The Role of Environmental Heterogeneity in Meta‐Analysis of Gene–Environment Interactions With Quantitative Traits

With challenges in data harmonization and environmental heterogeneity across various data sources, meta‐analysis of gene–environment interaction studies can often involve subtle statistical issues. In this paper, we study the effect of environmental covariate heterogeneity (within and between cohorts) on two approaches for fixed‐effect meta‐analysis: the standard inverse‐variance weighted meta‐analysis and a meta‐regression approach. Akin to the results in Simmonds and Higgins ( ), we obtain analytic efficiency results for both methods under certain assumptions. The relative efficiency of the two methods depends on the ratio of within versus between cohort variability of the environmental covariate. We propose to use an adaptively weighted estimator (AWE), between meta‐analysis and meta‐regression, for the interaction parameter. The AWE retains full efficiency of the joint analysis using individual level data under certain natural assumptions. Lin and Zeng (2010a, b) showed that a multivariate inverse‐variance weighted estimator retains full efficiency as joint analysis using individual level data, if the estimates with full covariance matrices for all the common parameters are pooled across all studies. We show consistency of our work with Lin and Zeng (2010a, b). Without sacrificing much efficiency, the AWE uses only univariate summary statistics from each study, and bypasses issues with sharing individual level data or full covariance matrices across studies. We compare the performance of the methods both analytically and numerically. The methods are illustrated through meta‐analysis of interaction between Single Nucleotide Polymorphisms in FTO gene and body mass index on high‐density lipoprotein cholesterol data from a set of eight studies of type 2 diabetes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107543/1/gepi21810.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107543/2/gepi21810-sup-0001-appendix.pd

Interventions to increase attendance for diabetic retinopathy screening

BACKGROUND: Despite evidence supporting the effectiveness of diabetic retinopathy screening (DRS) in reducing the risk of sight loss, attendance for screening is consistently below recommended levels.OBJECTIVES: The primary objective of the review was to assess the effectiveness of quality improvement (QI) interventions that seek to increase attendance for DRS in people with type 1 and type 2 diabetes.Secondary objectives were:To use validated taxonomies of QI intervention strategies and behaviour change techniques (BCTs) to code the description of interventions in the included studies and determine whether interventions that include particular QI strategies or component BCTs are more effective in increasing screening attendance;To explore heterogeneity in effect size within and between studies to identify potential explanatory factors for variability in effect size;To explore differential effects in subgroups to provide information on how equity of screening attendance could be improved;To critically appraise and summarise current evidence on the resource use, costs and cost effectiveness.SEARCH METHODS: We searched the Cochrane Library, MEDLINE, Embase, PsycINFO, Web of Science, ProQuest Family Health, OpenGrey, the ISRCTN, ClinicalTrials.gov, and the WHO ICTRP to identify randomised controlled trials (RCTs) that were designed to improve attendance for DRS or were evaluating general quality improvement (QI) strategies for diabetes care and reported the effect of the intervention on DRS attendance. We searched the resources on 13 February 2017. We did not use any date or language restrictions in the searches.SELECTION CRITERIA: We included RCTs that compared any QI intervention to usual care or a more intensive (stepped) intervention versus a less intensive intervention.DATA COLLECTION AND ANALYSIS: We coded the QI strategy using a modification of the taxonomy developed by Cochrane Effective Practice and Organisation of Care (EPOC) and BCTs using the BCT Taxonomy version 1 (BCTTv1). We used Place of residence, Race/ethnicity/culture/language, Occupation, Gender/sex, Religion, Education, Socioeconomic status, and Social capital (PROGRESS) elements to describe the characteristics of participants in the included studies that could have an impact on equity of access to health services.Two review authors independently extracted data. One review author entered the data into Review Manager 5 and a second review author checked them. Two review authors independently assessed risks of bias in the included studies and extracted data. We rated certainty of evidence using GRADE.MAIN RESULTS: We included 66 RCTs conducted predominantly (62%) in the USA. Overall we judged the trials to be at low or unclear risk of bias. QI strategies were multifaceted and targeted patients, healthcare professionals or healthcare systems. Fifty-six studies (329,164 participants) compared intervention versus usual care (median duration of follow-up 12 months). Overall, DRS attendance increased by 12% (risk difference (RD) 0.12, 95% confidence interval (CI) 0.10 to 0.14; low-certainty evidence) compared with usual care, with substantial heterogeneity in effect size. Both DRS-targeted (RD 0.17, 95% CI 0.11 to 0.22) and general QI interventions (RD 0.12, 95% CI 0.09 to 0.15) were effective, particularly where baseline DRS attendance was low. All BCT combinations were associated with significant improvements, particularly in those with poor attendance. We found higher effect estimates in subgroup analyses for the BCTs 'goal setting (outcome)' (RD 0.26, 95% CI 0.16 to 0.36) and 'feedback on outcomes of behaviour' (RD 0.22, 95% CI 0.15 to 0.29) in interventions targeting patients, and 'restructuring the social environment' (RD 0.19, 95% CI 0.12 to 0.26) and 'credible source' (RD 0.16, 95% CI 0.08 to 0.24) in interventions targeting healthcare professionals.Ten studies (23,715 participants) compared a more intensive (stepped) intervention versus a less intensive intervention. In these studies DRS attendance increased by 5% (RD 0.05, 95% CI 0.02 to 0.09; moderate-certainty evidence).Fourteen studies reporting any QI intervention compared to usual care included economic outcomes. However, only five of these were full economic evaluations. Overall, we found that there is insufficient evidence to draw robust conclusions about the relative cost effectiveness of the interventions compared to each other or against usual care.With the exception of gender and ethnicity, the characteristics of participants were poorly described in terms of PROGRESS elements. Seventeen studies (25.8%) were conducted in disadvantaged populations. No studies were carried out in low- or middle-income countries.AUTHORS' CONCLUSIONS: The results of this review provide evidence that QI interventions targeting patients, healthcare professionals or the healthcare system are associated with meaningful improvements in DRS attendance compared to usual care. There was no statistically significant difference between interventions specifically aimed at DRS and those which were part of a general QI strategy for improving diabetes care. This is a significant finding, due to the additional benefits of general QI interventions in terms of improving glycaemic control, vascular risk management and screening for other microvascular complications. It is likely that further (but smaller) improvements in DRS attendance can also be achieved by increasing the intensity of a particular QI component or adding further components.</p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

The IASLC Lung Cancer Staging Project: A Renewed Call to Participation

Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes ($\textit{ITGA4 }$ and $\textit{ITGB8}$) and at previously implicated loci ($\textit{ITGAL }$and $\textit{ICAM1}$). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, $\textit{PLCG2}$, and a negative regulator of inflammation, $\textit{SLAMF8}$. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.This work was co-funded by the Wellcome Trust [098051] and the Medical Research Council, UK [MR/J00314X/1]. Case collections were supported by Crohn’s and Colitis UK. KMdL, LM, CAL, YL, DR, JG-A, NJP, CAA and JCB are supported by the Wellcome Trust [098051; 093885/Z/10/Z; 094491/Z/10/Z]. KMdL is supported by a Woolf Fisher Trust scholarship. CAL is a clinical lecturer funded by the NIHR. We thank Anna Stanton for co-ordinating the Guy’s and St Thomas’ patient recruitment. We acknowledge support from the Department of Health via the NIHR comprehensive Biomedical Research Centre awards to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and to Addenbrooke’s Hospital, Cambridge in partnership with the University of Cambridge. This research was also supported by the NIHR Newcastle Biomedical Research Centre. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council