Dataset Information

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.

ABSTRACT: With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: "Definitive," "Strong," "Moderate," "Limited," "No Reported Evidence," or "Conflicting Evidence." Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.

SUBMITTER: Strande NT

PROVIDER: S-EPMC5473734 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.

Strande Natasha T NT Riggs Erin Rooney ER Buchanan Adam H AH Ceyhan-Birsoy Ozge O DiStefano Marina M Dwight Selina S SS Goldstein Jenny J Ghosh Rajarshi R Seifert Bryce A BA Sneddon Tam P TP Wright Matt W MW Milko Laura V LV Cherry J Michael JM Giovanni Monica A MA Murray Michael F MF O'Daniel Julianne M JM Ramos Erin M EM Santani Avni B AB Scott Alan F AF Plon Sharon E SE Rehm Heidi L HL Martin Christa L CL Berg Jonathan S JS

American journal of human genetics 20170525 6

With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has develop ...[more]

PMID: 28552198

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Project description:Reactive agility (RAG) and change of direction speed (CODS) are important determinants of success in football (soccer), but there is an evident lack of information on reliable and valid football-specific testing procedures which will be applicable in defining sport-specific RAG and CODS in youth players. This study evaluated reliability and construct validity of newly developed tests of football-specific RAG (FS_RAG) and CODS (FS_CODS), which involved the ball kicking football technique. Additionally, factors associated with FS_RAG and FS_CODS were evaluated. The participants were youth football players (n = 59; age: 13.40 ± 1.25 years) divided according to their age into U13 (11-12 years of age; n = 29), and U15 (13-14 years of age; n = 30) categories. Additionally, performance levels (starters [first-team] vs. non-starters [substitutes]) were observed in each age category. The dependent variables were newly developed FS_RAG and FS_CODS tests. The independent variables were sprinting capacities over 10 and 20 meters (S10M, S20M), countermovement jump (CMJ), the reactive strength index (RSI), and a generic CODS test of 20 yards (20Y). The newly developed FS_CODS and FS_RAG were observed as dependent variables. Results showed appropriate intra-testing and inter-testing reliability of the FS_RAG and FS_CODS, with somewhat better reliability of the FS_CODS (ICC=0.82 and 0.79, respectively). Additionally, better reliability was evidenced in U15 than in U13 (ICC: 0.82-0.85, and 0.78-0.80 for U15 and U13, respectively). Independent samples t-test indicated significant differences between U13 and U15 in S10 (t-test: 3.57, p < 0.001), S20M (t-test: 3.13, p < 0.001), 20Y (t-test: 4.89, p < 0.001), FS_RAG (t-test: 3.96, p < 0.001), and FS_CODS (t-test: 6.42, p < 0.001), with better performance in U15. Starters outperformed non-starters in most capacities among U13, but only in FS_RAG among U15 (t-test: 1.56, p < 0.05). Multiple regression calculations indicated nonsignificant association between independent and dependent variables in U13 (FS_CODS: 19%, FS_RAG: 21% of the explained variance, both p > 0.05), but independent variables explained significant proportion of both dependent variables in U15 (FS_CODS: 35%, FS_RAG: 33% explained variance, both p < 0.05). The study confirmed the applicability of newly developed tests in distinguishing studied age categories of players. Results indicate that superiority in all studied fitness capacities is translated into performance level in U13. Meanwhile, FS_RAG seems to be important determinant of quality in U15.

Project description:BackgroundPhysician decision-making skills training is a priority to improve adoption of the cerebral palsy (CP) clinical guideline and, through this, lower the age of CP diagnosis. Clinical guideline implementation aims to improve physician practice, but evaluating meaningful change is complex. Limitations in the validity evidence of evaluation instruments impact the evidence base. Validity frameworks, such as Kane's, enable a targeted process to gather evidence for instrument scores, congruent to context and purpose. Yet, application of argument-based methodology to implementation validation is rare. Key-features examination methodology has established validity evidence supporting its use to measure decision-making skills, with potential to predict performance. We aimed to apply Kane's framework to evaluate a pilot key-features examination on physician decision-making in early CP diagnosis.MethodsFollowing Kane's framework, we evaluated evidence across inferences of scoring, generalisation, extrapolation and implications in a study design describing the development and pilot of a CP diagnosis key-features examination for practising physicians. If found to be valid, we proposed to use the key-feature scores as an outcome measure of decision-making post education intervention to expedite CP diagnosis and to correlate with real-world performance data to predict physician practice.ResultsSupporting evidence for acceptance of scoring inferences was achieved through examination development with an expert group (n = 10) and pilot results (n = 10): (1) high internal consistency (0.82); (2) acceptable mean item-discrimination (0.34); and (3) acceptable reliability of examination scorers (95.2% congruence). Decreased physician acceptance of examination time (70%) was identified as a threat and prioritised in case reduction processes. Partial acceptance of generalisation, extrapolation and implications inferences were defensible with: (1) accumulated development evidence following established key-features methodology; (2) high pilot acceptance for authenticity (90%); and (3) plausibility of assumptions of score correlation with population register data.ConclusionsKane's approach is beneficial for prioritising sources of validity evidence alongside the iterative development of a key-features examination in the CP field. The validity argument supports scoring assumptions and use of scores as an outcome measure of physician decision-making for CP guideline education implementation interventions. Scoring evidence provides the foundation to direct future studies exploring association of key-feature scores with real-world performance.

Dataset Information

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.

Publications

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.

Similar Datasets

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