, AJCN, 2010) and high levels have been linked to a host of diseases from osteoporosis to dementia (Selhub, 2006). The evidence strongly suggests that it is a good thing to keep it low. So why have all these trials shown more or less no effect of homocysteine on heart disease? Quite possibly because all of them are looking at secondary prevention, i.e. the study patients in all the trials are exactly that, patients, already ill with heart disease. Maybe it’s to late to start lowering homocysteine if the damage has been done – just like no-one really expects calcium and vitamin D to have much positive benefit in people who already suffer from osteoporosis (incidentally in the paper the authors say “Low folate status and increased homocysteine levels have been associated with osteoporosis and fracture risk but fracture incidence was similar in the 2 groups” – not at all surprising, osteoporosis prevention does not start at >60 yrs old).

Post infarct reduction of cholesterol levels have been shown to be effective in secondary prevention (indeed all patients in the SEARCH trial were on simvastatin) but the mechanisms are different. Cholesterol clogs a pipe whereas homocysteine, if it is indeed involved, is likely to do so via damaging blood vessel walls. So we can talk about plumbing. If a pipe becomes blocked following years of calcium deposits in a high calcium water area, once the blockage is treated, recurrence can be prevented by reducing the calcium content. If the pipe develops a leak due to years of erosion due to acidic water, even after repairing the leak the pipe walls will still be weak and neutralising the water is not going to make much difference, the damage is done.
The SEARCH study was well done and they make good points about cancer, but the final sentence was disappointing:

In addition, these results highlight the importance of focusing on drug treatments (eg, aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid–based vitamin supplements, for the prevention of cardiovascular disease.

Drug treatments OK but talking about smoking and weight as of “proven benefit… for the prevention of cardiovascular disease” is misleading, it suggests that this study has something to say about primary prevention, which it certainly does not.

As discussed in the past, clinical trials of nutrients for primary prevention are pretty much impossible, we have to rely on the best evidence we have to give nutrition advice – the evidence is strongly in favour of homocysteine lowering with levels of folic acid much lower than 2mg per day (RDA of 400µg is enough for most, those with polymorphism in MTHFR will need more, of course it goes without saying that there was not genetic component to this study…). SEARCH and all the other trials have often been misused in the folic acid/homocysteine debate, they have often been cited as proof that the homocysteine theory is wrong – but they do no such thing and it would help if the authors of these studies made it clear that all conclusions are relevant (and useful) only as far as secondary prevention is concerned.

Not DTC and not even DTMD? – Genetichub announces itself

2010-06-06T17:03:00.001+02:00

There is a new “old” kid on the block – announced last week at the Consumer Genetics Conference by Dr Stephen Murphy, aka @genesherpas, http://genetichub.com/

This is just a short note about the site and service because it seems likely that it was finalised in a rush to get it ready for the CGC announcement. It’s too early to judge what it is and what it will become. Steve Murphy is of course very well known as an outspoken critic of most DTC genomics via his blog. I am wondering whether his now official status as a fully commercial genetics service provider, beyond his own medical practice, will affect the tone of his future posts. I doubt it…but it’s a fact that the situation is now different, the opposition is now the competition and a potential conflict of interest has to be acknowledged, at least. One thing is certain though – his blog history means that he has set himself very high standards regarding the delivery of genetic testing

So what is the Genetic Hub? At the moment the site has little content, most of it consisting of links to external sites or content:

What are Genes links to an embedded YouTube video of Francis Collins talking about…genes (DNA Day 2005)
Genetic Disorders links to University of Utah pages
Genetic Laws links to the excellent Genomics Law Report of Dan Vorhaus et. al
Genetics Blog looks to be the Sherpa blogs repackaged in GeneticHub clothes

As I said, it may have been a rush to get it ready in time. Anyhow, the hub of GeneticHub is of course business, selling products and services. The first (currently only, more coming soon for Coumadin and Tamoxifen) product is the CYP450 2C19 (PlavixTM) Gene Test together with a genetic physician consult. Clicking on the Buy Now link takes you to the pages of mymedlab.com who sell the test – the websites have similar designs but the relationship between mymedlab and genetichub is not clear. The test price includes 15 minutes with a “board-certified Genetic Physician across our secured platform”. Is that a phone call or a webchat? Expertise provided by “Dr. Steven Murphy and his Personalized Medicine Group”.

You can purchase the test straight away via the website so this IS actually a genetic test sold DTC. The difference between this and 23andme, decode, etc (but maybe not navigenics) is that 15 mins consult is included (and of course it is a declared clinical diagnostic test, not just for “educational use”). As I said, this is not a critical review, just an overview of a new provider of personal genetics services. There are a few questions and I am sure all will be cleared up by Dr Murphy in due course:

1. Does customer get the results before the consult?
2. If not can the customer get them before and choose to forgo the consult?
3. Is a medical prescription required (seems not, no mention on the site).
4. Can we see a sample results – what SNPs, what are the interpretations, etc? (I have no doubt that this service is high quality, but the next MD that comes along and sets up a company may be less knowledgeable – so transparency is, as always, a key requirement, for any provider).
5. Does insurance cover the costs?

Genetichub is actually entering into quite a competitive field. Pharmacogenetic testing has always been less controversial than the so-called predictive personal genetics and has been on offer, DTC and via MD, for several years. Among the the other offerings are

Genelex – they have a wide range of Pgx tests that are sold direct but only if customer has a medical prescription. I couldn’t find pricing, they say the test is billed direct to the insurer. They also give you 90 days access to their GeneMedRX “drug and gene interaction software so healthcare providers can see the effect of the genotype on all of your medications, herbals, and over-the counter medicines” Actually they will give a 30day free demo to anyone, even without any purchase. Does not appear to include a personal consult. Website provides a lot of information and a guide on how the results are interpreted.

DNAdirect test CYP2C19, plus many others. The CYP2C19 costs $199 with “toll free support” – not clear what this consists of as they also advertise Pre-test & Post-test Consultation for $250 per hour

The 23andme $429 health edition includes the CYP2C19 SNPs plus an interpretation of the results specifically for Plavix – recently announced partnership with Informed Medical Decisions provides genetic counselling consult for $99 or $375 for “Comprehensive Clinical Genetic Counseling” which they say will be reimbursed by insurance making the net cost just $35

Decodeme include the same SNPs but don’t seem to have a specific Plavix interpretation, they seem to have priced themselves out of the market at $2000 for the complete scan.

Pathway have a specific Plavix report in their $249 scan and access to Counselors but no indication of costs of this part of the service. (Still very unimpressed by the information available on their website).

Navigenics complete scan is $999, it specifically includes Plavix, among many other drugs and “Our counselors are available at any time to answer your questions, at no additional charge – even before you have signed up. You can call us any time at (866) 522-1585 to set up an appointment at your convenience.”

So with Genetichub and last weeks Existence Genetics it’s getting more and more crowded – bring on the NIH genetic testing registry please…(NIH is canvassing opinions, go here and give them yours, help them to get it right from the start).

Personal genetics: DTC or DTMD?

