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Article ; Online: RE: Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program.

Haiman, Christopher A / Kote-Jarai, Zsofia / Darst, Burcu F / Conti, David V

Journal of the National Cancer Institute

2023 Volume 115, Issue 3, Page(s) 341–342

MeSH term(s)	Male ; Humans ; Veterans ; Prostatic Neoplasms/epidemiology ; Prostatic Neoplasms/genetics ; Risk Factors
Language	English
Publishing date	2023-01-11
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djad005
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Article ; Online: Hierarchical joint analysis of marginal summary statistics-Part I: Multipopulation fine mapping and credible set construction.

Shen, Jiayi / Jiang, Lai / Wang, Kan / Wang, Anqi / Chen, Fei / Newcombe, Paul J / Haiman, Christopher A / Conti, David V

Genetic epidemiology

2024

Abstract: Recent advancement in genome-wide association studies (GWAS) comes from not only increasingly larger sample sizes but also the shift in focus towards underrepresented populations. Multipopulation GWAS increase power to detect novel risk variants and ... ...

Abstract	Recent advancement in genome-wide association studies (GWAS) comes from not only increasingly larger sample sizes but also the shift in focus towards underrepresented populations. Multipopulation GWAS increase power to detect novel risk variants and improve fine-mapping resolution by leveraging evidence and differences in linkage disequilibrium (LD) from diverse populations. Here, we expand upon our previous approach for single-population fine-mapping through Joint Analysis of Marginal SNP Effects (JAM) to a multipopulation analysis (mJAM). Under the assumption that true causal variants are common across studies, we implement a hierarchical model framework that conditions on multiple SNPs while explicitly incorporating the different LD structures across populations. The mJAM framework can be used to first select index variants using the mJAM likelihood with different feature selection approaches. In addition, we present a novel approach leveraging the ideas of mediation to construct credible sets for these index variants. Construction of such credible sets can be performed given any existing index variants. We illustrate the implementation of the mJAM likelihood through two implementations: mJAM-SuSiE (a Bayesian approach) and mJAM-Forward selection. Through simulation studies based on realistic effect sizes and levels of LD, we demonstrated that mJAM performs well for constructing concise credible sets that include the underlying causal variants. In real data examples taken from the most recent multipopulation prostate cancer GWAS, we showed several practical advantages of mJAM over other existing multipopulation methods.
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	605785-8
ISSN	1098-2272 ; 0741-0395
ISSN (online)	1098-2272
ISSN	0741-0395
DOI	10.1002/gepi.22562
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Article: Sign-based Shrinkage Based on an Asymmetric LASSO Penalty.

Kawaguchi, Eric S / Darst, Burcu F / Wang, Kan / Conti, David V

Journal of data science : JDS

2021 Volume 19, Issue 3, Page(s) 429–449

Abstract: Penalized regression provides an automated approach to preform simultaneous variable selection and parameter estimation and is a popular method to analyze high-dimensional data. Since the conception of the LASSO in the mid-to-late 1990s, extensive ... ...

Abstract	Penalized regression provides an automated approach to preform simultaneous variable selection and parameter estimation and is a popular method to analyze high-dimensional data. Since the conception of the LASSO in the mid-to-late 1990s, extensive research has been done to improve penalized regression. The LASSO, and several of its variations, performs penalization symmetrically around zero. Thus, variables with the same magnitude are shrunk the same regardless of the direction of effect. To the best of our knowledge, sign-based shrinkage, preferential shrinkage based on the sign of the coefficients, has yet to be explored under the LASSO framework. We propose a generalization to the LASSO, asymmetric LASSO, that performs sign-based shrinkage. Our method is motivated by placing an asymmetric Laplace prior on the regression coefficients, rather than a symmetric Laplace prior. This corresponds to an asymmetric
Language	English
Publishing date	2021-06-02
Publishing country	China (Republic : 1949- )
Document type	Journal Article
ZDB-ID	2139355-2
ISSN	1683-8602 ; 1680-743X
ISSN (online)	1683-8602
ISSN	1680-743X
DOI	10.6339/21-JDS1015
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Article ; Online: Bayesian variable selection with a pleiotropic loss function in Mendelian randomization.

Gkatzionis, Apostolos / Burgess, Stephen / Conti, David V / Newcombe, Paul J

Statistics in medicine

2021 Volume 40, Issue 23, Page(s) 5025–5045

Abstract: Mendelian randomization is the use of genetic variants as instruments to assess the existence of a causal relationship between a risk factor and an outcome. A Mendelian randomization analysis requires a set of genetic variants that are strongly ... ...

