Thursday, May 27, 2010

Personal genetics: DTC or DTMD?

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:

Capture

 

And from 23andme:

image

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.

Tuesday, May 11, 2010

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

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. 1. Sat fats are OK after all
  2. 2. Recently we were informed that the “5 a day” advice did not prevent cancer (see previous post)
  3. 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. 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. 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. 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:

image

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:

 

imageProstate 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