Dataset Information

Carrier screening by next-generation sequencing: health benefits and cost effectiveness.

ABSTRACT:

Background

Compared with conventional genotyping, which typically tests for a limited number of mutations, next-generation DNA sequencing (NGS) provides increased accuracy for carrier screening. The objective of this study was to evaluate the cost effectiveness of carrier screening using NGS versus genotyping for 14 of the recessive disorders for which medical society guidelines recommend screening.

Methods

Data from published literature, population surveys, and expert opinion were used to develop a decision tree model capturing decisions and outcomes related to carrier screening and reproductive health.

Results

Modeling a population of 1,000,000 couples that was representative of the United States population and that contained 83,421 carriers of pathogenic mutations, carrier screening using NGS averted 21 additional affected births as compared with genotyping, and reduced costs by approximately $13 million. As compared with no screening, NGS carrier screening averted 223 additional affected births. The results are sensitive to assumptions regarding mutation detection rates and carrier frequencies in multiethnic populations.

Conclusion

This study demonstrated that NGS-based carrier screening offers the greater benefit in clinical outcomes and lower total healthcare cost as compared with genotyping.

SUBMITTER: Azimi M

PROVIDER: S-EPMC4867563 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Publications

Carrier screening by next-generation sequencing: health benefits and cost effectiveness.

Azimi Mohammad M Schmaus Kyle K Greger Valerie V Neitzel Dana D Rochelle Robert R Dinh Tuan T

Molecular genetics & genomic medicine 20160129 3

<h4>Background</h4>Compared with conventional genotyping, which typically tests for a limited number of mutations, next-generation DNA sequencing (NGS) provides increased accuracy for carrier screening. The objective of this study was to evaluate the cost effectiveness of carrier screening using NGS versus genotyping for 14 of the recessive disorders for which medical society guidelines recommend screening.<h4>Methods</h4>Data from published literature, population surveys, and expert opinion wer ...[more]

PMID: 27247957

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Project description:Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~10% of pediatric hospitalizations. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening to most severe disease genes has hitherto been impractical. Here, we report a preconception carrier screen for 448 severe recessive childhood diseases. Rather than costly, complete sequencing of the human genome, 7717 regions from 437 target genes were enriched by hybrid capture or microdroplet polymerase chain reaction, sequenced by next-generation sequencing (NGS) to a depth of up to 2.7 gigabases, and assessed with stringent bioinformatic filters. At a resultant 160x average target coverage, 93% of nucleotides had at least 20x coverage, and mutation detection/genotyping had ~95% sensitivity and ~100% specificity for substitution, insertion/deletion, splicing, and gross deletion mutations and single-nucleotide polymorphisms. In 104 unrelated DNA samples, the average genomic carrier burden for severe pediatric recessive mutations was 2.8 and ranged from 0 to 7. The distribution of mutations among sequenced samples appeared random. Twenty-seven percent of mutations cited in the literature were found to be common polymorphisms or misannotated, underscoring the need for better mutation databases as part of a comprehensive carrier testing strategy. Given the magnitude of carrier burden and the lower cost of testing compared to treating these conditions, carrier screening by NGS made available to the general population may be an economical way to reduce the incidence of and ameliorate suffering associated with severe recessive childhood disorders.

Project description:In current clinical practice, genetic testing to detect Lynch syndrome mutations ideally begins with diagnostic testing of an individual affected with cancer before offering predictive testing to at-risk relatives. An alternative strategy that warrants exploration involves screening unaffected individuals via demographic and family histories, and offering genetic testing to those individuals whose risks for carrying a mutation exceed a selected threshold. Whether this approach would improve health outcomes in a manner that is cost-effective relative to current standards of care has yet to be demonstrated. To do so, we developed a simulation framework that integrated models of colorectal and endometrial cancers with a 5-generation family history model to predict health and economic outcomes of 20 primary screening strategies (at a wide range of compliance levels) aimed at detecting individuals with mismatch repair gene mutations and their at-risk relatives. These strategies were characterized by (i) different screening ages for starting risk assessment and (ii) different risk thresholds above which to implement genetic testing. For each strategy, 100,000 simulated individuals, representative of the U.S. population, were followed from the age of 20, and the outcomes were compared with current practice. Findings indicated that risk assessment starting at ages 25, 30, or 35, followed by genetic testing of those with mutation risks exceeding 5%, reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%, respectively. For a population of 100,000 individuals containing 392 mutation carriers, this strategy increased quality-adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY. The cost-effectiveness of screening for mismatch repair gene mutations is comparable to that of accepted cancer screening activities in the general population such as colorectal cancer screening, cervical cancer screening, and breast cancer screening. These results suggest that primary screening of individuals for mismatch repair gene mutations, starting with risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost-effective manner relative to current practice.

Dataset Information

Carrier screening by next-generation sequencing: health benefits and cost effectiveness.

Background

Methods

Results

Conclusion

Publications

Carrier screening by next-generation sequencing: health benefits and cost effectiveness.

Similar Datasets

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