by the Pathway Genomics Curation Team

How does Pathway identify the genetic markers to include in its tests?

Pathway employs an army of geneticists whose primary responsibility is to read genetic studies to identify reportable genotype-phenotype associations that can be added to Pathway’s tests.  This curation process seeks rigorous scientific evidence that specific traits or conditions (phenotype) can be associated with specific changes in the DNA sequence of a gene (genotype).

You might have heard of museum curators, whose job it is to acquire artwork or historical items for museums.  Genetics curators at Pathway have the job of acquiring genetic data from the available literature.  The most widely used (and freely available) database of literature is PubMed, which is maintained by the National Library of Medicine.  PubMed contains information on over 20 million studies, and is growing at an astonishing rate of 1 paper per minute. The curators spend hours poring over studies in PubMed and in other databases to identify new markers with high scientific validity that can be added to Pathway’s tests. For any phenotype (for example, satiety in Pathway Fit®, or warfarin sensitivity in our drug response test) that is reported, a curator may read between 3 to 50 scientific papers.

A commitment to high scientific validity

The curation team at Pathway establishes criteria for identifying genotype-phenotype associations that can be reported.  For complex traits tested in Pathway Fit, drug response, and Health Insight, these criteria include study characteristics such as population size, statistical significance, and ethnicity.  Many of these items are included in guidelines sponsored by the U.S. Centers for Disease Control (CDC) for strengthening the reporting of genetic prediction studies (PMID 21434890).  For our Pre-Pregnancy Planning Insight, we include mutations recommended  for carrier status screening by the American College of Medical Genetics and the American College of Obstetricians and Gynecologists.  For our drug response product, we look at recommendations for genetic testing that are approved by the Food and Drug Administration.

One universal criteria across all products is that the genotype-phenotype association must be found in human studies. Animal or in vitro studies are insufficient for reportability, although they may be additional support for a genotype-phenotype correlation found in humans.

Each genotype-phenotype association that is reported has passed a rigorous review process

For each genotype-phenotype association that is selected for reporting, the scientific evidence is reviewed by at least 4 Ph.D.-level geneticists. The initial curator identifies the genotype-phenotype association, and puts together a body of evidence (supporting documentation) to support the addition of the marker-trait to a particular test.  This literature is passed on to a second curator, who rereads the supporting documentation and looks for reasons that a marker-trait association cannot be reported.  For example, the trait may not be statistically significant or there may be studies showing conflicting results.  If the marker-trait passes this stage, the supporting documentation is delivered to the head of curation and chief scientific officer for approval.  If any assays need to be developed, scientists in research and development may also review the supporting documentation.  Thus, any new marker-trait association has been subjected to rigorous review.

Delivery of scientific valid test results with actionable recommendations

Curators write the initial draft of content for each test result.  This includes the description of the trait or condition, what each genotype result means, as well as some recommendations for lifestyle changes (if any).  For example, the C/C genotype at the rs4988235 marker in the MCM6 gene is associated with lactose intolerance (Pathway FIT). Non-dairy sources of calcium are recommended for people with this genotype.

The content for each test result is reviewed and edited by genetic counselors, physicians, and nutritionists.  A final review by the curation team ensures the validity of the test result.  Pathway’s intent is to deliver scientifically valid test results with actionable recommendations.

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