Roundtable on Translating Genomic-Based Research for Health, Institute of Medicine. "3 The Analysis of Genomic Data." Integrating Large-Scale Genomic Information into Clinical Practice: Workshop Summary. Washington, DC: The National Academies Press, 2012.
Federico Monzon from the Methodist Hospital Research Institute described how cancer screenings have evolved over time. For example, physicians who tested for breast cancer were originally limited to studying the morphology of the breast. Later, the science progressed to evaluating single biomarkers, such as analyzing estrogen receptors in tissue. Since that time, testing for breast cancer has advanced through biomarker panels, expression profiles, targeted sequencing of specific genes, exome sequencing, and, finally, to whole-genome sequencing. While this progression of tests has led to a greater understanding of disease morphology, it has also required laboratories and physicians to complete more complex analyses of the test results. As Monzon said, “This is an evolution of testing which is driven by our better understanding of disease, and with that better understanding of disease comes better clinical testing that we are doing in our laboratories.”
Based on his experience with the genomic testing of cancer tissues, Monzon offered several challenges that laboratories can expect to face when performing their analyses. Chief among them is demonstrating the analytical and clinical validity of the genetic test, no matter whether the test is for a single gene or for the whole genome. A laboratory is responsible for determining whether a test is able to detect all described variants—whether in sequences, transcripts, or some other biological indicator—as well as for validating that the data are correct when the test finds something new. Furthermore, patients and payers depend on the laboratory to determine whether a test identifies patients who have a disease or are at risk for a disease.
Today’s validation standards do not apply to multianalyte tests, much less to whole genomes. With millions of variants estimated to exist within a single genome, there are more potential backgrounds than individuals who can be used to validate the variants. It is thus a major question regarding how many patients or tumor types need to be identified for each variant detected; with the cross-genome differences among these patients, validating each variant in the same way that single-gene tests are handled is not possible, Monzon said.
No sequencing technology can validate every base pair, Monzon said, especially with variants that have never before been seen. Instead, laboratories will need to assess the concordance across results. Reference genomes will help in achieving analytically valid results. Laboratories will develop confidence in platforms based on experience, which will then generate confidence in results. Madhuri Hegde from the Emory University School of Medicine added that sequencing systems will inevitably introduce artifacts, and genomic analysis will need to separate those artifacts from real variants. As a result, some sort of confirmation, such as Sanger sequencing for the individual variant in question, will be necessary in many circumstances.