Clinical Utility of a Comprehensive, Whole Genome CMA Testing Platform in Pediatrics: A Prospective Randomized Controlled Trial of Simulated Patients in Physician Practices

John Peabody, Megan Martin, Lisa DeMaria, Jhiedon Florentino, David Paculdo, Michael Paul, Rena Vanzo, E Robert Wassman, Trever Burgon, John Peabody, Megan Martin, Lisa DeMaria, Jhiedon Florentino, David Paculdo, Michael Paul, Rena Vanzo, E Robert Wassman, Trever Burgon

Abstract

Background: Developmental disorders (DD), including autism spectrum disorder (ASD) and intellectual disability (ID), are a common group of clinical manifestations caused by a variety of genetic abnormalities. Genetic testing, including chromosomal microarray (CMA), plays an important role in diagnosing these conditions, but CMA can be limited by incomplete coverage of genetic abnormalities and lack of guidance for conditions rarely seen by treating physicians.

Methods: We conducted a longitudinal, randomized controlled trial investigating the impact of a higher resolution 2.8 million (MM) probe-CMA test on the quality of care delivered by practicing general pediatricians and specialists. To overcome the twin problems of finding an adequate sample size of multiple rare conditions and under/incorrect diagnoses, we used standardized simulated patients known as CPVs. Physicians, randomized into control and intervention groups, cared for the CPV pediatric patients with DD/ASD/ID. Care responses were scored against evidence-based criteria. In round one, participants could order diagnostic tests including existing CMA tests. In round two, intervention physicians could order the 2.8MM probe-CMA test. Outcome measures included overall quality of care and quality of the diagnosis and treatment plan.

Results: Physicians ordering CMA testing had 5.43% (p<0.001) higher overall quality scores than those who did not. Intervention physicians ordering the 2.8MM probe-CMA test had 7.20% (p<0.001) higher overall quality scores. Use of the 2.8MM probe-CMA test led to a 10.9% (p<0.001) improvement in the diagnosis and treatment score. Introduction of the 2.8MM probe-CMA test led to significant improvements in condition-specific interventions including an 8.3% (p = 0.04) improvement in evaluation and therapy for gross motor delays caused by Hunter syndrome, a 27.5% (p = 0.03) increase in early cognitive intervention for FOXG1-related disorder, and an 18.2% (p<0.001) improvement in referrals to child neurology for Dravet syndrome.

Conclusion: Physician use of the 2.8MM probe-CMA test significantly improves overall quality as well as diagnosis and treatment quality for simulated cases of pediatric DD/ASD/ID patients, and delivers additional clinical utility over existing CMA tests.

Conflict of interest statement

The authors have the following interests: MM, MP, RV, and EBW are employees of Lineagen, Inc; LD, JF, DP, and TB are all employees of QURE Healthcare. JP is the President of CPV Technologies, which owns the CPV IP used in the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flowchart of Physician Participant Selection.
Fig 1. Flowchart of Physician Participant Selection.
(139/147 (95%) physicians in the intervention arm confirmed viewing an educational webcast about the 2.8MM probe-CMA. No physicians in the control arm received any specific educational material.

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