Predicting breast cancer risk has long been a goal of medical research in the pursuit of precision medicine. The goal of this study is to develop novel penalized methods to improve breast cancer risk prediction by leveraging structure information in electronic health records. We conducted a retrospective case- control study, garnering 49 mammography descriptors and 77 high- frequency/low-penetrance single-nucleotide polymorphisms (SNPs) from an existing personalized medicine data repository. Structured mammography reports and breast imaging features have long been part of a standard electronic health record (EHR), and genetic markers likely will be in the near future. Lasso and its variants are widely used approaches to integrated learning and feature selection, and our methodological contribution is to incorporate the dependence structure among the features into these approaches. More specifically, we propose a new methodology by combining group penalty and $\ell^p$ ($1\leq p\leq2$) fusion penalty to improve breast cancer risk prediction, taking into account structure information in mammography descriptors and SNPs. We demonstrate that our method provides benefits that are both statistically significant and potentially significant to people's lives.

Hidden Markov random fields (HMRFs) are conventionally assumed to be homogeneous in the sense that the potential functions are invariant across different sites. However in some biological applications, it is desirable to make HMRFs heterogeneous, especially when there exists some background knowledge about how the potential functions vary. We formally define heterogeneous HMRFs and propose an EM algorithm whose M-step combines a contrastive divergence learner with a kernel smoothing step to incorporate the background knowledge. Simulations show that our algorithm is effective for learning heterogeneous HMRFs and outperforms alternative binning methods. We learn a heterogeneous HMRF in a real-world study.

It has been shown that graphical models can be used to leverage the dependence in large-scale multiple testing problems with significantly improved performance (Sun & Cai, 2009; Liu et al., 2012). These graphical models are fully parametric and require that we know the parameterization of f1, the density function of the test statistic under the alternative hypothesis. However in practice, f1 is often heterogeneous, and cannot be estimated with a simple parametric distribution. We propose a novel semiparametric approach for multiple testing under dependence, which estimates f1 adaptively. This semiparametric approach exactly generalizes the local FDR procedure (Efron et al., 2001) and connects with the BH procedure (Benjamini & Hochberg, 1995). A variety of simulations show that our semiparametric approach outperforms classical procedures which assume independence and the parametric approaches which capture dependence.

In large-scale applications of undirected graphical models, such as social networks and biological networks, similar patterns occur frequently and give rise to similar parameters. In this situation, it is beneficial to group the parameters for more efficient learning. We show that even when the grouping is unknown, we can infer these parameter groups during learning via a Bayesian approach. We impose a Dirichlet process prior on the parameters. Posterior inference usually involves calculating intractable terms, and we propose two approximation algorithms, namely a Metropolis-Hastings algorithm with auxiliary variables and a Gibbs sampling algorithm with stripped Beta approximation (GibbsSBA). Simulations show that both algorithms outperform conventional maximum likelihood estimation (MLE). GibbsSBA's performance is close to Gibbs sampling with exact likelihood calculation. Models learned with Gibbs_SBA also generalize better than the models learned by MLE on real-world Senate voting data.