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Discovering weaker genetic associations guided by known associations.

ABSTRACT: BACKGROUND:The current understanding of the genetic basis of complex human diseases is that they are caused and affected by many common and rare genetic variants. A considerable number of the disease-associated variants have been identified by Genome Wide Association Studies, however, they can explain only a small proportion of heritability. One of the possible reasons for the missing heritability is that many undiscovered disease-causing variants are weakly associated with the disease. This can pose serious challenges to many statistical methods, which seems to be only capable of identifying disease-associated variants with relatively stronger coefficients. RESULTS:In order to help identify weaker variants, we propose a novel statistical method, Constrained Sparse multi-locus Linear Mixed Model (CS-LMM) that aims to uncover genetic variants of weaker associations by incorporating known associations as a prior knowledge in the model. Moreover, CS-LMM accounts for polygenic effects as well as corrects for complex relatednesses. Our simulation experiments show that CS-LMM outperforms other competing existing methods in various settings when the combinations of MAFs and coefficients reflect different scenarios in complex human diseases. CONCLUSIONS:We also apply our method to the GWAS data of alcoholism and Alzheimer's disease and exploratively discover several SNPs. Many of these discoveries are supported through literature survey. Furthermore, our association results strengthen the belief in genetic links between alcoholism and Alzheimer's disease.

SUBMITTER: Wang H

PROVIDER: S-EPMC7038505 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Discovering weaker genetic associations guided by known associations.

Wang Haohan H Vanyukov Michael M MM Xing Eric P EP Wu Wei W

BMC medical genomics 20200224 Suppl 3

<h4>Background</h4>The current understanding of the genetic basis of complex human diseases is that they are caused and affected by many common and rare genetic variants. A considerable number of the disease-associated variants have been identified by Genome Wide Association Studies, however, they can explain only a small proportion of heritability. One of the possible reasons for the missing heritability is that many undiscovered disease-causing variants are weakly associated with the disease. ...[more]

PMID: 32093702

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Project description:BackgroundThe Health Information Technology for Economic and Clinical Health Act (HITECH) has greatly accelerated the adoption of electronic health records (EHRs) with the promise of better clinical decisions and patients' outcomes. One of the core criteria for "Meaningful Use" of EHRs is to have a problem list that shows the most important health problems faced by a patient. The implementation of problem lists in EHRs has a potential to help practitioners to provide customized care to patients. However, it remains an open question on how to leverage problem lists in different practice settings to provide tailored care, of which the bottleneck lies in the associations between problem list and practice setting.MethodsIn this study, using sampled clinical documents associated with a cohort of patients who received their primary care at Mayo Clinic, we investigated the associations between problem list and practice setting through natural language processing (NLP) and topic modeling techniques. Specifically, after practice settings and problem lists were normalized, statistical χ2 test, term frequency-inverse document frequency (TF-IDF) and enrichment analysis were used to choose representative concepts for each setting. Then Latent Dirichlet Allocations (LDA) were used to train topic models and predict potential practice settings using similarity metrics based on the problem concepts representative of practice settings. Evaluation was conducted through 5-fold cross validation and Recall@k, Precision@k and F1@k were calculated.ResultsOur method can generate prioritized and meaningful problem lists corresponding to specific practice settings. For practice setting prediction, recall increases from 0.719 (k = 2) to 0.931 (k = 10), precision increases from 0.882 (k = 2) to 0.931 (k = 10) and F1 increases from 0.790 (k = 2) to 0.931 (k = 10).ConclusionTo our best knowledge, our study is the first attempting to discover the association between the problem lists and hospital practice settings. In the future, we plan to investigate how to provide more tailored care by utilizing the association between problem list and practice setting revealed in this study.

Project description:A genome-wide association study (GWAS) typically involves examining representative SNPs in individuals from some population. A GWAS data set can concern a million SNPs and may soon concern billions. Researchers investigate the association of each SNP individually with a disease, and it is becoming increasingly commonplace to also analyze multi-SNP associations. Techniques for handling so many hypotheses include the Bonferroni correction and recently developed bayesian methods. These methods can encounter problems. Most importantly, they are not applicable to a complex multi-locus hypothesis which has several competing hypotheses rather than only a null hypothesis. A method that computes the posterior probability of complex hypotheses is a pressing need.We introduce the bayesian network posterior probability (BNPP) method which addresses the difficulties. The method represents the relationship between a disease and SNPs using a directed acyclic graph (DAG) model, and computes the likelihood of such models using a bayesian network scoring criterion. The posterior probability of a hypothesis is computed based on the likelihoods of all competing hypotheses. The BNPP can not only be used to evaluate a hypothesis that has previously been discovered or suspected, but also to discover new disease loci associations. The results of experiments using simulated and real data sets are presented. Our results concerning simulated data sets indicate that the BNPP exhibits both better evaluation and discovery performance than does a p-value based method. For the real data sets, previous findings in the literature are confirmed and additional findings are found.We conclude that the BNPP resolves a pressing problem by providing a way to compute the posterior probability of complex multi-locus hypotheses. A researcher can use the BNPP to determine the expected utility of investigating a hypothesis further. Furthermore, we conclude that the BNPP is a promising method for discovering disease loci associations.

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Discovering weaker genetic associations guided by known associations.

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Discovering weaker genetic associations guided by known associations.

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