The promise and peril of genomic screening in the general population

Abstract

PurposeUtilization of sequencing to screen the general population for preventable monogenic conditions is receiving substantial attention due to its potential to decrease morbidity and mortality. However, the selection of which variants to return is a serious implementation challenge. Procedures must be investigated to ensure optimal test characteristics and avoidance of harm from false positive test results.MethodsWe scanned exome sequences from 478 well-phenotyped individuals for potentially pathogenic variants in 17 genes representing 11 conditions that are among the most medically actionable Mendelian disorders in adults. We developed 5 variant selection algorithms with increasing sensitivity and measured their specificity in these 17 genes.ResultsVariant selection algorithms with increasing sensitivity exhibited decreased specificity, and performance was highly dependent on the genes analyzed. The most sensitive algorithm ranged from 88.8% to 99.6% specificity among the 17 genes.ConclusionFor very low prevalence conditions, small reductions in specificity greatly increase false positives. This inescapable test characteristic governs the predictive value of genomic sequencing in the general population. To address this issue, test performance must be evaluated systematically for each condition so that the false negatives and false positives can be tailored for optimal outcomes, depending on the downstream clinical consequences.

The prevalence of DICER1 pathogenic variation in population databases

“…For disorders without readily apparent precursor lesions or symptoms and thus a pre-emptive requirement for surgery or device implantation ( e.g., BRCA1/2 , Lynch syndrome, long QT syndrome), the tolerance for false positives is likely low or very low. For disorders with readily available, low-cost, low-morbidity screening or exposure-avoidance ( e.g., familial hypercholesterolemia, Marfan syndrome, hemochromatosis, alpha-1-anti-trypsin deficiency), the tolerance for false positives is likely higher 42 . The tolerance for false positives screening results in the DICER1 syndrome is unknown, but likely falls between these two extremes, given the current need to use ionizing radiation to detect the precursor PPB type I.…”

Newborn Sequencing in Genomic Medicine and Public Health

“…48,49 Determining criteria for disclosure of information will be a challenge for clinicians and policymakers and will require development of decisional supports to help parents determine the information they want to learn. 50 52 The benefits of detecting true positives must therefore be balanced against the magnitude of harms.…”

Precisely Where Are We Going? Charting the New Terrain of Precision Prevention

“…Others propose the application of genomic sequencing technologies to efficiently screen healthy adults for unrecognized genetic health risks, which are promoted as a way to detect subsets of the general population that might benefit from increased medical surveillance or intervention (24). For example, researchers have recommended that some methods of identifying deleterious variants be used for opportunistic screening during clinical sequencing (51), studied as a clinical service (1, 22), or implemented within major health systems (11, 21). Projects like these have been included on the promissory agendas of public health genomics and precision public health (55, 56).…”