A systematic review and standardized clinical validity assessment of genes involved in female reproductive failure.
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ABSTRACT:
SUBMITTER: Volozonoka L
PROVIDER: S-EPMC9066658 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Study questionWhich genes are confidently linked to human monogenic male infertility?Summary answerOur systematic literature search and clinical validity assessment reveals that a total of 78 genes are currently confidently linked to 92 human male infertility phenotypes.What is known alreadyThe discovery of novel male infertility genes is rapidly accelerating with the availability of next-generating sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes.Study design, size, durationWe performed a systematic literature search and evidence assessment for all publications in Pubmed until December 2018 covering genetic causes of male infertility and/or defective male genitourinary development.Participants/materials, setting, methodsTwo independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify.Main results and the role of chanceFrom a total of 23 526 records, we included 1337 publications about monogenic causes of male infertility leading to a list of 521 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n = 38) to strong (n = 22), moderate (n = 32), limited (n = 93) or no evidence (n = 160). A total of 176 gene-disease relationships could not be classified because our scoring method was not suitable.Large scale dataNot applicable.Limitations, reasons for cautionOur literature search was limited to Pubmed.Wider implications of the findingsThe comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and help to identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations for the field of male infertility.Study funding/competing interest(s)This work was supported by a VICI grant from The Netherlands Organization for Scientific Research (918-15-667 to J.A.V.), the Royal Society, and Wolfson Foundation (WM160091 to J.A.V.) as well as an investigator award in science from the Wellcome Trust (209451 to J.A.V.).Prospero registration numberNone.
| S-EPMC6505449 | biostudies-literature
Project description:Ascertaining a diagnosis through exome sequencing can provide potential benefits to patients, insurance companies, and the healthcare system. Yet, as diagnostic sequencing is increasingly employed, vast amounts of human genetic data are produced that need careful curation. We discuss methods for accurately assessing the clinical validity of gene-disease relationships to interpret new research findings in a clinical context and increase the diagnostic rate. The specifics of a gene-disease scoring system adapted for use in a clinical laboratory are described. In turn, clinical validity scoring of gene-disease relationships can inform exome reporting for the identification of new or the upgrade of previous, clinically relevant gene findings. Our retrospective analysis of all reclassification reports from the first 4 years of diagnostic exome sequencing showed that 78% were due to new gene-disease discoveries published in the literature. Among all exome positive/likely positive findings in characterized genes, 32% were in genetic etiologies that were discovered after 2010. Our data underscore the importance and benefits of active and up-to-date curation of a gene-disease database combined with critical clinical validity scoring and proactive reanalysis in the clinical genomics era.
| S-EPMC5655771 | biostudies-literature
Project description:BackgroundAdvances in sequencing technology have led to expanded use of multi-gene panel tests (MGPTs) for clinical diagnostics. Well-designed MGPTs must balance increased detection of clinically significant findings while mitigating the increase in variants of uncertain significance (VUS). To maximize clinical utililty, design of such panels should include comprehensive gene vetting using a standardized clinical validity (CV) scoring system.MethodsTo assess the impact of CV-based gene vetting on MGPT results, data from MGPTs for cardiovascular indications were retrospectively analyzed. Using our CV scoring system, genes were categorized as having definitive, strong, moderate, or limited evidence. The rates of reported pathogenic or likely pathogenic variants and VUS were then determined for each CV category.ResultsOf 106 total genes, 42% had definitive, 17% had strong, 29% had moderate, and 12% had limited CV. The detection rate of variants classified as pathogenic or likely pathogenic was higher for genes with greater CV, while the VUS rate showed an inverse relationship with CV score. No pathogenic or likely pathogenic findings were observed in genes with a limited CV.ConclusionThese results demonstrate the importance of a standardized, evidence-based vetting process to establish CV for genes on MGPTs. Using our proposed system may help to increase the detection rate while mitigating higher VUS rates.
| S-EPMC6503028 | biostudies-literature
Project description:IntroductionThe authors developed a Standardized Assessment for Evaluation of Team Skills (SAFE-TeamS) in which actors portray health care team members in simulated challenging teamwork scenarios. Participants are scored on scenario-specific ideal behaviors associated with assistance, conflict resolution, communication, assertion, and situation assessment. This research sought to provide evidence of the validity and feasibility of SAFE-TeamS as a tool to support the advancement of science related to team skills training.MethodsThirty-eight medical and nursing students were assessed using SAFE-TeamS before and after team skills training. The SAFE-TeamS pretraining and posttraining scores were compared, and participants were surveyed. Generalizability analysis was used to estimate the variance in scores associated with the following: examinee, scenario, rater, pretraining/posttraining, examinee type, rater type (actor-live vs. external rater-videotape), actor team, and scenario order.ResultsThe SAFE-TeamS scores reflected improvement after training and were sensitive to individual differences. Score variance due to rater was low. Variance due to scenario was moderate. Estimates of relative reliability for 2 raters and 8 scenarios ranged from 0.6 to 0.7. With fixed scenarios and raters, 2 raters and 2 scenarios, reliability is greater than 0.8. Raters believed SAFE-TeamS assessed relevant team skills. Examinees' responses were mixed.ConclusionsThe SAFE-TeamS was sensitive to individual differences and team skill training, providing evidence for validity. It is not clear whether different scenarios measure different skills and whether the scenarios cover the necessary breadth of skills. Use of multiple scenarios will support assessment across a broader range of skills. Future research is required to determine whether assessments using SAFE-TeamS will translate to performance in clinical practice.
