Genome-Wide Sequencing for Unexplained Developmental Disabilities or Multiple Congenital Anomalies: A Health Technology Assessment

Abstract

Background: People with unexplained developmental disabilities or multiple congenital anomalies might have had many biochemical, metabolic, and genetic tests for a period of years without receiving a diagnosis. A genetic diagnosis can help these people and their families better understand their condition and may help them to connect with others who have the same condition. Ontario Health (Quality), in collaboration with the Canadian Agency for Drugs and Technologies in Health (CADTH) conducted a health technology assessment about the use of genome-wide sequencing for patients with unexplained developmental disabilities or multiple congenital anomalies. Ontario Health (Quality) evaluated the effectiveness, cost-effectiveness, and budget impact of publicly funding genome-wide sequencing. We also conducted interviews with patients and examined the quantitative evidence of preferences and values literature to better understand the patient preferences and values for these tests.

Methods: Ontario Health (Quality) performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Risk of Bias Assessment tool for Non-randomized Studies (RoBANS) and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We also performed a search of the quantitative evidence and undertook direct patient engagement to ascertain patient preferences for genetic testing for unexplained developmental disabilities or multiple congenital anomalies. CADTH performed a review of qualitative literature about patient perspectives and experiences, and a review of ethical issues.Ontario Health (Quality) performed an economic literature review of genome-wide sequencing in people with unexplained developmental disabilities or multiple congenital anomalies. Although we found eight published cost-effectiveness studies, none completely addressed our research question. Therefore, we conducted a primary economic evaluation using a discrete event simulation model. Owing to its high cost and early stage of clinical implementation, whole exome sequencing is primarily used for people who do not have a diagnosis from standard testing (referred to here as whole exome sequencing after standard testing; standard testing includes chromosomal microarray and targeted single-gene tests or gene panels). Therefore, in our first analysis, we evaluated the cost-effectiveness of whole exome sequencing after standard testing versus standard testing alone. In our second analysis, we explored the cost-effectiveness of whole exome and whole genome sequencing used at various times in the diagnostic pathway (e.g., first tier, second tier, after standard testing) versus standard testing. We also estimated the budget impact of publicly funding genome-wide sequencing in Ontario for the next 5 years.

Results: Forty-four studies were included in the clinical evidence review. The overall diagnostic yield of genome-wide sequencing for people with unexplained development disability and multiple congenital anomalies was 37%, but we are very uncertain about this estimate (GRADE: Very Low). Compared with standard genetic testing of chromosomal microarray and targeted single-gene tests or gene panels, genome-wide sequencing could have a higher diagnostic yield (GRADE: Low). As well, for some who are tested, genome-wide sequencing prompts some changes to medications, treatments, and referrals to specialists (GRADE: Very Low).Whole exome sequencing after standard testing cost an additional $3,261 per patient but was more effective than standard testing alone. For every 1,000 persons tested, using whole exome sequencing after standard testing would lead to an additional 240 persons with a molecular diagnosis, 272 persons with any positive finding, and 46 persons with active treatment change (modifications to medications, procedures, or treatment). The resulting incremental cost-effectiveness ratios (ICERs) were $13,591 per additional molecular diagnosis. The use of genome-wide sequencing early in the diagnostic pathway (e.g., as a first- or second-tier test) can save on costs and improve diagnostic yields over those of standard testing. Results remained robust when parameters and assumptions were varied.Our budget impact analysis showed that, if whole exome sequencing after standard testing continues to be funded through Ontario's Out-of-Country Prior Approval Program, its budget impact would range from $4 to $5 million in years 1 to 5. If whole exome sequencing becomes publicly funded in Ontario (not through the Out-of-Country Prior Approval Program), the budget impact would be about $9 million yearly. We also found that using whole exome sequencing as a second-tier test would lead to cost savings ($3.4 million per 1,000 persons tested yearly).Participants demonstrated consistent motivations for and expectations of obtaining a diagnosis for unexplained developmental delay or congenital anomalies through genome-wide sequencing. Patients and families greatly value the support and information they receive through genetic counselling when considering genome-wide sequencing and learning of a diagnosis.

Conclusions: Genome-wide sequencing could have a higher diagnostic yield than standard testing for people with unexplained developmental disabilities or multiple congenital anomalies. Genome-wide sequencing can also prompt some changes to medications, treatments, and referrals to specialists for some people tested; however, we are very uncertain about this. Genome-wide sequencing could be a cost-effective strategy when used after standard testing to diagnose people with unexplained developmental disabilities or multiple congenital anomalies. It could also lead to cost savings when used earlier in the diagnostic pathway. Patients and families consistently noted a benefit from seeking a diagnosis through genetic testing.

Figure 1:. PRISMA Flow Diagram—Clinical Search Strategy

Figure 2:. Diagnostic Yield by Genome-Wide Sequencing Technology

Figure 3:. Comparative Diagnostic Yield of Genome-Wide Sequencing Versus Standard Genetic Testing

Figure 4:. Variants of Unknown Significance Yield by Genome-Wide Technology

Figure 5:. PRISMA Flow Diagram—Economic Search Strategy

Figure 6:. Standard Testing Pathway and Current Testing Pathway with WES

Figure 7:. Model Structure

Figure 8:. Analytic Framework of Budget Impact Analysis

Figure 9:. Estimation of the Size of the Target Population

Figure 10:. PRISMA Flow Diagram—Quantitative Evidence of Preferences and Values Search Strategy

Figure A1:. Sensitivity Analysis^a of Comparative Diagnostic Yield of Genome-Wide Sequencing Versus Standard Genetic Testing

Figure A2:. Diagnostic Yield of Genome-Wide Sequencing Among a Subset of Comparative Effectiveness Studies

Figure A3:. Diagnostic Yield of Standard Testing Among a Subset of Comparative Effectiveness Studies

Figure A4:. Diagnostic Yield of Whole Exome Sequencing by Use of Trio Testing

Figure A5:. Diagnostic Yield of Whole Genome Sequencing by Use of Trio Testing

Figure A6:. Diagnostic Yield of Whole Exome Sequencing by Testing Method Using Trio or Mixed Methods

Figure A7:. Diagnostic Yield of Whole Genome Sequencing by Testing Method Using Trio or Mixed Methods

Figure A8:. Diagnostic Yield of Whole Exome Sequencing by Timing of Use

Figure A9:. Diagnostic Yield of Whole Genome Sequencing by Timing of Use

Figure A10:. Secondary Findings Yield by Genome-Wide Sequencing Test

Figure A11:. Diagnostic Yield of Chromosomal Microarray

Figure A12:. Cost-Effectiveness Plane Showing Incremental Cost and Effectiveness of Whole Exome Sequencing After Standard Testing Versus Standard Testing

Figure A13:. Cost-Effectiveness Acceptability Curve—Whole Exome Sequencing After Standard Testing Versus Standard Testing

Figure A14:. Cost-Effectiveness Plane Showing Total Cost and Effectiveness of Various Testing Strategies

Figure A15:. Cost-Effectiveness Acceptability Curves Showing Probability of Testing Strategies Being Cost-Effective Across a Range of Willingness-to-Pay Values