2010-05-27T12:12:00.001+02:00

Yesterday I ordered a book from Amazon called “Outsmart Your Genes” – this was prompted by a tweet from @genesherpas:

Just got my copy http://www.outsmartyourgenes.com/ my Friend Brandon Colby MD's great work. It is a must read for all. That means AnneW too.

It wasn’t too expensive and it may be interesting – it also could be part of a slick marketing campaign, a few days previously a press release announced the launch of “Existence Genetics LLC, the world’s first predictive medicine company…”. With the website of the book linking to the Existence website, the twitter and facebook links, and so on, it does look like:

@dgmacarthur The "Outsmart your genes" book that @GeneSherpas is spruiking looks like extended ad for author's company: http://bit.ly/8Zanrd

We’ll see, I’ll update when I read the book, meanwhile I learnt some Australian slang as well…

First of all – there is nothing wrong with any of the above, it’s all fine and I have not much to say about the service offered by Existence Genetics (EG), I don’t know enough about it to comment. I am seriously interested in the service from a professional point of view – our aim at Eurogene is to bring such services to the practitioner in Europe – we have set up the software, systems and infrastructure to do so, to incorporate the genetics into the rest of the medical history, but we don’t develop our own genetic panels so EG could be interesting.

I’m also interested in the comparison between DTC such as decode and 23andme vs. DTMD (direct to medical doctor) like EG because a few days ago the regulatory waters were stirred up by the Pathway/Walgreen partnership (why that prompted it I don’t know – DTC via internet since 2007 = OK, DTC through pharmacy ≠ OK ?? Actually I fear it’s a knee-jerk response due to what in the UK would be called “tabloid pressure” on the FDA. But follow the link above to Genome Law Report, there you will find all you need on the current state of affairs). While I support some form of regulation / oversight (strong code of practice is my preference) but I also support DTC for easy access by anyone and full transparency.

The point is that the FDA may be jerked and lobbied into banning DTC and the only source of genetic health analysis would be through services like those of EG. The question is would that be better? There has been a lot of vocal opposition to the DTC services – they say that these are clinical services that need to go through a medical doctor. So is the EG service fine because it does go through a medical doctor, does it mean that the consumer/patient is protected by this relationship?

If I go to decode or 23andme I can see on the website a LOAD of information – the SNPs analysed, the references used to calculate the relative risks, the actual methods used in the calculations, and so on. They are both very transparent as far as what they are offering goes – and all this is available before I purchase. Which also means it is all available to anyone else to scrutinise, to error check and to validate, which is very important.

On the EG website there is very little information – no genes, SNPs, calculation methods or costs. I don’t know if they make available all the information on request – my request got this not too promising auto-reply:

Thank you for contacting Existence Genetics. While we do try to respond to e-mail inquiries, we are extremely busy and may not always be able to respond to all. Also, we are unable to answer any medical or health-related questions via e-mail.

Make sure to visit www.existencegenetics.com and www.outsmartyourgenes.com for more information and to sign up for our industry-leading Predictive Medicine Newsletter.

Thank you,
Soraya K. and The Existence Team

There are some pages from sample reports though. Here is a screen dump of a portion of the single page heart attack report:

And from 23andme:

One subtle but interesting difference: EG says this is YOUR risk while 23andme talk about population risks referring to people with similar genotypes. I prefer the latter style because that’s where the data come from, studies of populations, I’m not sure that it’s correct to state that this % is my actual risk given that my actual risk still depends on many unknowns (other genes and my lifestyle). That’s my opinion and I stand to be corrected if it’s wrong.

Another comparison is EG and Decode who both test for Alzheimers:

Decode:
The lifetime risk of your type: It is estimated that 39 of every 1000 males of European ancestry with your genotype variants develop this disease in their lifetime.
The average lifetime risk: On average, about 60 of every 1000 males of European ancestry develop this disease in their lifetime

Although there is currently no treatment available that can delay or stop the brain degeneration that causes AD, several drugs have been approved by the US Food and Drug Administration (FDA) that can temporarily slow worsening of symptoms for 6 to 12 months. As these drugs are mainly useful in the early stages of the disease, some individuals may choose to know their risk factors for the disease.

Individuals at high risk for AD may benefit from regular screening for early symptoms of the disease by their primary care provider. Early, active medical management, through available treatment options and utilization of programs and support services, can improve quality of life through all stages of the disease for diagnosed individuals and their caregivers.

EG:
Your lifetime risk 54%
Generic lifetime risk 17% [misread this as genetic at first, confused me!]
This is equal to a 220% increased risk
Clinical significance: This potential disease is very important to your health & wellness
Actionability: Preventive measures have been shown to help prevent or delay onset/progression of this disease [and it lists these as protect head from trauma, low animal fat diet, increase exercise, red wine, statins, aspirin, yoga]

Note: the founder Brandon Colby, talks about Alzheimer in a Huff Post article:

Predictive medicine's strategy in defeating Alzheimer's is straightforward: first, we use genetic screening to identify those individuals who are at increased risk; second, for those who are at increased risk, we use further genetic analysis to determine the most effective forms of prevention; and third, we institute these genetically tailored preventive measures throughout the person's life, starting as young as possible. With a simple, relatively low-cost test requiring only some saliva (no needles, no blood), we can now predict who is at risk for Alzheimer's and what will be the most effective methods of prevention against it.

Hmmm…I would really like to see the articles that are the basis of this Alzheimer prevention.

There are many questions, but first of all I would like to not get into definitions about “is it medicine” or not – that’s been gone over so many times it’s become a sterile and distracting occupation. The overall question that the FDA and others want to sort out is should decode and 23andme et al. be able to continue to offer their services DTC or should they need to be delivered to the consumer via a medical doctor. Further – should the decode and 23andme services be strictly controlled as medical devices with lengthy, costly pre-market scrutiny and FDA approval required before selling (which would effectively put them out of business)?

1. Decode and 23andme provide details of how they calculate risks, EG does not provide much information at all but makes much stronger claims and promises.

2. Should EG be subjected to the same scrutiny as 23andme etc., has it been required to submit the same sort of information requested by the FDA of the DTC companies, or does going via MDs make the service immune from this?

3. Can the EG service be freely sold in New York or California without having to go through the approval steps necessary for the DTC companies?

4. How much will the EG service cost me and what information will be supplied – will I get the results of all the SNPs on the proprietory “Nexus Gene SNP” for which there is no information on the website?

5. What is the scientific basis for the EG “Disease Matrix technology” and “Reflex Analysis” ? How have the algorithms been validated?

And so on. To be clear I am not saying that the EG service is poor, wrong, bad, or whatever – I don’t know, I can’t know, there is no way of finding out as far as I can determine. Let’s say that they are very good - that the service is excellent and life saving – great, but that’s not the point. EG may be good but the next DTMD service may not be, and we would not be able to tell. If all personal genetics were delivered DTMD would that be OK for the critics of DTC, is that what they demanding? If it were all DTMD then would there be no reason for the FDA to get involved as it has done recently? Would it have all stayed under the radar screen?

