Validation of Genomic-Based Assay

Abstract

Molecular biomarker assays are the key to unlocking the promise of personalized medicine. Molecular assays need to be developed on clinically relevant samples and be rigorously validated. First and foremost, we need to establish the assay’s clinical relevance using appropriate patient populations, in order to answer the fundamental question “why this molecular assay is useful and what unmet medical need does it fill?” Once the medical utility of the assay has been demonstrated, we need to ensure the assay can be accurately measured. One major branch of molecular assays is genomic alterations, including DNA point mutations, fusions, copy number alterations, loss of heterozygosity (LOH), and translocations. Efficient measurements on these DNA alterations across the genome become increasingly feasible with advancements in sequencing technology. However, reliable detection and accurate quantification of these important genomic-based assays may not be as straightforward as we think. While clinical validation on an independent test set against a reference standard is critical and necessary, it is only the first step. The final performance observed in the test set must be maintained in real-life settings amidst commonly encountered interfering substances and across different reagent lots, sequencing machines, and human operators. Adding to the complexity, when the genomic alteration is rare, it poses additional challenges on cost effectiveness. Innovation on methodology becomes key in keeping the highest scientific rigor while conducting the evaluation in the most efficient manner.