| S-EPMC6623970 | biostudies-literature
Project description:Schistosomiasis affects more than 200 million people globally. The pathology of schistosome infections is due to chronic tissue inflammation and damage from immune generated granulomas surrounding parasite eggs trapped in host tissues. Schistosoma species are unique among trematode parasites because they are dioecious; females require paring with male parasites in order to attain reproductive maturity and produce viable eggs. Ex vivo cultured females lose the ability to produce viable eggs due to an involution of the vitellarium and loss of mature oocytes. In order to better understand schistosome reproductive biology we used data generated by serial analysis of gene expression (SAGE) to identify uncharacterized genes which have different transcript abundance in mature females, those that have been paired with males, and immature females obtained from unisexual infections. To characterize these genes we used bioinformatics, transcript localization, and transcriptional analysis during the regression of in vitro cultured females. Genes transcribed exclusively in mature females localize primarily in the vitellocytes and/or the ovary. Genes transcribed exclusively in females from single sex infections localize to vitellocytes and subtegumental cells. As female reproductive tissues regress, eggshell precursor proteins and genes involved in eggshell synthesis largely have decreased transcript abundance. However, some genes with elevated transcript abundance in mature adults have increased gene expression following regression indicating that the genes in this study function both in eggshell biology as well as vitellogenesis and maintenance of female reproductive tissues. In addition, we found that genes enriched in females from single sex infections have increased expression during regression in ex vivo females. By using these transcriptional analyses we can direct research to examine the areas of female biology that are both relevant to understanding the overall process of female development and worm pairing while determining novel therapeutic approaches directed at the maturation of female schistosomes.
| S-EPMC3499410 | biostudies-literature
Project description:CONTEXT: Health care professions have replaced traditional multiple choice tests or essays with structured and practical, performance-based examinations with the hope of eliminating rater bias and measuring clinical competence. OBJECTIVE: To establish the validity and reliability of the Standardized Orthopedic Assessment Tool (SOAT) as a measure of clinical competence of orthopaedic injury evaluation. DESIGN: Descriptive laboratory study. SETTING: University. PATIENTS OR OTHER PARTICIPANTS: A total of 60 undergraduate students and 11 raters from 3 Canadian universities and 1 standardized patient. INTERVENTION(S): Students were required to complete a 30-minute musculoskeletal evaluation in 1 of 2 randomly assigned mock scenarios involving the knee (second-degree medial collateral ligament sprain) or the shoulder (third-degree supraspinatus muscle strain). MAIN OUTCOME MEASURE(S): We measured interreliability with an intraclass correlation coefficient (ICC) (2,k) and stability of the tool with standard error of measurement and confidence intervals. Agreement was measured using Bland-Altman plots. Concurrent validity was measured using a Pearson product moment correlation coefficient whereby the raters' global rating of a student was matched to the cumulative mean grade score. RESULTS: The ICCs were 0.75 and 0.82 for the shoulder and knee cases, respectively. Bland-Altman plots indicated no systematic bias between raters. In addition, Pearson product moment correlation analysis demonstrated a strong relationship between the overall cumulative mean grade score and the global rating score of the examinees' performances. CONCLUSIONS: This study demonstrated good interrater reliability of the SOAT with a standard error of measurement that indicated very modest stability, strong agreement between raters, and correlation indicative of concurrent validity.
| S-EPMC4080604 | biostudies-other
Project description:BackgroundHereditary ataxias are a heterogeneous group of degenerative diseases of the cerebellum, brainstem, and spinal cord. They may present with isolated ataxia or with additional symptoms going beyond cerebellar deficits. There are an increasing number of clinical studies with the goal to define the natural history of these disorders, develop biomarkers, and investigate therapeutic interventions. Especially, early and preclinical disease stages are currently of particular interest.Methods and resultsEvidence-based, we review standards for sampling and storage of biomaterials, clinical and neuropsychological assessment, as well as neurophysiology and neuroimaging and recommendations for standardized assessment of ataxia patients in multicenter studies.ConclusionsDNA, RNA, serum, and, if possible, cerebrospinal fluid samples should be processed following established standards. Clinical assessment in ataxia studies must include use of a validated clinical ataxia scale. There are several validated clinical ataxia scales available. There are no instruments that were specifically designed for assessing neuropsychological and psychiatric symptoms in ataxia disorders. We provide a list of tests that may prove valuable. Quantitative performance tests have the potential to supplement clinical scales. They provide additional objective and quantitative information. Posturography and quantitative movement analysis-despite valid approaches-require standardization before implemented in multicenter studies. Standardization of neurophysiological tools, as required for multicenter interventional trials, is still lacking. Future multicenter neuroimaging studies in ataxias should implement quality assurance measures as defined by the ADNI or other consortia. MRI protocols should allow morphometric analyses.