If that is the case then I sincerely hope that the future is not restricted to DTMD – this is the situation in Germany, the paradox is that going down this route actually reduces scrutiny, quality control, transparency and will lead to the marketing of dubious products and services (like in Italy – through medics only for a mere €700 plus doctor fees you can buy Nutrigenecode, 50 anonymous SNPs, then you buy the magic supplements. It sounds good though because “it’s prevention and will save you loads of money in future doctor fees” plus DNA really is the “fountain of eternal youth” – so there).

Those who call for health related genetic tests to go through medics need to demonstrate how restricting the services to the EG type model is really better, because that is not at all apparent from the information available. Strong regulation can have serious damaging and harmful consequences if not done properly – see this Genetic Future post from Daniel MacArthur for a good review.

Really I don’t think we need to tie ourselves in too many knots over this regulation stuff – 90% of the problems would disappear with a good code of practice, transparency and the recently proposed NIH genetic test registry.

I hope that the FDA will see the possible futures and allow us all to continue to pay our money and make our choice.

Something is not working – is it the vitamins or the trials?

2010-05-11T13:39:00.001+02:00

This article in today’s Independent prompted me to finish off and post this – as far as good nutritional advice is concerned confusion reigns.

1. Sat fats are OK after all
2. Recently we were informed that the “5 a day” advice did not prevent cancer (see previous post)
3. We read that >400 IU / day vitamin E increases mortality thanks to a 2005 meta-analysis (Conclusion: “High-dosage (≥400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided”)
4. In 2007, a widely cited meta-analysis proved “the myth of antioxidant supplements” – they simply do no good and may even do harm
5. The subject of this post – 2 major studies show that vitamin E and Selenium, despite early promise, do not protect against prostate cancer (SELECT and PHS)
6. According to one author of the SELECT study – “The prospects for cancer prevention through micronutrient supplementation have never looked worse”

So how much of all this is true? Probably some, none or all of it – we really don’t know, none of the work cited can be used to establish as fact such sweeping statements. We know that nutrition research is tricky – we need to improve it but we also need to be very careful what we conclude from studies. There is the temptation to overstate what the results really mean, maybe in order to justify the vast amounts spent on the studies (and with an eye on future grants).

There were a couple of high profile studies published in JAMA last year (SELECT and PHS) on vitamin E and selenium in cancer prevention. Very large studies, expensive, well designed randomised clinical trials (the “gold standard”) that showed no beneficial effect of either vit E or selenium leading to headlines like:

I don’t have a great problem with the studies themselves, they must have seemed like a good idea at the time and we have the advantage of hindsight. But I do have problems with some of the rather strident conclusions from what were basically negative (and no doubt disappointing) results. These lead to headlines that get ingrained into common beliefs. For example with vitamin E mortality (see 3 above) – the actual studies cited in the meta-analysis showed that it required much higher levels (1-2,000IU) before there was any increase in mortality (this is mentioned in the SELECT study paper – (“…the finding of increased mortality was driven by studies using doses far higher than 400 IU/d”). Regarding the “antioxidant myth” (point 4), The 2007 Bjelakovic magnum opus “proving” that antioxidants don’t work is a very highly cited paper but very contentious with over half a page of errata and a lively debate on the Cochrane site.

I’m not “for” or “against” supplements (opinions are very polarised on this subject – just like with personal genetics, and as usual the poles are not the most useful places to be). But I am against some of the dogma (like RCT being the gold standard - it’s fine for single agents with powerful effects on well defined pathways but useless for anything much more complex), and against making conclusions that are not justified, especially in high profile studies where they will become the headlines without proper scrutiny of the work.

These recent studies on prostate cancer, vitamin E and selenium highlight several problems with current approaches. The caveats were thoroughly discussed but the conclusions were far too emphatic and anyway, probably wrong.

Brief background. Several studies had shown evidence that selenium and/or Vitamin E may reduce prostate cancer risk in particular the Nutritional Prevention of Cancer (NPC – see also this NPC study) study and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study. This lead to 2 very large randomised clinical trials the results of which were published in JAMA: SELECT Lippman et al, and the Physicians Health Study – Gaziano et al

SELECT:
35533 men from 2001 – 2008 (stopped early for lack of benefit)
1. Placebo
2. Selenium (200 µg/day)
3. Vitamin E (400 IU/day)
4. Selenium (200 µg/day) + Vitamin E (400 IU/day)
Conclusion: Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.

Physicians Health Study:
14 641 male physicians in the United States initially aged 50 years
Mean follow up – 8 years
1. Placebo
2. Vitamin E (400 IU/every other day) plus Vitamin C (600 mg/day)
Conclusions: No benefit

What they said:
SELECT:
1. Furthermore, the large sample size, inclusion of a substantial proportion of non-white men, and equal distribution of known risk factors across all trial groups make the conclusions drawn from SELECT especially robust and generalizable.
Problem: As even the authors say, African American men have among the highest prostate cancer risks in the world. The authors are proud of their ethnic mix, but it was actually 80% white and only 13% African American. Not really generalizable.

2. In conclusion, SELECT has definitively demonstrated that selenium, vitamin E, or selenium + vitamin E (at the tested doses and formulations) did not prevent prostate cancer in the generally healthy, heterogeneous population of men in SELECT
Problem: “definitively demonstrated” – this is false, the many limitations of both trials (see below) do not allow such a bold statement to be made

3. These findings also compel the medical research community to continue the search for new, effective agents for prostate cancer prevention.
Problem: Really? The situation is the same as before, these results have not excluded vitamin E or selenium, they cannot be discarded quite yet

Physicians Health Study:
”In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men.”
Problem: A very carefully worded conclusion. “These data” indeed “do not support…”. But they don’t support anything at all really, it’s quite a meaningless statement but of course the “meaning” that comes across is that the vitamins don’t work

Limitations of both trials
1.    the studies were conducted in a well-nourished population - “SELECT men generally were replete in selenium”
2.    single dosages (also, curious that the ATBC used 50 IU and these trials used 400 IU vitamin E)
3.    synthetic α-tocopherol was used in the study (proper vitamin E = α, β, γ, δ-tocopherol and α, β, γ, δ-tocotrienol)
4.    Adherence - did they really not take supplements?
5.    Regular observation for early detection of prostate cancers
6.    No genetic or diet analysis

The adherence is a really difficult problem. Both studies claimed that the subjects behaved themselves. In SELECT a subset were tested for blood levels once during the trial which showed adherence. But not really, if you are buying your own supplements you would stop taking them a few days before the blood test appointment. Also, you are part of a study the hypothesis of which is that antioxidants are good for you – you are reminded of this every day when you open the specially labelled clinical trials supplement bottle. This can make you a) not bother, b) improve diet and lifestyle in general, c) increase antioxidants in the diet, d) buy non vitamin E / selenium supplements or e) buy your own vitamin E and selenium.

Something really interesting was pointed out in the associated commentary – there was just 1 death from prostate cancer in the SELECT trial when up to 100 would have been expected, just being part of the clinical trial seemed to significantly reduce the risk (which could be reasonable - but that’s now an epidemiological observation, it needs testing, by RCT?!). Also most of the cancer cases were non-aggressive and there is other evidence that antioxidants have more protective effect against aggressive cancers.

