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2018 Colloquia

Revisiting the Genome Wide Threshold of 5 X 10-8 in 2018

Bhramar Mukherjee, Ph.D.
University of Michigan

During the past two years, there has been much discussion and debate around the perverse use of the P-value threshold of 0.05 to declare statistical significance for single null hypothesis testing. A recent recommendation by many eminent statisticians is to redefine statistical significance at P<0.005 [Benjamin et al, Nature Human Behavior, 2017].  This new threshold is motivated by the use of Bayes Factors and true control of false positive report probability.  In genome wide association studies, a much smaller threshold of 5 x 10-8 has been used with notable success in yielding reproducible results while testing millions of genetic variants.  I will first discuss the historic rationale for using this threshold.  We will then investigate whether this threshold that was proposed about a decade ago needs to be revisited with the current genome wide data we have in terms of the newer sequencing platforms, imputation strategies, testing rare versus common variants, the existing knowledge we have gathered regarding true association signals, or for controlling other metrics associated with multiple hypotheses testing beyond the family wise error rate.  I will discuss notions of Bayesian error rates for multiple testing and use connections between the Bayes Factor and the Frequentist Factor (the ratio of power and Type 1 error) for declaring new discoveries.  Empirical studies using data from the Global Lipids Consortium will be used to evaluate if we applied various thresholds/decision rules in 2008 or 2009, how many of the most recent GWAS results (in 2013) would we detect and what would be our “true” false discovery rate. This is joint work with Zhongsheng Chen and Michael Boehnke at the University of Michigan.

Friday, April 20, 2018
4:00 p.m. - 5:00 p.m.
River Campus - Wegmans Hall Room 1400

Does DNA-Methylation Mediate the Effect of Maternal Smoking on Birth Weight? Exposure Misclassification in Mediation Analyses for Environmental Epigenetic Studies

Linda Valeri, Ph.D.
McLean's
Psychiatric Biostatistics Laboratory

Assessing whether epigenetic alterations mediate associations between environmental exposures and health outcomes is increasingly popular. We investigate the impact of exposure misclassification in such investigations. We quantify bias and false positive rates due to exposure misclassification in mediation analysis and assess the performance of SIMEX correction approach. Further, we evaluate whether DNA-methylation mediates smoking-birth weight relationship in the MoBa birth cohort. Ignoring exposure misclassification increases Type I error in mediation analysis. The direct effect is underestimated and, when the mediator is a biomarker of the exposure, as is true for smoking, the indirect effect is overestimated. Misclassification correction plus cautious interpretation are recommended for mediation analyses in the presence of exposure misclassification.

Thursday, April 12, 2018

A Model for the Regulation of Follicular Dendritic Cells Predicts Invariant Reciprocal-Time Decay of Post-Vaccine Antibody Response

Anthony Almudevar, Ph.D.
University of Rochester

Follicular dendritic cells (FDC) play a crucial role in the regulation of humoral immunity. They are believed to be responsible for long-term persistence of antibody, due to their role in antibody response induction and their ability to retain antigen in immunogenic form for long periods. In this talk, a regulatory control model is described which links persistence of humoral immunity with cellular processes associated with FDCs (Almudevar 2017, Immunology and Cell Biology). The argument comprises three elements. The first is a review of population-level studies of post-vaccination antibody persistence. It is found that reciprocal-time (= 1/t) decay of antibody levels is widely reported, over a range of ages, observation times and vaccine types. The second element is a mathematical control model for cell population decay for which reciprocal-time decay is a stable attractor. Additionally, control effectors are easily identified, leading to models of homeostatic control of the reciprocal-time decay rate. The final element is a review of known FDC functionality. This reveals a striking concordance between cell properties required by the model and those widely observed of FDCs, some of which are unique to this cell type. The proposed model is able to unify a wide range of disparate observations of FDC function under one regulatory principle, and to characterize precisely forms of FDC regulation and dysregulation. Many infectious and immunological diseases are increasingly being linked to FDC regulation, therefore a precise understanding of the underlying mechanisms would be of significant benefit for the development of new therapies.

Thursday, March 22, 2018

Clustering Three-Way Data Using Mixture Models

Paul McNicholas, Ph.D.
McMaster University

Clustering is the process of finding underlying group structures in data. Although mixture model-based clustering is firmly established in the multivariate case, there is a relative paucity of work on matrix variate distributions. Several mixtures of matrix variate distributions are discussed, along with some details on parameter estimation. Real and simulated data are used for illustration, and some suggestions for future work are discussed.

Thursday, March 1, 2018