The Population Genetic Signature of Polygenic Local Adaptation

Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We first describe a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of $Q_{ST}/F_{ST}$ comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.Comment: 42 pages including 8 figures and 3 tables; supplementary figures and tables not included on this upload, but are mostly unchanged from v

Unsupervised learning for anomaly detection in Australian medical payment data

Fraudulent or wasteful medical insurance claims made by health care providers are costly for insurers. Typically, OECD healthcare organisations lose 3-8% of total expenditure due to fraud. As Australia’s universal public health insurer, Medicare Australia, spends approximately $A 34 billion per annum on the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme, wasted spending of$A1–2.7 billion could be expected.However, fewer than 1% of claims to Medicare Australia are detected as fraudulent, below international benchmarks. Variation is common in medicine, and health conditions, along with their presentation and treatment, are heterogenous by nature. Increasing volumes of data and rapidly changing patterns bring challenges which require novel solutions. Machine learning and data mining are becoming commonplace in this field, but no gold standard is yet available. In this project, requirements are developed for real-world application to compliance analytics at the Australian Government Department of Health and Aged Care (DoH), covering: unsupervised learning; problem generalisation; human interpretability; context discovery; and cost prediction. Three novel methods are presented which rank providers by potentially recoverable costs. These methods used association analysis, topic modelling, and sequential pattern mining to provide interpretable, expert-editable models of typical provider claims. Anomalous providers are identified through comparison to the typical models, using metrics based on costs of excess or upgraded services. Domain knowledge is incorporated in a machine-friendly way in two of the methods through the use of the MBS as an ontology. Validation by subject-matter experts and comparison to existing techniques shows that the methods perform well. The methods are implemented in a software framework which enables rapid prototyping and quality assurance. The code is implemented at the DoH, and further applications as decision-support systems are in progress. The developed requirements will apply to future work in this fiel

Multivariate Data Modeling and Its Applications to Conditional Outlier Detection

With recent advances in data technology, large amounts of data of various kinds and from various sources are being generated and collected every second. The increase in the amounts of collected data is often accompanied by increase in the complexity of data types and objects we are able to store. The next challenge is the development of machine learning methods for their analyses. This thesis contributes to the effort by focusing on the analysis of one such data type, complex input-output data objects with high-dimensional multivariate binary output spaces, and two data-analytic problems: Multi-Label Classification and Conditional Outlier Detection. First, we study the Multi-label Classification (MLC) problem that concerns classification of data instances into multiple binary output (class or response) variables that reflect different views, functions, or components describing the data. We present three MLC frameworks that effectively learn and predict the best output configuration for complex input-output data objects. Our experimental evaluation on a range of datasets shows that our solutions outperform several state-of-the-art MLC methods and produce more reliable posterior probability estimates. Second, we investigate the Conditional Outlier Detection (COD) problem, where our goal is to identify unusual patterns observed in the multi-dimensional binary output space given their input context. We made two important contributions to the definition and solutions of COD. First, by observing a gap in between the development of unconditional and conditional outlier detection approaches, we propose a ratio of outlier scores (ROS) that uses a pair of unconditional scores to calculate the conditional scores. Second, we show that by applying the chain decomposition of the probabilistic model, the probabilistic multivariate COD score decomposes to a set of probabilistic univariate COD scores. This decomposition can be subsequently generalized and extended to a broad spectrum of multivariate COD scores, including the new ROS score and its variants, leading to a new multivariate conditional outlier scoring framework. Through experiments on synthetic and real-world datasets with simulated outliers, we provide empirical results that support the validity of our COD methods

Anomaly Detection in Categorical Datasets with Artificial Contrasts

abstract: Anomaly is a deviation from the normal behavior of the system and anomaly detection techniques try to identify unusual instances based on deviation from the normal data. In this work, I propose a machine-learning algorithm, referred to as Artificial Contrasts, for anomaly detection in categorical data in which neither the dimension, the specific attributes involved, nor the form of the pattern is known a priori. I use RandomForest (RF) technique as an effective learner for artificial contrast. RF is a powerful algorithm that can handle relations of attributes in high dimensional data and detect anomalies while providing probability estimates for risk decisions. I apply the model to two simulated data sets and one real data set. The model was able to detect anomalies with a very high accuracy. Finally, by comparing the proposed model with other models in the literature, I demonstrate superior performance of the proposed model.Dissertation/ThesisMasters Thesis Industrial Engineering 201

Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors.

Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing. Using RNA-sequencing data from breast tumors and germline genotypes from The Cancer Genome Atlas, we tested the association between each risk SNP genotype and exon-, exon-exon junction- or transcript-specific expression of nearby genes. Six SNPs were associated with differential transcript expression of seven nearby genes at FDR < 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4). We next developed a Bayesian approach to evaluate, for each SNP, the overlap between the signal of association with breast cancer and the signal of association with alternative splicing. At one locus (SRGAP2D), this method eliminated the possibility that the breast cancer risk and the alternate splicing event were due to the same causal SNP. Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay. Our results suggest that the regulation of differential transcript isoform expression is the functional mechanism of some breast cancer risk SNPs and that we can use these associations to identify causal SNPs, target genes and the specific transcripts that may mediate breast cancer risk

Big data analytics for preventive medicine

© 2019, Springer-Verlag London Ltd., part of Springer Nature. Medical data is one of the most rewarding and yet most complicated data to analyze. How can healthcare providers use modern data analytics tools and technologies to analyze and create value from complex data? Data analytics, with its promise to efficiently discover valuable pattern by analyzing large amount of unstructured, heterogeneous, non-standard and incomplete healthcare data. It does not only forecast but also helps in decision making and is increasingly noticed as breakthrough in ongoing advancement with the goal is to improve the quality of patient care and reduces the healthcare cost. The aim of this study is to provide a comprehensive and structured overview of extensive research on the advancement of data analytics methods for disease prevention. This review first introduces disease prevention and its challenges followed by traditional prevention methodologies. We summarize state-of-the-art data analytics algorithms used for classification of disease, clustering (unusually high incidence of a particular disease), anomalies detection (detection of disease) and association as well as their respective advantages, drawbacks and guidelines for selection of specific model followed by discussion on recent development and successful application of disease prevention methods. The article concludes with open research challenges and recommendations