The impact of benign genetic variation on clinical misclassification and overtreatment in biomarker-driven care

Abstract

Diagnostic biomarkers such as laboratory tests guide clinician decision-making, but interpretation relies on reference intervals and clinical decision thresholds derived from populations that may be either unrepresentative or under sample the populations to which the thresholds are applied. Traditional approaches can adjust for measurable sources of variability, such as age and sex, but a growing body of evidence indicates that individuals possess stable biomarker "set points" that are genetically influenced and not accounted for in current practice. Misalignment of clinical decision thresholds to these set points can lead to misclassification, unnecessary procedures, and extensive diagnostic uncertainty. We hypothesize that benign genetic variation underlies many unnecessary diagnostic odysseys and can be used as a risk stratification tool to reduce unnecessary testing and interventions. In the first application, we demonstrate that a benign genetic predisposition to higher prostate-specific antigen (PSA) increases the risk of urology referrals for false-positive PSA elevations. In patients undergoing prostate biopsy, genetically elevated PSA was associated with a lower likelihood of prostate cancer. In evaluations for underlying pathology in children with unexplained short stature, polygenic scores for height effectively distinguish between benign polygenic short stature and pathologic growth disorders, particularly among patients whose average parental heights do not accurately reflect their genetic predisposition. Finally, we observe that polygenic variation underlying neutrophil counts further increases the risk of benign neutropenia in patients with the Duffy null genotype. This genotype, present in two-thirds of patients of African ancestry, causes a benign form of neutropenia that can predispose patients to unnecessary bone marrow biopsies and chemotherapy modifications due to provider concerns for a low neutrophil count. Using a polygenic score, we create genotype-adjusted reference ranges for neutrophil counts, demonstrating a proactive approach to preventing inappropriate referrals. Together, these findings demonstrate the value of genetic personalization in biomarker interpretation, reducing diagnostic uncertainty and unnecessary diagnostic odysseys and interventions.