So Good that You Have to Break the Law!

I was asked today by a reporter if I ever gave the thought to the argument that the DTC tests were so groundbreaking, so very vital a technology that the LAWS HAD TO BE BROKEN.

For the betterment of society, these DTC companies HAD to break the law. It was their Moral imperative.

Really? Hmmm......let me see.

Francis is glad these companies are out there raising awareness about genetics. I don't share his thoughts.

1) These companies put their genetic data out as fact. Not exactly raising awareness in the right way.

23andME does rate articles, but that being said, it isn't exactly and independent evaluation. Navigenics gives you rates or likelihoods, which people often don't get. I say the awareness is often hype and confusion, not a true understanding. The recent Cogent study presented at SACGHS bears this out. Great! These companies painted a flawed and confusing picture for the public.

Shouldn't NIH/NHGRI/HHS and leading academic centers be doing the education of the public?

2) These companies broke the law for the betterment of society?

Ok, I ask how is society better from this testing. We now agree as a scientific community that SNPs aren't everything. They may in fact only be a little of the picture. With the recent studies showing family history and blood pressure as better predictors of MI instead of a VERY SCIENTIFICALLY VALID SNP. So I ask, how are we better because of these company breaking the law? We aren't. New York Agrees with me I am certain other states will as well

Sufferage? Yes, Change The Law! Jim Crowe? Yes, break the Law.

DTC testing of patients? Not so clear that it is a moral imperative to make a few quick bucks........on a clinically unvalidated tool.

3) Current research methods are flawed and thus 23andME breaks the mold.

Again, is this needed? Is it ok to violate current international agreements on research in the name of moral imperative? NO. Social networking research over the internet, I think Coriell is doing this. I am certain Academic Centers with IRBs can do this as well. If research partners have IRBs that is good. But if research is done on these companies own, they need an IRB. How is it ok to break these agreements and standards of research?

It is NOT OK.

The Sherpa Says: This bull$h!t argument that these guys are breaking the law as a moral imperative makes me double over and laugh. Is society that foolish to believe this? I for one am not.

Translated yet???

I am posting in response to Drew at ThinkGene. He says no one will follow mandates unless they have the history to understand those rules. To lay some background for why medical researchers have policies, rather than gunsling it out I will give some background. From HHS.....

The modern story of human subjects protections begins with the Nuremberg Code, developed for the Nuremberg Military Tribunal as standards by which to judge the human experimentation conducted by the Nazis. The Code captures many of what are now taken to be the basic principles governing the ethical conduct of research involving human subjects.

In case you may have not learned in school or just forgot this lovely wikipedia article will refresh your memory. So will this list:

1 Experiments
1.1 Experiments on twins
1.2 Freezing experiments
1.3 Malaria experiments
1.4 Mustard gas experiments
1.5 Sulfonamide experiments
1.6 Sea water experiments
1.7 Sterilization experiments
1.8 Experiments with poison
1.9 Incendiary bomb experiments
1.10 High altitude experiments

The first provision of the Code states that "the voluntary consent of the human subject is absolutely essential."

Freely given consent to participation in research is thus the cornerstone of ethical experimentation involving human subjects.

The Code goes on to provide the details implied by such a requirement: capacity to consent, freedom from coercion, and comprehension of the risks and benefits involved. Other provisions require the minimization of risk and harm, a favorable risk/benefit ratio, qualified investigators using appropriate research designs, and freedom for the subject to withdraw at any time.

Now 23andMe is not exposing patients to mustard gas or mutilating genitals....But the principles exist not just for unethical research, but for ethical research too!.

From Wired Magazine, a quote from Anne Wojcicki regarding her Gene Journal and risk calculator"A lot of this is unknown. It's totally experimental," Wojcicki told me a few weeks before the science board meeting. "No one has looked at all eight diabetes markers together. They've all been identified individually, but they don't know exactly how they work together. So we've tried to make that clear."To crunch these numbers and determine one person's risk factor, 23andMe has opted to multiply the risks together. But a competing school of thought argues for adding the risk from SNP to SNP. The two approaches can result in wildly different tallies.

Welcome to the first Google driven experiment in genetics, paid for by the customers......Unfortunately that poor author from the NYT demonstrated her clear lack of that understanding. And she is a learned journalist, what's to happen to the layperson who has never had any education in genetics/science?

IRBs were formed to protect research subjects. Why could Dr George Church only get a select few for his first personal genome project? The IRB deemed laypeople unable to give informed consent. How did 23andMe end around the IRB?

23andME "Genetics By Business"
The Mission? Mission Statement23andMe's mission is to be the world's trusted source of personal genetic information

I want to over IRBs history a little more. Because, Trust is a very important word.