The limitation about the well nourished population was very convincingly put in follow-up letters by Margaret Rayman and Sue Fairweather-Tait who both pointed out that actually the selenium evidence before the trials (and since) is that it is effective only in people who have low baseline levels of selenium, far below those in the SELECT trial who were “selenium replete”. I thought that the authors reply was rather shirty and dismissive (SELECT was a very large study and anyway “At present, the possibility that selenium may prevent prostate cancer in men with low plasma selenium levels is an unproved hypothesis that has not been tested as a primary end point of any clinical trial”. Well yes, precisely – and of course in the paper they don’t suggest any such trial, instead “These findings also compel the medical research community to continue the search for new, effective agents…”)

Further problems with the study population: PHS was 100% white and well-off (they were physicians). SELECT was 80% white and the majority (>80%) had higher education. This is the distribution of prostate cancer risk:

Prostate cancer mortality rates, by education level and race, for men aged 25-64 years in the United States, 2001
Albano, J. D. et al. J. Natl. Cancer Inst. 2007 99:1384-1394

So both trials were looking at the group with already the lowest risk (forget the 13% African American in SELECT, not enough to make a difference). Neither of the trials have shown anything regarding the usefulness or uselessness of vitamin E and selenium because, among the many other limitations, the wrong population was chosen.

PHS concluded:
”In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men.”

A less misleading conclusion should be:
“These data provide no support for the use of synthetic α-tocopherol and a single vitamin C dose in a group of healthy, wealthy, intelligent, upper middle-class male health professionals…maybe…”

I hope that these are the tail end of these types of studies. I also hope that something useful can be teased out of them through sub-group analysis (e.g. concentrate on those with low baseline selenium) and genotyping the DNA samples (SELECT authors say that this is underway). Meanwhile we need to rethink this dogmatic belief in RCT as gold standard for complex research questions and we should question the use of complex endpoints, concentrating on pathways and risk factors. There is a promising approach discussed by one of the Select authors at Cancer Epidemiology, Biomarkers & Prevention (Alan Krystal - Are Clinical Trials the “Gold Standard” for Cancer Prevention Research?)

Conclusions

1.    I think that one of the most important things to do, given the “genie out of the bottle” era we live in, is that accurate, useful and balanced information is given when translating medical research into something that can be understood by the general public – we all have to eat something and it would be helpful to have good information about ourselves (inc from genetics) and our environment so that we can make our own mind up. This for us at Eurogene is crucial, our job is to provide the tools and the means to translate research findings into meaningful decision making tools for healthcare professionals and individuals.
2.    These are 2 very large, well designed (in method at least), expensive, long (10+ years with planning, recruitment etc) randomised clinical trials – the gold standard – that have told us almost nothing about the questions they were supposed to address. SELECT cannot conclude that it has “definitively demonstrated” that vit E / selenium are not effective. There was only 1 death and very low rates of aggressive cancer – the subjects were mainly from the lowest risk groups and the trials were not long enough to see if there was any protection. Why choose these groups? Presumably for convenience – ease of recruitment, follow-up, adherence, etc. Convenient yes, but not useful.
3.    Studies should target the highest risk groups for all the obvious reasons (except of course convenience)
4.    These, any many others (HOPE2 and NORVIT for vitamins B) have maybe “definitively demonstrated” that the RCT will not work for optimising diet/lifestyle/behaviour for primary prevention. They have not produced any useful evidence, either way, in 20 years of trying, now is the time to try something different
5.    The hope, of course this is what I hope, is that genetics, genomics, other –omics, will bring us the tools to for better pathway analysis and better monitoring of health status

STOP PRESS: Just found this and this – subgroup analysis of the physicians health study showing benefits of selenium but only in some:

“This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype”. Cancer Prev Res; 3(5); 604–10

Is nutrition research any use without genetics & genomics?

2010-04-08T11:22:00.001+02:00

Headlines all over the press today were “5 a day doesn’t prevent cancer”. So after all these years set in stone it’s all been a waste of time? Hard to tell really, the paper in question is all about cancer but as the Walter Willett editorial points out the same study group provided evidence that 5 a day reduces stroke and heart disease by 30%. But maybe that’s not right either, maybe Dr Aragon in Woody Allen’s Sleeper was right (this is from an interesting article about nutritional genomics by the way):

The study: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition (EPIC) by Boffetta et al, published online in the Journal of the National Cancer Institute. It involved almost 500,000 people in a prospective study looking at nutrition and cancer between 1992-2000. Over 30,000 developed cancer but the detailed analysis revealed only a minor F&V protective effect of a few percent, if any at all.

Disappointing to say the least, an EPIC failure on the Cecil B. DeMille scale as far as cancer is concerned. So what about cancer, we assume it is preventable but is it (apart from smoking and sunlight)? Is there just so much endogenously generated DNA damage that we are really at the mercy of our genetics with no environmental components to modify for the majority of cancers? That’s hard to swallow, surely nutrition should modify cancer risk shouldn’t it? The most likely, or rather the more acceptable alternative is that this study is not really helpful either way. “Cancer” and “5 a day” – in between those inverted commas there are a whole host of biochemical processes and an even greater number of nutritional components.

What fruit, what veg?
Where from, how processed, cooked etc?
The subjects were aged between 25-70
Self-reported consumption data (which was just a single assessment of past 12 months using a food frequency questionnaire)
10 different countries from Europe, north to south
Etc.

Doesn’t make for precise results. An ambitious, extremely expensive study but it’s really a rather blunt tool.

This is such a big problem with nutrition, it’s so hard to design studies with precise hypotheses to be able to pin down what exactly is going on. The most important aspect of any experiment is to control for all the variables – even a simple lab experiment needs about 10 control results per single test result.

Nowadays it seems that then best you can say about nutrition research is that it’s “mostly harmless”. It had its heyday in the first half of the last century – hunting down deficiencies in vitamins and minerals. Pure biochemistry with powerful results. It was important research, one of my biochem lecturers would recount his stories about the research he did on trying to create vitamin E deficiencies in WW2 conscientious objectors – the things they were able to get away with (but they failed to induce vit E deficiency, never found out what it’s for).

Today it’s not so powerful, it’s about optimising nutrition rather than curing malnutrition. A child with rickets is a tragedy, a 65 yr old with colon cancer is a pity. In fact it seems that most nutrition research is justified by the devastating effects of chronic disease on the economy rather than on reducing suffering, especially because there is a certain amount of freewill in lifestyle choice.

Will genetics and –omics help? They will certainly help to improve precision, stratifying those 500,000+ 25-70yr olds into different genetic pots. Perhaps it will also be better to accept that DNA damage is a better endpoint, in many ways, than “cancer”.

There are many studies where the genetics have been crucial in sorting out the associations and here are a few:

Palli et al, carcinogenesis – DNA damage was reduced by high fruit and veg diet but ONLY when the 600 subjects were grouped according to GSTM1+ or GSTM1null genotypes

Lampe et al showed that the effect of cruciferous on GST activity was only seen in GSTM1nulls

Brennan et al in the Lancet reported that a protective effect of cruciferous veg on lung cancer was only seen when stratyfying according to GSTM1 and GSTT1 genotype. A meta-analysis showed more or less the same thing

Cornelis et al in JAMA – coffee consumption had no effect on heart attack risk in the study population until CYP1A2 genotype was accounted for (CYP1A2 metabolises caffeine)

Li et al, in cancer research - antioxidants had little effect on prostate cancer unless stratified according to SOD2 genotype.