Abstract	Mendelian randomization is the use of genetic variants as instruments to assess the existence of a causal relationship between a risk factor and an outcome. A Mendelian randomization analysis requires a set of genetic variants that are strongly associated with the risk factor and only associated with the outcome through their effect on the risk factor. We describe a novel variable selection algorithm for Mendelian randomization that can identify sets of genetic variants which are suitable in both these respects. Our algorithm is applicable in the context of two-sample summary-data Mendelian randomization and employs a recently proposed theoretical extension of the traditional Bayesian statistics framework, including a loss function to penalize genetic variants that exhibit pleiotropic effects. The algorithm offers robust inference through the use of model averaging, as we illustrate by running it on a range of simulation scenarios and comparing it against established pleiotropy-robust Mendelian randomization methods. In a real-data application, we study the effect of systolic and diastolic blood pressure on the risk of suffering from coronary heart disease (CHD). Based on a recent large-scale GWAS for blood pressure, we use 395 genetic variants for systolic and 391 variants for diastolic blood pressure. Both traits are shown to have significant risk-increasing effects on CHD risk.
MeSH term(s)	Bayes Theorem ; Causality ; Genetic Pleiotropy ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis ; Risk Factors
Language	English
Publishing date	2021-06-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	843037-8
ISSN	1097-0258 ; 0277-6715
ISSN (online)	1097-0258
ISSN	0277-6715
DOI	10.1002/sim.9109
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Article ; Online: Proteomic and Metabolomic Signatures of Diet Quality in Young Adults.

Costello, Elizabeth / Goodrich, Jesse A / Patterson, William B / Walker, Douglas I / Chen, Jiawen Carmen / Baumert, Brittney O / Rock, Sarah / Gilliland, Frank D / Goran, Michael I / Chen, Zhanghua / Alderete, Tanya L / Conti, David V / Chatzi, Lida

Nutrients

2024 Volume 16, Issue 3

Abstract: The assessment of "omics" signatures may contribute to personalized medicine and precision nutrition. However, the existing literature is still limited in the homogeneity of participants' characteristics and in limited assessments of integrated omics ... ...

Abstract	The assessment of "omics" signatures may contribute to personalized medicine and precision nutrition. However, the existing literature is still limited in the homogeneity of participants' characteristics and in limited assessments of integrated omics layers. Our objective was to use post-prandial metabolomics and fasting proteomics to identify biological pathways and functions associated with diet quality in a population of primarily Hispanic young adults. We conducted protein and metabolite-wide association studies and functional pathway analyses to assess the relationships between a priori diet indices, Healthy Eating Index-2015 (HEI) and Dietary Approaches to Stop Hypertension (DASH) diets, and proteins (
MeSH term(s)	Humans ; Young Adult ; Proteomics ; Diet ; Metabolomics ; Dietary Approaches To Stop Hypertension ; Amino Acids
Chemical Substances	Amino Acids
Language	English
Publishing date	2024-01-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu16030429
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Article ; Online: Elucidation of causal direction between asthma and obesity: a bi-directional Mendelian randomization study.

Xu, Shujing / Gilliland, Frank D / Conti, David V

International journal of epidemiology

2019 Volume 48, Issue 3, Page(s) 899–907

Abstract: Background: Observational associations between asthma and obesity are well established, but inferring causality is challenging. We leveraged publicly available summary statistics to ascertain the causal direction between asthma and obesity via Mendelian ...

Abstract	Background: Observational associations between asthma and obesity are well established, but inferring causality is challenging. We leveraged publicly available summary statistics to ascertain the causal direction between asthma and obesity via Mendelian randomization in European-ancestry adults. Methods: We performed two-sample bi-directional Mendelian randomization analysis using publicly available genome-wide association studies summary statistics. Single nucleotide polymorphisms associated with asthma and body mass index at genome-wide significance were combined using a fixed effect meta-analysis in each direction. An extensive sensitivity analysis was considered. Results: There was evidence in support of increasing causal effect of body mass index on risk of asthma (odds ratio 1.18 per unit increase, 95% confidence interval (CI) (1.11, 1.25), P = 2 × 10-8. No significant causal effect of asthma on adult body mass index was observed [estimate -0.004, 95% CI (-0.018, 0.009), P = 0.553]. Conclusions: Our results confirmed that in European-ancestry populations, adult body mass index is likely to be causally linked to the risk of asthma; yet the effect of asthma on body mass index is small, if present at all.
MeSH term(s)	Adult ; Aged ; Asthma/epidemiology ; Asthma/genetics ; Body Mass Index ; Causality ; Female ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Obesity/epidemiology ; Obesity/genetics ; Odds Ratio ; Polymorphism, Single Nucleotide ; United Kingdom/epidemiology
Language	English
Publishing date	2019-04-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	187909-1
ISSN	1464-3685 ; 0300-5771
ISSN (online)	1464-3685
ISSN	0300-5771
DOI	10.1093/ije/dyz070
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Article ; Online: Combining magnetic resonance imaging with a multi-ancestry polygenic risk score to improve identification of clinically significant prostate cancer.

