On 2014 Feb 20, David Keller commented:

If the patient requested a consultation with a genetic counselor, I would refer him to one. If he requested me to explain his results to him, I would do so based on my study of his genetic profile. As a 23andMe customer, I found their reports to be well-written and easy to interpret, and I would have no problem explaining the results of such a report. I rely on the FDA to ensure the accuracy of the raw test data, and the accuracy of its association with increased or decreased probability of disease. Beyond that, I favor maximizing the degree of control and autonomy patients can exert over their own health care, within reason. This philosophy demands that competent adults behave responsibly. Companies which supply tests to consumers should not be held responsible when individuals misuse their test results or violate an agreement to discuss their results with their physician before acting on them. If we demand that the government protect us from our own failure to act responsibly, then all direct-to-consumer testing companies will be regulated out of existence, and we will be left with fewer choices.

On 2014 Feb 19, John French commented:

In regard to the FDA's closure of a personal genomic service, I take the main issues of concern to the writer, an internist, is the accuracy of 23andMe's reported conclusion based upon the statistical association of the variant in question for PD. There is very little information on both type 1 and type 2 error rates on test accuracy which calls into question the reported statistical association. PD and most other diseases are polygenic with tens if not hundreds of variants genome contributing to varying levels of cumulative risk along with other contributing intrinsic and extrinsic factors. A main concern of the FDA was in regard to the lack of published validation studies for the methodologies used by this and other personal genomic services. Your response to a hypothetical patient seems appropriate. If they did not include such advice in their report to you, 23andMe should have offered similar caveats. Without sufficient characterization of significant intrinsic and extrinsic factors for the individuals in the candidate gene or genome wide association studies, the data cannot be weighted and is inconclusive. Where are the genetic counselors? Would you refer your patient to a genetic counselor?

Yandell et al. A probabilistic disease-gene finder for personal genomes. Genome Res.21(9): 1529–1542, 2011. doi: 10.1101/gr.123158.111 Elizabeth T. Cirulli & David B. Goldstein. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nature Reviews Genetics 11, 415–30, 2010) doi:10.1038/nrg2779

On 2014 Feb 17, David Keller commented:

Why I Care About the FDA's Closure of 23andMe's Personal Genomic Service

I am an internist and a 23andMe customer. I paid $25 for their genetic test kit several years ago as part of their campaign to identify a cohort of Parkinson disease (PD) patients carrying the LRRK-2 gene. In return, I received an extensive genetic report, as part of which I learned that LRRK-2 is not the cause of my PD. I therefore was not included in the LRRK-2 research cohort, but its findings may very well help the vast majority of PD patients who do not carry that mutation. I participated for several years in other online research projects conducted by 23andMe, which helped to define the natural history of PD and correlate it with the findings in their large genetic database. As a result of their research, a number of new mutations have been discovered to be associated with PD (1). The FDA’s action has shut down this valuable research effort, along with the direct-to-consumer genetic testing service.

As a PD patient, I discussed my 23andMe genetic profile with my treating neurologist, and I requested that he include it on my chart. My main concerns as a patient are:

1) Are my genetic test results accurate, as reported by 23andMe ?

2) Are the reported statistical associations with diseases accurate ?

It is appropriate for the FDA to monitor the accuracy of test results and associated interpretive data supplied by direct-to-consumer genetic test providers. However, the FDA should not hold test providers responsible when consumers misuse this data for unintended purposes, such as for adjusting their warfarin dose without INR testing, or as a substitute for recommended cancer screening tests or regular medical care.

To address the clinical scenario posed in the editorial, here is what I would do if an asymptomatic patient came to my office with a direct-to-consumer genetic test positive for a mutation conferring elevated risk for Crohn’s disease. First, I would reassure him that having a genetic variation associated with increased risk of a disease does not mean that disease will necessarily develop, and many people exhibit such variations and live long and healthy lives. I would add that Crohn’s disease, like other immune disorders, exhibits substantial discordance between identical twins, and thus must have significant environmental risk factors (2). Next, I would perform a complete history and physical exam, appropriate for his age and condition and concerns, including careful examinations of his mouth, abdomen, and anus. I would make certain that he was up to date on his colon cancer screening, per the current guidelines. I would discuss the signs and symptoms of Crohn’s disease with him, and give him a stool test kit for occult blood and draw basic blood labs to check for occult anemia and iron and B-12 deficiency, and any basic labs he might be due for. I would tell him that smoking seems to worsen Crohn’s disease, and offer him assistance with smoking cessation. I would ask him to schedule a follow-up visit in a few weeks, and to call me in the unlikely event he developed any of the signs or symptoms of Crohn’s disease. During the intervening weeks, I would study his genetic report and phone a GI colleague for advice. If the patient is at elevated risk of Crohn’s disease, an early diagnosis would allow time for smoking cessation and surveillance to reduce the risk of future fistulas and other complications.