And so on. Nutrigenomics will help by giving us tools to analyse & monitor better the biochemical pathways, to go beyond simple HDL and LDL measurements and to get away from using end points such as cancer, heart attack, stroke, etc.

Here is an optimistic quote – I hope it comes true (very last para of the article):

“What is certain is that nutritional genomics is coming fast. It will arrive piece by piece until it can be assembled into what will likely be the most powerful weapon in the arsenal of preventive medicine, a road map that can help us live longer and healthier lives”

Without genetics & nutrigenomics, epidemiological nutritional research will remain “mostly harmless”. Or to paraphrase a less amusing person maybe it’s like trying to govern the Italians - “not difficult, just a waste of time”

See also reports by American Institute for Cancer Research (AICR) and NHS Choices

Regulations, Clinical Utility & Personal Genetics

2010-03-17T16:39:00.001+01:00

Personal genetics is moving faster than ever, we began with a few variants in an affordable genetic test, now we have hundreds of thousands, soon it will be sequencing of all our genes (exome sequencing) and finally, the whole genome by 2011, 2012, 2013? Who’s prepared to predict?

What’s the use of it though – the technology is moving much more rapidly than the knowledge of the effects of genetic variation and we still only really have a few “clinically useful” applications? A problem that has not yet been fixed is the oversight of commercial services, the fact that there are not yet any new specific regulations to deal with personal genetics is probably just as well because by the time any law is passed it would be likely to be out of date. The lack of really effective clinical utility and the existence of commercial interests increases the confusion though. It’s hard to sell something that is interesting, “fun”(?), quite expensive, but not actually that useful to the majority right now. Hard to sell means sometimes over the top marketing. It’s also hard for the media to know what to do with it so we end up with confusion borne of ignorance. Many are getting worried that it’s being oversold, others worry about over-regulation. I think we have to be patient, it will become irresistibly useful sometime. The clinical applications will be clear as will the non-clinical uses. Maybe it’s like the early days of the motor car – useless (I can walk faster than that thing and when I need real transport I’ll use my horse – for transport read medicine and for horse read family history) and potentially dangerous but also interesting and “fun” (and expensive).

For now we have what we have, it’s not going away and we need to make the best of it. Since there has just been some twitter discussion about utility and since we wrote a review recently that’s about to be submitted I thought I’d post some maybe relevant excerpts here.

What to Regulate?
The types of services offered include health risk assessments, nutrigenetics, ancestry, parentage, pharmacogenetics and neonatal genotyping – the last category is particularly sensitive especially as services based on infant growth, IQ, dietary requirements etc are starting to appear. These offerings will develop whether or not the evidence exists to support the services (see for example My Child Talent Profile) and the presentations of these highly questionable services will become ever more sophisticated and convincing.

Regulations or strong guidelines are required for at least two purposes, both with the same aim of reducing the possibility of harm while trying not to be overly cautious and exclude possible benefits for the consumer. They are needed to protect the delivery and growth of serious beneficial personal genetics services, allow the existence of harmless even if not necessary beneficial services and to reduce the influence of questionable, potentially harmful services. Regulations serve to protect both the consumer from harm and the reputable service providers from disreputable competition, and they also need to protect from harm by not prohibiting potentially useful services.

There are several areas that are potentially subject to regulation:

1. Analytical validity – this covers the laboratory process and is a measure of the accuracy of the genotyping. It is relatively straightforward and each country has its own laboratory accreditation procedures which cover accuracy and reproducibility although they vary from one country to another.

2. Clinical validity – the genetic results are interpreted based on current knowledge. Clinical validity concerns the accuracy of the interpretation, i.e. the accuracy with which a test predicts a clinical outcome. For example a certain set of SNPs might be predicted to influence cholesterol levels under given dietary circumstances. Clinical validity is less clear cut but generally straightforward for many genetic risks and gene-environment interactions however there is not always wide agreement on when genetic association may be considered valid.

3. Clinical utility – the measure of the likelihood that the recommended therapy or intervention will lead to a beneficial outcome. Clinical utility tends to be assessed after the test is offered and the decision is usually made by the payer such as the government or private insurance. For personal genetic testing which is not yet reimbursed by either payer, the decision maker will be the end user (practitioner and/or patient/customer).

Utility is far from clear
Clinical utility is the most controversial aspect; it is often difficult to define and has to take into consideration many factors including positive or negative psychological or motivational effects on the end user. It is generally proposed that clinical utility can only be thoroughly established through randomised clinical trials (RCT) but these are challenging for the personal genetics environment which is rapidly evolving, often includes diet, lifestyle & behavioural changes and has small cumulative effects over decades (see Gulcher & Stefansson and Ransohoff & Khoury for an example of the current debate) and benefit may extend beyond purely clinical utility (Foster, et al). For example an Alzheimer's risk assessment would not seem to have much clinical utility at the moment but that does not mean it has no utility to the individual. A negative result can bring relief where there is a family history of the disease and a positive result can enable preparations for the increased possibility. There does seem to be demand for this sort of knowledge and there is no evidence that it is harmful, on the contrary (caveat: providing of course that there is full explanation of the consequences of the test before it is given) see Green et al and Vernarelli et al.

A further problem is what is the definition of a clinical benefit? A gene may not be associated directly with disease risk, such as myocardial infarction, but to intermediate phenotypes, e.g. lipid levels, hypertension, homocysteine, etc, which are independent risk factors for disease. Some commentators require that clinical utility is demonstrated as a reduction in disease incidence, the majority view though accepts that lowering of intermediate risk factors is acceptable (as is the case for phytosterols and their cholesterol lowering properties). However there are those who insist that clinical utility can only be proven through suitable randomised clinical trials (RCTS) even if that takes years (Ransohoff & Khoury).

It is also the most difficult category to regulate, if at all possible, and a common point of view is that the regulations should cover the analytical validity, the truth of the material used to disseminate information about the test (e.g. advertising & marketing) and the personal information itself at least in the short term.

Lifestyle vs. Medical

Adding to the difficulty of reaching clear regulations (or consensus) is the definition of a test – what is a “lifestyle” test and what is “medical”. A nutrigenetic test for example, is often described as a lifestyle test and the results are not used to give individuals a “risk assessment” for various diseases. However it is argued that you cannot talk about genes, health and lifestyle without there being a medical component and the fact that individuals are given genetic results for which disease risk information is easily available on the internet means that it should be classified as “medical”. The tests offered by 23andMe and DeCodeMe would appear to be clearly “medical” as they describe disease risk however both companies argue that they are providing information for education purposes only and not for the purposes of making health decisions. It is a very grey area but there is a good argument that any overtly medical risk assessment being sold DTC should at least require some sort of pre-market review. Note I am not referring to the actual gentoyping on which there should not be restrictions. It is the information itself, the interpretations, to which a pre-market review should apply. Who does the review is another thing entirely but if the industry took a lead from journal peer-review, while not perfect, it could be a good beginning.

