Practical Experience of the Application of a Weighted Burden Test to Whole Exome Sequence Data for Obesity and Schizophrenia

For biological and statistical reasons it makes sense to combine information from variants at the level of the gene. One may wish to give more weight to variants which are rare and those that are more likely to affect function. A combined weighting scheme, implemented in the SCOREASSOC program, was applied to whole exome sequence data for 1392 subjects with schizophrenia and 982 with obesity from the UK10K project. Results conformed fairly well with null hypothesis expectations and no individual gene was strongly implicated. However, a number of the higher ranked genes appear plausible candidates as being involved in one or other phenotype and may warrant further investigation. These include MC4R, NLGN2, CRP, DONSON, GTF3A, IL36B, ADCYAP1R1, ARSA, DLG1, SIK2, SLAIN1, UBE2Q2, ZNF507, CRHR1, MUSK, NSF, SNORD115, GDF3 and HIBADH. Some individual variants in these genes have different frequencies between cohorts and could be genotyped in additional subjects. For other genes, there is a general excess of variants at many different sites so attempts at replication would be more difficult. Overall, the weighted burden test provides a convenient method for using sequence data to highlight genes of interest.     

An exploration of the disease burden due to Cryptosporidium in consumed surface water for sub-Saharan Africa

The protozoan pathogen Cryptosporidium is an important cause of diarrhoeal disease, but in many contexts its burden remains uncertain. The Global Waterborne Pathogen model for Cryptosporidium (GloWPa-Crypto) predicts oocyst concentrations in surface water at 0.5 by 0.5° (longitude by latitude) resolution, allowing us to assess the burden specifically associated with the consumption of contaminated surface water at a large scale. In this study, data produced by the GloWPa-Crypto model were used in a quantitative microbial risk assessment (QMRA) for sub-Saharan Africa, one of the regions most severely affected by diarrhoeal disease. We first estimated the number of people consuming surface water in this region and assessed both direct consumption and consumption from a piped (treated) supply. The disease burden was expressed in disability adjusted life years (DALYs). We estimate an annual number of 4.3 × 10⁷ (95% uncertainty interval [UI] 7.4 × 10⁶–5.4 × 10⁷) cases which represent 1.6 × 10⁶ (95% UI 3.2 × 10⁵–2.3 × 10⁶) DALYs. Relative disease burden (DALYs per 100,000 persons) varies widely, ranging between 1.3 (95% UI 0.1–5.7) for Senegal and 1.0 × 10³ (95% UI 4.2 × 10²–1.4 × 10³) for Eswatini. Countries that carry the highest relative disease burden are primarily located in south and south-east sub-Saharan Africa and are characterised by a relatively high HIV/AIDS prevalence. Direct surface water consumption accounts for the vast majority of cases, but the results also point towards the importance of stable drinking water treatment performance. This is, to our knowledge, the first study to utilise modelled data on pathogen concentrations in a large scale QMRA. It demonstrates the potential value of such data in epidemiological research, particularly regarding disease aetiology.     

Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

Objectives

Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC.

Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts

BackgroundTumor mutational burden (TMB) is an emerging biomarker used to identify patients who are more likely to benefit from immuno-oncology therapy. Aside from various unsettled technical aspects, biological variables such as tumor cell content and intratumor heterogeneity may play an important role in determining TMB.MethodsTMB estimates were determined applying the TruSight Oncology 500 targeted sequencing panel. Spatial and temporal heterogeneity was analyzed by multiregion sequencing (two to six samples) of 24 pulmonary adenocarcinomas and by sequencing a set of matched primary tumors, locoregional lymph node metastases, and distant metastases in five patients.ResultsOn average, a coding region of 1.28 Mbp was covered with a mean read depth of 609x. Manual validation of the mutation-calls confirmed a good performance, but revealed noticeable misclassification during germline filtering. Different regions within a tumor showed considerable spatial TMB variance in 30% (7 of 24) of the cases (maximum difference, 14.13 mut/Mbp). Lymph node–derived TMB was significantly lower (p = 0.016). In 13 cases, distinct mutational profiles were exclusive to different regions of a tumor, leading to higher values for simulated aggregated TMB. Combined, intratumor heterogeneity and the aggregated TMB could result in divergent TMB designation in 17% of the analyzed patients. TMB variation between primary tumor and distant metastases existed but was not profound.ConclusionsOur data show that, in addition to technical aspects such as germline filtering, the tumor content and spatially divergent mutational profiles within a tumor are relevant factors influencing TMB estimation, revealing limitations of single-sample–based TMB estimations in a clinical context.     

Alcohol and the burden of disease

World Health Organization (WHO) lists alcohol consumption as a leading risk to health, contributing 4% to the global burden of disease. This serves as justification for far-reaching preventive interventions. The purpose of this article is to recapitulate in narrative some of the assumptions upon which WHO conclusions rest and to interpret their validity accordingly. First, it may be misleading to include ‘alcohol use’ as a risk to health. As alcohol use has beneficial, protective as well as harmful properties, burden assessment should be based on harmful aspects only, e.g., ‘hazardous patterns of alcohol use’. Second, assessments of interventions aimed at reducing risks from alcohol use to disease burden should also consider such interventions’ impact on dimensions other than health or disease–in particular, psychosocial benefits of alcohol consumption. Third, the uncertainties associated with both the database and methodology for estimating the disease burden attributable to alcohol are high and need to be considered in the interpretation of findings.