Comprehensive Genotyping in Two Homogeneous Graves' Disease Samples Reveals Major and Novel HLA Association Alleles

BACKGROUND: Graves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR]  = 1.33, Bonferroni corrected combined P [P(Bc)]  = 1.17 x 10⁻²), DPB1*05:01 (OR  = 2.34, P(Bc) = 2.58 x 10⁻¹⁰), DQB1*03:02 (OR  = 0.62, P(Bc)  = 1.97 x 10⁻²), DRB1*15:01 (OR  = 1.68, P(Bc) = 1.22 x 10⁻²) and DRB1*16:02 (OR  = 2.63, P(Bc)  = 1.46 x 10⁻⁵) were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk. CONCLUSIONS/SIGNIFICANCE: These GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Accuracy of Patient Health Questionnaire-9 (PHQ-9) for screening to detect major depression: individual participant data meta-analysis

Objective: To determine the accuracy of the Patient Health Questionnaire-9 (PHQ-9) for screening to detect major depression. Design: Individual participant data meta-analysis. Data sources: Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, and Web of Science (January 2000-February 2015). Inclusion criteria: Eligible studies compared PHQ-9 scores with major depression diagnoses from validated diagnostic interviews. Primary study data and study level data extracted from primary reports were synthesized. For PHQ-9 cut-off scores 5-15, bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, among studies that used semistructured diagnostic interviews, which are designed for administration by clinicians; fully structured interviews, which are designed for lay administration; and the Mini International Neuropsychiatric (MINI) diagnostic interviews, a brief fully structured interview. Sensitivity and specificity were examined among participant subgroups and, separately, using meta-regression, considering all subgroup variables in a single model. Results: Data were obtained for 58 of 72 eligible studies (total n=17 357; major depression cases n=2312). Combined sensitivity and specificity was maximized at a cut-off score of 10 or above among studies using a semistructured interview (29 studies, 6725 participants; sensitivity 0.88, 95% confidence interval 0.83 to 0.92; specificity 0.85, 0.82 to 0.88). Across cut-off scores 5-15, sensitivity with semistructured interviews was 5-22% higher than for fully structured interviews (MINI excluded; 14 studies, 7680 participants) and 2-15% higher than for the MINI (15 studies, 2952 participants). Specificity was similar across diagnostic interviews. The PHQ-9 seems to be similarly sensitive but may be less specific for younger patients than for older patients; a cut-off score of 10 or above can be used regardless of age.. Conclusions: PHQ-9 sensitivity compared with semistructured diagnostic interviews was greater than in previous conventional meta-analyses that combined reference standards. A cut-off score of 10 or above maximized combined sensitivity and specificity overall and for subgroups. Registration: PROSPERO CRD42014010673

Probability of major depression diagnostic classification using semi-structured vs. fully structured diagnostic interviews

Background: Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification. Aims: To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics. Method: Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analyzed. Binomial Generalized Linear Mixed Models were fit. Results: 17,158 participants (2,287 major depression cases) from 57 primary studies were analyzed. Among fully structured interviews, odds of major depression were higher for the MINI compared to the Composite International Diagnostic Interview (CIDI) [OR (95% CI) = 2.10 (1.15-3.87)]. Compared to semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores 6) as having major depression [OR (95% CI) = 3.13 (0.98-10.00)], similarly likely for moderate-level symptoms (PHQ-9 scores 7-15) [OR (95% CI) = 0.96 (0.56-1.66)], and significantly less likely for high-level symptoms (PHQ-9 scores 16) [OR (95% CI) = 0.50 (0.26-0.97)]. Conclusions: The MINI may identify more depressed cases than the CIDI, and semi- and fully structured interviews may not be interchangeable methods, but these results should be replicated

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Survey of Ambient Air Pollution Health Risk Assessment Tools

Analysts quantify the health impacts of air pollution to estimate the total public health burden of ambient air pollution and the potential health benefits of reducing air pollution levels. Risk assessors and policy analysts now employ several tools to automate air pollution health impact assessments. This paper reviews 12 multinational air pollution health impact assessment tools that are currently available, categorizes the tools according to key technical and operational characteristics for different assessment contexts, and identifies information gaps that should be considered for future work. Key characteristics include spatial resolution, pollutants and health effect outcomes evaluated, and method for characterizing of population exposure, as well as tool format, accessibility, complexity, and degree of peer-review and application in policy contexts. The range of key characteristics among the tools demonstrates that there is an important trade-off between technical refinement and accessibility for a broad range of applications. Guidance should be developed to help analysts identify the tool most appropriate for the purpose of the assessment and to assist users in interpreting and communicating results. Future work should also strive to better account for multiple sources of uncertainty and to integrate ambient outdoor air pollution health impact assessment tools with those addressing household air pollution and other health factors, such as vehicle accidents and physical activity.JRC.H.2-Air and Climat