Date of Award

Summer 5-2019

Degree Name

Doctor of Philosophy (PhD)

Advisor(s)

J. MICHAEL SWINT, PHD

Second Advisor

SEEMA R. LALANI, MD

Third Advisor

MARCIA C. DE OLIVEIRA OTTO, PHD

Abstract

Whole exome sequencing (ES) is an extensive form of genetic testing and increasingly used as a diagnostic tool. Clinical uptake of genome-scale sequencing occurred without clear guidelines for application or robust information regarding potential impact on patient health outcomes or cost of care. For infants in intensive care with suspected genetic conditions, ES can be especially powerful to identify a specific diagnosis and inform crucial decisions about medical care. However, little is known about the cost-effectiveness of ES compared to other diagnostic strategies. This project first assessed the literature on pediatric clinical ES. Then, using electronic medical record, diagnostic laboratory, and hospital cost data, we analyzed and compared outcomes and costs of care for patients with suspected genetic etiologies admitted to intensive care within the first year of life in two patient cohorts: those who had ES (ES, n=368) and did not have ES (No-ES, n=368) as part of a diagnostic workup at a large children’s hospital. Molecular diagnostic yield (25.8% No-ES, 27.7% ES; p=0.56) and 1-year survival (84.8% No-ES, 80.2% ES; p=0.10) were similar between cohorts, while ES patients had higher total cost, diagnostic investigation cost, and genetic test cost during the index admission and for the year after the date of first inpatient genetics consultation (all p<0.01). ES demonstrated important diagnostic utility for patients with monogenic disease, yet other genetic tests, especially chromosomal microarray, remain important given the burden of chromosomal abnormalities in this population. As clinically applied over the first 5 years, ES does not appear to be a cost-effective diagnostic tool for the broad population of newborns and infants with suspected genetic disease compared to standard diagnostic tests such as chromosomal microarray analysis and panel/single gene testing. Further work is needed to develop outcome measures to capture utility of ES results – both diagnostic and non-diagnostic – for clinicians, patients, and patients’ families, and to specify clinical guidelines for appropriate ES application.

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