In July of 1974, the passage of the National Research Act established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Commission met from 1974 to 1978. In keeping with its charge, the Commission issued reports and recommendations identifying the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and recommending guidelines to ensure that research is conducted in accordance with those principles.

The Commission's report setting forth the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects is titled The Belmont Report

The Report, named after the Belmont Conference Center at the Smithsonian Institution where the discussions which resulted in its formulation were begun, sets forth the basic ethical principles underlying the acceptable conduct of research involving human subjects. Those principles, respect for persons, beneficence, and justice, are now accepted as the three quintessential requirements for the ethical conduct of research involving human subjects.

While recognizing that the distinction between research and therapy is often blurred, practice is described as "interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment, or therapy to particular individuals."

The Commission distinguishes research as designat[ing] an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective.

"The Report recognizes that "experimental" procedures do not necessarily constitute research, and that research and practice may occur simultaneously. It suggests that the safety and effectiveness of such "experimental" procedures should be investigated early, and

that institutional oversight mechanisms, such as medical practice committees (exist).

So this is why I have a trust issue. Drew points this out at ThinkGene today.

If the Fox is watching the Henhouse.......how can we have significant trust? Just like the senators getting campaign donations by Freddie and Fannie.....this reeks!

The Sherpa Says: Since 23andME is not practicing genomic medicine, it must be researching genomic medicine. So according to the Belmot Report and Nuremberg code, their "subjects" should be able to withdraw from research and have the benefit of an IRB. As for sample removal......it should be justified which tests will be run and patients have the opportunity to refuse or be reconsented.....That's how you win my trust....

LRRK2, NYT, Trust and Sergey!

What I find interesting is how a SNP finding and a blogger can set the press a fire.....especially when the blogger is a junior member of the billionaire's club.


In this case I am speaking of course about Sergey Brin who recently published a blog post on his risk for Parkinson Disease. It helps understand why his wife launched 23andWe......

This research would have great potential if the Company 23andMe would obey the "rules and ethics" of common human research by allowing patients to remove their samples from 23andMe's database if tehy so chose.....and more importantly, consenting a patient when the sample (which 23andMe would now own) would be tested for other things...

23andMe's mission is to be the world's trusted source of personal genetic information

They have a long way to go........

That being said....I think we should talk about LRRK2 and what it means for Sergey and others who carry it. From Sergey

It is clear that I have a markedly higher chance of developing Parkinson's in my lifetime than the average person. In fact, it is somewhere between 20 percent to 80 percent, depending on the study and how you measure," Brin said.

That is 20 percent to 80 percent higher than the average risk......Not 80 percent likelihood to develop Parkinson Disease. That 80% risk is the case for BRCA carriers in breast cancer, but not this LRRK2! This was a statement on his post which some people may get confused by...so don't.

The New York Times reporter did

Mr. Brin, who made the announcement on a blog, says he does not have the disease and that the exact implications of the discovery are not clear. Studies show that his likelihood of contracting Parkinson’s disease in his lifetime may be 20 percent to 80 percent, Mr. Brin said.

Parkinson Disease affects approximately 1% of the population by age 65% and 4 to 5% by age 85 years. Therefore the lifetime risk is 2-5%. So a 1.2 to 2.1 Odds ratio would be 4% to 10% roughly. Not 80%!

There are several genes that have been linked to PD, including alpha synuclein, PARKN, PINK1, DJ1 which have all been linked to familial PD. LRRK2 is a realtive newcomer to the field with good publications starting in 2005. For reference the first BRCA publications were in 1994. It took us 10 years to really be able to fully understand and explain what the risks are. We still have problems with this though.

There are several misconceptions about BRCA as there are for LRRK2....worse yet, counseling for LRRK2 can be confusing. Which is why perhaps

Because there are only a small number of genes which are known to have a very substantial effect on health (e.g. 10 times the average risk)
I felt the possibility of discovering something very important to my health was just a hypothetical exercise. So, when my wife asked me to look up G2019S in my raw data (23andMe scientists had had the forethought to include it on their chip), I viewed it mostly as entertainment.....

LRRK2 is not one those genes that increases your risk by tenfold...

LRRK2 mutation accounts for 5 to 6% of familial PD and 1-2% of sporadic PD. Not exactly what I would call useful for a screening test. Mind you this is given for North Americans and Europeans.

These numbers however do change for a few ethnicities including North African Arabs, Ashkenzi Jews where it goes up to 29-37% of familial cases and 7-14% in sporadic....some studies say as high as 41% in sporadics, but the high sporadic data is not replicated.

What is familial PD? Well, at least one first degree relative must carry a diagnosis of PD.