In the meantime – follow the code…

A low GI (glycemic index) and high MUFA Mediterranean diet performed better (for HDL and glycemia) than traditional Med or ADA diet

2010-03-02T11:46:00.001+01:00

This post does not have much in the way of personal genetics but is not completely unrelated. If personal genetics is going to work then it will have to involve lifestyle changes especially diet, not just for weight loss but for health. As far as obesity is concerned there have been plenty of GWAS and many genes associated, hopefully the results will be be useful for understanding mechanisms because a gene panel for predicting obesity does not seem to be terribly useful right now, it’s one of the phenotypic traits that most people are aware of without any genetic testing. One much sought after goal though is to use genetics to predict what sort of weight loss diet will be most effective – there are some tantalising studies and there is one company, Interleukin Genetics, that recently introduced a weight loss panel. They claim to be able to select the best diet but until they actually publish their work that they refer to we cannot judge. For now the only weight loss use of nutrigenetics that has been published is a small study from our group (open access in Nutrition Journal) – here the genetics was used to “optimise” the diet rather than actually choose which type. Maybe this is where nutrigenetics can help, as a sort of “meta-diet”, whatever you are trying to do to lose weight, you are probably eating fewer calories so it’s important that those calories contain all the nutrients that you need.

Anyway, back to the subject of this post – an interesting paper comparing 3 types of diet: a traditional Mediterranean diet (MED), what they call low carb med diet (LCM) which I think is better described as a low GI/high MUFA diet, and the ADA diet (American Dietetic Association). The study involved 259 patients over 12 months

The diets:

	Carbs	Fats	Protein	Fibre
ADA	50-55 %	30 %	20 %	15 g
MED	50-55 % (Low GI)	30 % (high level MUFA)	15-20 %	30 g
LCM	35 % (Low GI)	45 % (high level MUFA)	15-20 %	30 g

The best results for weight loss we with the LCM:
LCM = 10.1 kg
MED = 7.4 kg
ADA = 7.7 kg

Reduction of HbA1C (a measure of glucose control) was greater in LCM:
LCM = - 2,0 %
MED = -1.8 %
ADA = -1.6 %

Serum TG reduction:
LCM = -1.52 mmol/l
TM = -1.46
ADA = -0.88

Finally HDL was raised only on the LCM diet (from 1.08 to 1.21 mmol/l)

In general the Mediterranean diet results were better and in particular the med diet with low GI and high MUFA was the best – it’s important to note the levels of MUFA, it’s not simply a “low-carb” Med diet, but the carbs were replaced mainly with one type of fat, MUFA (as in olive oil) and probably a better term (less catchy of course) would be the High MUFA Mediterranean diet:

	MUFA	PUFA	Grassi saturi
ADA	10 % di grassi	12 % di grassi	7 %
MED	10 % di grassi	12% di grassi	7 %
LCM	23 % di grassi	15 % di grassi	7 %

Diabetes Obes Metab. 2010 Mar;12(3):204-9
A low carbohydrate Mediterranean diet improves cardiovascular risk factors and diabetes control among overweight patients with type 2 diabetes mellitus. A one-year prospective randomized intervention study
A. Elhayany ^1,2 , A. Lustman ^2,3 , R. Abel ² , J. Attal-Singer ^4,5 , S. Vinker ^2,3
¹ Meir Hospital, Kfar Saba, Israel 44821 ² Department of Family Medicine, Central District Clalit Health Services, Rishon Le Zion, Israel ³ Department of Family Medicine, Tel Aviv University, Tel Aviv, Israel ⁴⁵ The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Endocrinology Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva Israel

KEYWORDS Diabetes mellitus • cardiovascular risk • Mediterranean diet • dietary intervention

ABSTRACT

Background: The appropriate dietary intervention for overweight persons with type 2 diabetes mellitus (DM2) is unclear. Trials comparing the effectiveness of diets are frequently limited by short follow-up times and high dropout rates.

Aim: We compared the effects of a low carbohydrate Mediterranean (LCM), a traditional Mediterranean (TM), and the 2003 American Diabetic Association (ADA) diet, on health parameters during a twelve-month period.

Methods: In this twelve-month trial, we randomly assigned 259 overweight diabetic patients (mean age 55 years, mean body mass index 31.4 kg/m²) to one of the three diets. The primary end-points were reduction of fasting plasma glucose, HbA1c, and triglyceride levels.

Results: 194/259 patients (74.9%) completed follow-up. After 12 months, the mean weight loss for all patients was 8.3kg: 7.7 kg for ADA, 7.4 kg for TM and 10.1 kg for LCM diets. The reduction in HbA1c was significantly greater in the LCM than in the ADA diet (-2.0%, and -1.6%, respectively p<0.022). HDL cholesterol increased (0.1 mmol/l±0.02) only on the LCM (p<0.002). The reduction in serum triglyceride was greater in the LCM (-1.3 mmol/l) and TM (-1.5 mmol/l) than in the ADA (-0.7 mmol/l), p = 0.001.

Conclusions: An intensive 12-month dietary intervention, in a community-based setting was effective in improving most modifiable cardiovascular risk factors in all the dietary groups. Only the LCM improved HDL levels and was superior to both the ADA and TM in improving glycemic control.

Celiac disease – Genetic testing and clinical utility

2010-02-25T11:17:00.001+01:00

Celiac disease is a digestive disease that damages the small intestine and interferes with absorption of nutrients from food. People who have celiac disease cannot tolerate gluten, a protein in wheat, rye, and barley. Gluten is found mainly in foods but may also be found in everyday products such as medicines, vitamins, and lip balms. When people with celiac disease eat foods or use products containing gluten, their immune system responds by damaging or destroying villi—the tiny, fingerlike protrusions lining the small intestine. Villi normally allow nutrients from food to be absorbed through the walls of the small intestine into the bloodstream. Without healthy villi, a person becomes malnourished, no matter how much food one eats. Celiac disease is both a disease of malabsorption—meaning nutrients are not absorbed properly—and an abnormal immune reaction to gluten. Celiac disease is also known as celiac sprue, nontropical sprue, and gluten-sensitive enteropathy. Celiac disease is genetic, meaning it runs in families. Sometimes the disease is triggered—or becomes active for the first time—after surgery, pregnancy, childbirth, viral infection, or severe emotional stress (NIDDK).

CD is caused by a reaction to gliadin, a prolamin (gluten protein) found in wheat, and similar proteins found in the crops of the tribe Triticeae (which includes other cultivars such as barley and rye). Upon exposure to gliadin, and certain other prolamins, the enzyme tissue transglutaminase modifies the protein, and the immune system cross-reacts with the small-bowel tissue, causing an inflammatory reaction. That leads to a truncating of the villi lining the small intestine (called villous atrophy). This interferes with the absorption of nutrients, because the intestinal villi are responsible for absorption. The only known effective treatment is a lifelong gluten-free diet.

