Trusting Consumer Genomics

Do 23andMe's foibles signify a rocky road for DTC genomics?

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As I warned a few years ago

As I warned a few years ago in several of my previous The Daily Scan commentaries, the woes that are faced today by the DTC firms that offer health advice based purely on gene sequence analysis is completely predictable on several accounts. Except for rather rare disorders, almost always, diverse different genetic defects can contribute to the etiology of most diseases. The most common diseases have a wide range of contributing proteins and mutations within these proteins that can facilitate disease development. Current genomic analyses by DTC firms are SNP-based. With over 50 million SNP differences thought to exist between humans, only a tiny fraction of a percentage of these SNP are actually tracked presently with SNP chips. Consequently, it will be impossible at this stage for these type of analyses to provide statistically accurate and meaningful predictions of actual disease risks.

Genome-wide-sequencing will ultimately permit identification of all of the SNP's in an individual's genome. However, despite the relatively low costs now in acquiring this data, its interpretation is a totally different matter. It is evident that perfectly healthy people have SNP's that have been identified as deleterious and disease causing. While the physiological impact of the vast majority of SNP's remain obscure, the functional roles of about 40% of the protein-coding genes in the human genome are still unknown at this juncture. Even less is known about how these and other proteins are regulated and partnered with other proteins, nucleic acids and other biomolecules. Unfortunately, sequencing the complete genomes of hundreds of thousands of individuals, as is now planned, is not going to provide much further insight in these regards.

Most importantly, it is clearly evident that environmental exposures to diverse agents and an individual's life style have profound effects on disease development. The proteome is extremely dynamic in being able to compensate for genetic and environmental challenges. Ultimately, phenotype is reflected by the levels of functional proteins and their interactions. Until DTC firms exist that actually track changes in critical proteins beyond their primary structures and there are companion drugs that effectively and specifically target those anomalously affected proteins, personalized medicine will remain elusive.

Perhaps this paper can answer

Perhaps this paper can answer some of these questions:

Regarding the difficulty 23andMe may face in convincing the FDA, this free, Open Access article may be interesting:

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Catherine A Brownstein, Alan H Beggs, Nils Homer, Barry Merriman, Timothy W Yu, Katherine C Flannery, Elizabeth T DeChene, Meghan C Towne, Sarah K Savage, Emily N Price, Ingrid A Holm, Lovelace J Luquette, Elaine Lyon, Joseph Majzoub, Peter Neupert, David McCallie, Peter Szolovits, Huntington F Willard, Nancy J Mendelsohn, Renee Temme, Richard S Finkel, Sabrina W Yum, Livija Medne, Shamil R Sunyaev, Ivan Adzhubey, Christopher A Cassa, Paul IW de Bakker, Hatice Duzkale, Piotr Dworzy¿ski, William Fairbrother et al.

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Genome Biology 2014, 15:R53 doi:10.1186/gb-2014-15-3-r53

Published: 25 March 2014
Abstract (provisional)

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data was donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.

A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.

The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

The complete article is available as a provisional PDF, The fully formatted PDF and HTML versions are in production.