1: 23andMe Parkinson’s disease research results website, accessed on 2/12/2014: http://blog.23andme.com/23andme-research/23andme-and-parkinsons-past-present-and-future/

2: Orholm M, Binder V, Sørensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000 Oct;35(10):1075-81. PubMed PMID: 11099061

On 2014 Feb 17, David Keller commented:

Why I Care About the FDA's Closure of 23andMe's Personal Genomic Service

I am an internist and a 23andMe customer. I paid $25 for their genetic test kit several years ago as part of their campaign to identify a cohort of Parkinson disease (PD) patients carrying the LRRK-2 gene. In return, I received an extensive genetic report, as part of which I learned that LRRK-2 is not the cause of my PD. I therefore was not included in the LRRK-2 research cohort, but its findings may very well help the vast majority of PD patients who do not carry that mutation. I participated for several years in other online research projects conducted by 23andMe, which helped to define the natural history of PD and correlate it with the findings in their large genetic database. As a result of their research, a number of new mutations have been discovered to be associated with PD (1). The FDA’s action has shut down this valuable research effort, along with the direct-to-consumer genetic testing service.

As a PD patient, I discussed my 23andMe genetic profile with my treating neurologist, and I requested that he include it on my chart. My main concerns as a patient are:

1) Are my genetic test results accurate, as reported by 23andMe ?

2) Are the reported statistical associations with diseases accurate ?

It is appropriate for the FDA to monitor the accuracy of test results and associated interpretive data supplied by direct-to-consumer genetic test providers. However, the FDA should not hold test providers responsible when consumers misuse this data for unintended purposes, such as for adjusting their warfarin dose without INR testing, or as a substitute for recommended cancer screening tests or regular medical care.

To address the clinical scenario posed in the editorial, here is what I would do if an asymptomatic patient came to my office with a direct-to-consumer genetic test positive for a mutation conferring elevated risk for Crohn’s disease. First, I would reassure him that having a genetic variation associated with increased risk of a disease does not mean that disease will necessarily develop, and many people exhibit such variations and live long and healthy lives. I would add that Crohn’s disease, like other immune disorders, exhibits substantial discordance between identical twins, and thus must have significant environmental risk factors (2). Next, I would perform a complete history and physical exam, appropriate for his age and condition and concerns, including careful examinations of his mouth, abdomen, and anus. I would make certain that he was up to date on his colon cancer screening, per the current guidelines. I would discuss the signs and symptoms of Crohn’s disease with him, and give him a stool test kit for occult blood and draw basic blood labs to check for occult anemia and iron and B-12 deficiency, and any basic labs he might be due for. I would tell him that smoking seems to worsen Crohn’s disease, and offer him assistance with smoking cessation. I would ask him to schedule a follow-up visit in a few weeks, and to call me in the unlikely event he developed any of the signs or symptoms of Crohn’s disease. During the intervening weeks, I would study his genetic report and phone a GI colleague for advice. If the patient is at elevated risk of Crohn’s disease, an early diagnosis would allow time for smoking cessation and surveillance to reduce the risk of future fistulas and other complications.

1: 23andMe Parkinson’s disease research results website, accessed on 2/12/2014: http://blog.23andme.com/23andme-research/23andme-and-parkinsons-past-present-and-future/

2: Orholm M, Binder V, Sørensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000 Oct;35(10):1075-81. PubMed PMID: 11099061

On 2014 Feb 19, John French commented:

In regard to the FDA's closure of a personal genomic service, I take the main issues of concern to the writer, an internist, is the accuracy of 23andMe's reported conclusion based upon the statistical association of the variant in question for PD. There is very little information on both type 1 and type 2 error rates on test accuracy which calls into question the reported statistical association. PD and most other diseases are polygenic with tens if not hundreds of variants genome contributing to varying levels of cumulative risk along with other contributing intrinsic and extrinsic factors. A main concern of the FDA was in regard to the lack of published validation studies for the methodologies used by this and other personal genomic services. Your response to a hypothetical patient seems appropriate. If they did not include such advice in their report to you, 23andMe should have offered similar caveats. Without sufficient characterization of significant intrinsic and extrinsic factors for the individuals in the candidate gene or genome wide association studies, the data cannot be weighted and is inconclusive. Where are the genetic counselors? Would you refer your patient to a genetic counselor?

Yandell et al. A probabilistic disease-gene finder for personal genomes. Genome Res.21(9): 1529–1542, 2011. doi: 10.1101/gr.123158.111 Elizabeth T. Cirulli & David B. Goldstein. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nature Reviews Genetics 11, 415–30, 2010) doi:10.1038/nrg2779