| S-EPMC6178745 | biostudies-literature
Project description:PurposeSeveral genes on hereditary breast and ovarian cancer susceptibility test panels have not been systematically examined for strength of association with disease. We employed the Clinical Genome Resource (ClinGen) clinical validity framework to assess the strength of evidence between selected genes and breast or ovarian cancer.MethodsThirty-one genes offered on cancer panel testing were selected for evaluation. The strength of gene-disease relationship was systematically evaluated and a clinical validity classification of either Definitive, Strong, Moderate, Limited, Refuted, Disputed, or No Reported Evidence was assigned.ResultsDefinitive clinical validity classifications were made for 10/31 and 10/32 gene-disease pairs for breast and ovarian cancer respectively. Two genes had a Moderate classification whereas, 6/31 and 6/32 genes had Limited classifications for breast and ovarian cancer respectively. Contradictory evidence resulted in Disputed or Refuted assertions for 9/31 genes for breast and 4/32 genes for ovarian cancer. No Reported Evidence of disease association was asserted for 5/31 genes for breast and 11/32 for ovarian cancer.ConclusionEvaluation of gene-disease association using the ClinGen clinical validity framework revealed a wide range of classifications. This information should aid laboratories in tailoring appropriate gene panels and assist health-care providers in interpreting results from panel testing.
| S-EPMC6579711 | biostudies-literature
Project description:Male-derived accessory gland proteins that are transferred to females during mating have profound effects on female reproductive physiology including increased ovulation, mating inhibition, and effects on sperm utilization and storage. The extreme rates of evolution seen in accessory gland proteins may be driven by sperm competition and sexual conflict, processes that may ultimately drive complex interactions between female- and male-derived molecules and sperm. However, little is known of how gene expression in female reproductive tissues changes in response to the presence of male molecules and sperm. To characterize this response, we conducted parallel genomic and proteomic analyses of gene expression in the reproductive tract of 3-day-old unmated and mated female Drosophila melanogaster. Using DNA microarrays, we identified 539 transcripts that are differentially expressed in unmated vs. mated females and revealed a striking peak in differential expression at 6 h postmating and a marked shift from primarily down-regulated to primarily up-regulated transcripts within 3 h after mating. Combining two-dimensional gel electrophoresis and liquid chromatography mass spectrometry analyses, we identified 84 differentially expressed proteins at 3 h postmating, including proteins that appeared to undergo posttranslational modification. Together, our observations define transcriptional and translational response to mating within the female reproductive tract and suggest a bimodal model of postmating gene expression initially correlated with mating and the final stages of female reproductive tract maturation and later with the declining presence of male reproductive molecules and with sperm maintenance and utilization.
| S-EPMC1502462 | biostudies-literature
Project description:Dietary assessment methods that are recognized as appropriate for the general population are usually applied in a similar manner to athletes, despite the knowledge that sport-specific factors can complicate assessment and impact accuracy in unique ways. As dietary assessment methods are used extensively within the field of sports nutrition, there is concern the validity of methodologies have not undergone more rigorous evaluation in this unique population sub-group. The purpose of this systematic review was to compare two or more methods of dietary assessment, including dietary intake measured against biomarkers or reference measures of energy expenditure, in athletes. Six electronic databases were searched for English-language, full-text articles published from January 1980 until June 2016. The search strategy combined the following keywords: diet, nutrition assessment, athlete, and validity; where the following outcomes are reported but not limited to: energy intake, macro and/or micronutrient intake, food intake, nutritional adequacy, diet quality, or nutritional status. Meta-analysis was performed on studies with sufficient methodological similarity, with between-group standardized mean differences (or effect size) and 95% confidence intervals (CI) being calculated. Of the 1624 studies identified, 18 were eligible for inclusion. Studies comparing self-reported energy intake (EI) to energy expenditure assessed via doubly labelled water were grouped for comparison (n = 11) and demonstrated mean EI was under-estimated by 19% (-2793 ± 1134 kJ/day). Meta-analysis revealed a large pooled effect size of -1.006 (95% CI: -1.3 to -0.7; p < 0.001). The remaining studies (n = 7) compared a new dietary tool or instrument to a reference method(s) (e.g., food record, 24-h dietary recall, biomarker) as part of a validation study. This systematic review revealed there are limited robust studies evaluating dietary assessment methods in athletes. Existing literature demonstrates the substantial variability between methods, with under- and misreporting of intake being frequently observed. There is a clear need for careful validation of dietary assessment methods, including emerging technical innovations, among athlete populations.
| S-EPMC5748763 | biostudies-literature