I am not certain of Sergey's Ancestry.....perhaps he is African Arab or Ashkenazi Jewish? That might put his likelihood of having a mutation in LRRK2 higher.....

Interestingly in the largest study of Ashkenaim with PD to date the odds ratio to develop PD was 5.77 which is very high and fairly significant. Unfortunately, these data ONLY apply to Ashkenazi Jews from Israel as this was the population studied.

So don't go thinking it is that high for everyone. In this study, the Odds Ratio for developing PD in Ashkenazi patients with the LRRK2 G2019S mutation was 5.7 (CI 2.8 to 11.7). It is increases when you match age and sex to 8.6. Which has us thinking perhaps this is a sex effect? Not that sex, you perv!

What is the percent of unaffected carriers in the general population of Ashkenazi? 2.2%

That is a scary stat for my Jewish friends. That means this mutation is not nearly as common in the unaffected Ashkenazi Jewish population. This should be only interpreted for this Ethnicity! Not for Europeans or for Americans who do not have Ashkenazi ancestry!!

It was crazy that none of the other mutations in LRRK2 were detected in this Ashkenazi cohort. That certainly speaks for a founder effect!! Similar to the founder mutations in BRCA1/2

In dissecting out thet data a little more we see that the G2019S was found more commonly in Women and in Familial Cases for the Ashkenazi population.

So, I hope that helps. These data and perhaps the numbers Sergey quoted were likely those for Ashkenazi Jews. So if you are Tom Smith from Nebraska, chances are that the LRRK2 data you now could afford to get are not so dire. And even if you are Jewish, the penetrance of this mutation is 24 to 85%

Sergey's post was great and highlights a special issue. Ethnicity and its role in disease. We cannot apply one ethnic groups data to another. A study done on the Chinese does not apply to Northern Europeans. This is why SNP data can mislead and scare.

Here's the big question, when you found out you might get Parkinson Disease Sergey, were you alone? Would have liked to have someone there? Would you have liked to talk with a geneticist? Or was it like Joanna Mountain said to a friend of mine "Aww, Come on, this testing is just for fun"

The Sherpa Says:

At Helix Health of Connecticut, patients are seen that have family history of Parkinson Disease. I believe that all asymptomatic testing of this nature can be confusing and requires appropriately trained consultation....plain and simple. What if Sergey didn't have billions to through at this disease in hopes of a cure and to give him hope? He might be hopeless. In that case he might have even contemplated suicide......in the privacy of his own CPU......

14 years and still no good genes!

I am preparing a talk for the Connecticut Geriatric Society and I am just can't get over it. We haven't found good genes for Late Onset Alzheimer's Disease since 1994. Sure we have SORL1, GALP and MAPT from the sexy Genome Wide Studies....but nothing increases risk like APOE Epsilon4.

In fact when you look at all the other genetic risks, NONE top an Odds Ratio of 1.5. Why do a I always harp on Odds Ratios? It's simple. If you can't beat the family history risk increase (300-500%) for a first generation relative, then you can't have much clinical significance, unless you have a multiple gene panel that does.

Why is clinical utility so important? Why not just test everyone with everything. I see several problems with this.

1. False Reassurances, patients are led to believe they won't get some devastating disease and thus fail to plan appropriately. And in some cases take preventative measure...This is called Harm to Patient and it is malpractice.

2. Inappropriate Action, there are several modifiable risk factors in many diseases. This often is argued as the reason FOR testing everyone. But this only assumes that modifying behaviors are actually good things. But, did you know some things like vitamins can actually be bad and promote things like cancers? So you mega dose on Folate and end up promoting breast or colon cancer because you found out that you "Process Folate poorly" on a Nutrigenomics test. And that is just Folate, what about preventative medications? Even more dangerous!

3. Exposure to Discrimination, as I stated in previous posts GINA has passed, but will not go into effect until 2009. In addition, GINA does not cover disability, life, or long term care insurance. Nor does it cover any form of discrimination outside of workplace or health insurance. Medical records can be subpoenaed. However, in most states it is illegal to ask for health records without good cause. Unlike corporate information, which can be bought and sold without YOUR permission! This includes identifying factors Ladies and Gentleman!!! This is why this testing should be done in the realm of healthcare protection.

These are merely 3 of the many reasons I see that we should not be applying SNP scans to everyone. There has to be some clinical significance for actions. If you want consumer enabled research, then you have to protect the consumer. Just as if they were a subject under the protections of an Institutional Review Board.

The Sherpa Says: I could go on a diatribe about this forever. But I have a talk to prepare. Imagine this 80% heritability and only 1 gene for Late Onset Alzhemiers....we must not be looking in the right place.