From a genetic testing point of view CD is an interesting case, the majority (>97%) of people with CD have either HLA DQ2, DQ8 or both and the number of alleles also influences the risk of developing the disease. Having said that, roughly 30% of the population carry one or more of these alleles but the prevalence of CD is only around 1-2%, so the HLA alleles are necessary, but not sufficient, for the development of celiac disease. They are not particularly predictive either (although homozygous DQ2 and DQ2/DQ8 have a much higher risk, of the order of 1/7-1/10 – Megiorni et al, 2009) so is there any use in testing for these alleles in asymptomatic individuals? The interesting thing is that a genetic test based on HLA alleles has an almost perfect negative predictive value, if the HLA alleles are not there then the chances of developing, or of any symptoms being due to, CD are minimal, move on to the next candidate for the diagnosis. There are also arguments in favour of testing based on some interesting facts about CD:

1. The majority of people with CD don’t even know that they have it, only about 10-20% of cases have been diagnosed, the rest remain undiagnosed for a variety of reasons, mainly because symptoms are not yet so severe that they lead to diagnostic testing. The diagnosis itself is not so easy either, the full diagnosis requires a biopsy of the intestine and histological examination of the villi to establish that they are damaged (JAMA commentary).

2. The biopsy is the final diagnosis if the individual tests positive for anti-TG (transglutaminase) and/or anti-endomysium antibodies. In most countries (at least in Europe) the biopsy is required to be positive before there is any reimbursement of gluten free foods, which are quite expensive. This is not really a good situation, often it is the case that gluten sensitivity is suspected and the sources are eliminated leading to some recovery – at this point, if the patient wants reimbursement he/she has to become ill again, and not trivially since it involves actual physical damage to the small intestine.

3. CD is on the increase, in the USA levels are 4 fold higher than 50 years ago, and this is not because of better diagnosis as the samples were compared to actual stored blood samples, the data reflect a true increase in the prevalence of the disease (Rubio-Tapia, et. Al, 2009)

4. Approx 50% of people with type 1 diabetes showed some immunological reaction to gluten and other wheat proteins and about 10% are actually diagnosed as CD (Mojibian, 2009)

5. CD sufferers have higher mortality, as described in a recent study of >40,000 individuals (Ludvigsson, 2009), but the surprising finding was that even higher mortality was seen in the antibody positive but biopsy negative groups:

	HR for increased mortality
Celiac disease	1.39
Inflammation (no villous atrophy)	1.72
Latent Celiac (antibodies but normal mucosa)	1.35

In Sweden only those with celiac disease are treated with a gluten free diet while very few with inflammation or latent disease are. The hypothesis is that the continued consumption has health risks. Note that the study looked at mortality rates but of course this is a marker for overall poorer long term health and increased incidence of chronic disease. Many European countries will only reimburse gluten free foods for those with full celiac disease – these data make the diagnostic situation even less acceptable.

6. CD may be preventable? There is evidence that infant feeding can affect onset of CD. Interesting data from the Swedish epidemic when CD levels went up 3-4-fold during 1984-1996 whereas there was no change in neighbouring countries. The rise in CD coincided with a change in the instructions given to mothers (for which compliance is >90% in Sweden), leading to abrupt gluten introduction and cessation of breast feeding. In 1996 the instructions were changed to encourage longer breast feeding and to introduce gluten gradually between months 4-6 and while still breast feeding – the CD rate dropped 4-fold in the ensuing years (Olsson, 2008; Myléus, 2009).

7. A study by Norris et al showed that feeding between 4-6 months was linked to the lowest risk of developing CD (Norris 2005).

The combined evidence lead to the ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Agostoni et al 2008) to issue a statement advising avoidance of early (<4 months) and late (>6 months) introduction of gluten, and to do so gradually while still breast feeding. Although the evidence is not from clinical trials, babies have to be fed and a choice needs to be made, in the circumstances the evidence points to this being the best advice (there are some clinical trials in progress or recruiting but they seem to be comparing introduction at 6 months and 12 months, except for 1 Finnish trial which does not specify - clinicaltrials.gov). As always, clinical trials and nutrition is a difficult subject – given the evidence would you want your child to be in the late introduction arm?

Arguments for genetic testing: In newborns it would be helpful to identify the genetically predisposed so that the correct feeding advice can be given (it’s not just celiac disease but other autoimmune diseases as well, with shared HLA alleles). Why test though, why not give the same advice to all? The feeding program needs to be carefully followed and not all populations are as compliant as the Swedish (certainly not the Italians!) so it makes sense to target just the at risk groups, and if we don’t start somewhere we’ll never get to personalised medicine!

Are some people squeamish about the idea of genetically testing newborns for disease risk? It shouldn’t be the case here, there is a clear prevention advantage and in any case, if it were proposed to serologically HLA type them then I bet there would not be protests – it’s genetic exceptionalism…

For older children and adults – at least it can be useful in relatives of CD patients, excluding those who are not predisposed and identifying those who should be screened for auto-antibodies and then the biopsy if necessary. As a general screen? Maybe not an economical test yet for the state or insurers to pay for but it could be encouraged, the statistic that only 10-20% of CD sufferers are diagnosed is highly significant. If the true numbers were correctly diagnosed, and also if the bar was lowered to include antibody positives then all of a sudden there would be 10-20 fold more gluten sensitive individuals and this would have a positive effect on the gluten free food market, prices would drop, choice would increase and the lot of the CD suffer would improve. After all it’s not really necessary for it to be a disease, “just” avoid the gluten. Unfortunately it’s not so easy to do so, gluten is everywhere, and it’s use has increased enormously over the last few decades. It’s used as an ingredient in most processed food, to give texture - I am based in Italy, in a salumeria recently I was choosing some prosciutto, there were two types (actually being Italy there were probably about 20 types, just using licence here) and I asked the difference: one was free of phosphates while the other was also free of lactose and gluten – what the hell was gluten doing in ham in the first place, in Italy of all places?!

Some testing options:

Prometheus have a fairly expensive test at $329
Genelex at even more - $445
Decode and 23andme do not have SNPs that comprehensively type the HLA alleles but do have some other slight risk alleles discovered by GWAS. Not sure about Navigenics and Pathway as I couldn’t find the SNPs on their sites.

A promising recent development was published in PLOS One (Monsuur et al, 2009) where they describe 6 tagging SNPs that comprehensively genotype the relevant HLA alleles – any test based on these SNPs would be a lot cheaper than the PCR based methods used by Prometheus – e.g. 23andme could add them to their scan (as long as there are no exorbitant licence fees since the authors have applied for a patent on the findings … that’s another story for another day…)

What’s wrong with GWAS?

2010-02-18T18:54:00.001+01:00

A paper was published in JAMA a few days ago (Paynter et al, Association Between a Literature-Based Genetic Risk Score and Cardiovascular Events in Women) showing that a genetic score based on 101 CVD related SNPs was not effective as a screening tool. So what happened to the promise of GWAS? One or two SNPs are not enough but we were told that when we get to panels of 30, 40 or more then we would see something real and useful, apparently we are not, so is it over? Is the fate for GWAS that of the candidate gene studies where initial positives were generally shown to be chance?

Maybe not. But maybe this study is proving, just like with candidate gene studies, that it is naïve to think that “blind” association studies of genes with complex diseases will provide useful results – these are diseases where the causes are many-fold involving genetics, behaviour and environment, but where in general just the disease end-point and the genetics are actually measured.

