Sunday, November 28, 2010

Personal Genetics & Utility: Round 2 – Mind the EGAPP

ResearchBlogging.org
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

Thursday, November 11, 2010

Personal Genetics has a Family History of getting beaten up

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 thatused 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.

Thursday, November 4, 2010

Nutrigenetics–a little bit of history, but no miracles

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.