The Paynter paper used a collection of SNPs chosen from the NHGRI database that had an association with either:

“…cardiovascular disease (myocardial infarction [MI], stroke, coronary disease, and/or cardiovascular death) or an intermediate phenotype (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, diabetes, hemoglobin A1c or fasting blood glucose, and high-sensitivity C-reactive protein)…”

Wow, that’s quite a heterogeneous mixture of associations and maybe is one of the problems. They calculated the genetic score and compared it to the endpoint: “incident MI, ischemic stroke, coronary revascularization, and cardiovascular deaths, which were combined to calculate total cardiovascular disease.”

Again, a lot of heterogeneity – are we asking too much? CVD is not just one disease with one cause, it’s a constellation of diseases involving some or all of inflammation, dislipidemia, hypertension, etc. If we took it to the next extreme we could say why not add all of the type 2 diabetes related SNPs and then see if we have a genetic predictor of the disease “cardiovascular diabetes” – and what would that cover, about 60-70% of the population at risk?

So a likely problem is in the initial GWAS studies that use not very precise endpoints to discover “blind” (as in hypothesis free) associations and yield a very imprecise and apparently useless screening tool. Another “problem” is that most of the SNPs are related to intermediate phenotypes (lipid levels, hypertension, inflammation etc) and so of course the genetic score is not going to measure a risk that is “over and above” the contribution of traditional risk factors and family history. The CTFR mutation in cystic fibrosis will not contribute much “over and above” the sweat test as a predictor of the disease – this doesn’t mean that genetics have no value - no help (yet) for CTFR of course but obvious that it would be nice to have a predictor that didn’t actually depend on having raised risk levels).

But apart from the poorly focussed heterogeneous endpoints, and therefore associations, from GWAS, one major missing feature of almost all studies is the effect of environment/behaviour on the associations, generally this means assessing diet and lifestyle, which is very difficult. But is this where some of the “missing” heritablity lies? When you are looking at a disease which affects 40% percent of the population it means that a lot more than 40% will be “genetically” predisposed but did not get the disease because of a healthier lifestyle. This makes finding a control group for the initial GWAS rather tricky – are the healthy controls healthy because they don’t have the risk alleles or because they have different lifestyles/environment? Almost certainly a mixture of both, but one is usually ignored resulting in dampened down low ORs and probably some missed associations.

The other possibility is one which is becoming more fashionable right now – the many rare variants proposal. It’s attractive from a certain point of view – nice to get the multimillion $ grants to buy the latest sequencing technology and play away – but it is still hard to imagine getting the right answer without environment/behaviour assessment. Smoking is always assessed in cancer studies, it’s much easier to do so and no-one would think of looking for cancers genes without the smoking assessment, so why is it OK with CVD and diabetes?

Of the much maligned candidate gene studies those that have held up have been those where the gene-environment interaction was assessed. A good example is SOD2 rs4880 SNP and breast/prostate cancer. An early publication linked the Ala allele to breast cancer but subsequent publications were contradictory (table 1), however ALL studies which looked at gene + disease + diet gave the same results – Ala allele was linked to increased risk when antioxidant intake was low (table 2).

Table 1. SOD2 Ala-Val allele association with cancer

Ovarian cancer	Ala	Olsen, 2004
Lung cancer	Val	Liu 2004
Lung cancer	Val	Liu 2004
Bladder	Neither	Terry 2005
Breast & prostate	Ala	Taufer, 2005
Breast	Neither	Cebrian, 2006
Breast	Neither	Oestergaard, 2006
Lymphoma	Ala	Lightfoot, 2006
Breast	Neither	Justenhoven, 2008
Brain	Ala	Rajaraman, 2008
Breast meta-anal	Neither	Bag, 2008*

* However, a proper evaluation of this polymorphism with cancer link demands experiments involving large sample size, cross-tabulation of gene-gene, gene-environment interactions (author comment)

Table 2. SOD2 Ala-Val: Gene x Environment association with cancer

Breast	Ala	Ambrosone, 1999
Breast	Ala	Cai, 2004
Prostate	Ala	Li, 2007
Prostate	Ala	Kang, 2007
Prostate	Ala	Mikhak, 2008
Prostate	Ala	Cooper, 2008

So we see with a diabetes panel in a recent publication (Qi et. al., 2009, Genetic predisposition, Western dietary pattern, and the risk of type 2 diabetes in men) – they used a panel of GWAS SNPs and assessed the impact of diet on the risk score – the high risk score together with poor diet lead to much higher risk ratios:

We’re getting quite impatient – at Eurogene we would like to start using effective panels. The commercial offerings are interesting but not really that useful in the clinic, at least for our needs. We are looking forward to GWAS studies with precise goals (narrowly defined end points) which take into consideration lifestyle/environment and will lead to useful tools because of course by establishing the gene-environment interactions it is much easier to understand what are the risk-lowering interventions – much more useful than just to be told you have a higher risk of heart disease or diabetes. These studies WILL lead to genetic predictive tools that will be useful in clinical decision making, especially for prevention. I’m confident they will be coming along also because I know that one of the groups actively researching this area is that of Jose Ordovas and Larry Parnell from Tufts – a group that has discovered (and continues to discover/confirm) many gene-environment associations in candidate genes which have stood the test of time. They are already starting to publish and I’m sure many more will be coming (no pressure then Larry!) – keep up with the news on twitter and via Larry’s blog (@larry_parnell and “Variable Genome”)

Personal Genetics - Code of Practice

2010-02-11T18:38:00.000+01:00

This blog is about personal genetics and disease prevention - the EUROGENE eTEN project was set up and funded by the EU to establish the infrastructure to deliver personal genetics services via practitioner or direct to consumer.

The aim of the blog will be to report on progress of the project and comment on relevant research / developments in related areas. One of the tasks of the project was a review of the European regulatory framework - this has been completed and will be summarised in a later blog (the full review has also been submitted for publication.

The main finding is the absence of formal regulations in place now and the probability that this unclear situation will not change for some time. Meanwhile personal genetics services roar ahead, with prices falling and genome coverage increasing. Our opinion is that we should follow and promote the Industry Code of Practice proposed by the UK Human Genetics Commission (HGC). This code was developed by academics, regulators, industry members and medical stakeholders to cover all aspects including testing, marketing, customer support, quality of information. In the absence of formal regulation we welcome the code and feel very strongly that the customer (both the practitioner and the end-user) should be fully informed about all aspects of the genetic testing services and all information should be easily available online. The first thing that any potential user of a genetic test, is full disclosure and transparency and we also feel that all companies should protect both the industry and consumers by following the HGC guidelines

“Common Framework of Principles for direct-to-consumer genetic testing services”

• Claims must be accurate (promotional and technical), evidence transparent

• Genetic variants tested must have been clinically validated

• Risk assessments must use accepted methods and be transparent

• Clarity on privacy and use of customer’s DNA

• Full and clear information for the customer to understand the test including accuracy and limitations

• Recommendations to purchase follow-on products (e.g. supplements) must be fully and transparently supported by scientific evidence

• For some tests professional genetic and medical help should be available if needed

• Tests should not be supplied DTC to adults unable to provide informed consent