Plym, Anna / Madueke, Ikenna / Naik, Sachin / Isabelle, Mark / Conti, David V / Haiman, Christopher A / Penney, Kathryn L / Mucci, Lorelei A / Khorasani, Rhamin / Kibel, Adam S

JNCI cancer spectrum

2024 Volume 8, Issue 2

Abstract: Multi-parametric magnetic resonance imaging (mpMRI) has emerged as an important tool for identifying clinically significant prostate cancer. We examined if the addition of a 400-variant multi-ancestry polygenic risk score (PRS) to mpMRI has the potential ...

Abstract	Multi-parametric magnetic resonance imaging (mpMRI) has emerged as an important tool for identifying clinically significant prostate cancer. We examined if the addition of a 400-variant multi-ancestry polygenic risk score (PRS) to mpMRI has the potential to improve identification. Based on data from 24 617 men from the Mass General Brigham Biobank, we identified 1243 men who underwent mpMRI. Men in the top PRS quartile were more likely to have clinically significant prostate cancer (47.1% vs 28.6% in the bottom PRS quartile, adjusted relative proportion 1.72 [95% CI = 1.35 to 2.19]). Both among men with a positive and a negative mpMRI, men in the top PRS quartile had the highest frequency of clinically significant cancer. In a constructed scenario for selecting men to undergo biopsy, use of the PRS lowered the frequency of missed clinically significant cancers from 9.1% to 5.9%. Our study provides initial support for using the PRS to improve identification of potentially lethal prostate cancer.
MeSH term(s)	Male ; Humans ; Genetic Risk Score ; Prostatic Neoplasms/diagnostic imaging ; Prostatic Neoplasms/genetics ; Magnetic Resonance Imaging/methods ; Biopsy
Language	English
Publishing date	2024-03-02
Publishing country	England
Document type	Journal Article
ISSN	2515-5091
ISSN (online)	2515-5091
DOI	10.1093/jncics/pkae014
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Article ; Online: Environmental impacts and leachate analysis of waste rubber incorporated in construction and road materials: A review

Mohajerani, Abbas / Kurmus, Halenur / Conti, David / Cash, Lucinda / Semcesen, Adrian / Mohammed Abdurahman / Rahman, Md Tareq

Science of the total environment. 2022 Aug. 20, v. 835 p.155269-

2022

Abstract: In recent years, the recycling of waste tyre rubber in construction and road materials has emerged as a potential innovative solution to the growing waste rubber tyre dilemma. However, to determine the feasibility of any recycling method, it is crucial ... ...

Abstract	In recent years, the recycling of waste tyre rubber in construction and road materials has emerged as a potential innovative solution to the growing waste rubber tyre dilemma. However, to determine the feasibility of any recycling method, it is crucial to assess the potential environmental implications of the proposed method. The environmental conditions waste tyre rubber products are exposed to are often not accurately simulated in leachate studies, leading to incomplete findings. The Toxicity Characteristics Leaching Procedure (TCLP) (1997) and Australian Bottle Leaching Procedure (ABLP) (1992), which have been used in most leachate studies in the past, have been criticised for inadequate replication of site conditions when applied to assess the leachability of modified materials. The objective of this study is to (1) review standard leachate testing methods and subsequently investigate the adequacy of these methods, (2) review all available major research focusing on the leaching characteristics and environmental and health implications of products recycled with waste tyre rubber, (3) prepare recommendations for the improvement of future leachate studies and testing based on the assessment of existing research. The existing leachate analysis studies that assess the environmental implications of different applications of waste tyre rubber have demonstrated that considerable knowledge gaps exist in the current body of knowledge. It was found leachate studies involving the recently published ABLP (2019) and Leaching Environmental Assessment Framework (LEAF) (2017) appeared to better replicate local environmental conditions and yield results of higher integrity and precision due to improved testing procedures. This study recommends that the ABLP and LEAF testing methods be applied to assess the leachability of heavy metals and organic materials (on which minimal research has been conducted) of all currently available products incorporated with waste tyre rubber, as well as in future leachate studies of waste tyre rubber.
Keywords	environmental assessment ; leachates ; leaves ; rubber ; tires ; toxicity ; Waste Tyre rubber ; Recycling ; Construction materials ; Leachate testing methods ; Leachate analysis ; Environmental sustainability
Language	English
Dates of publication	2022-0820
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2022.155269
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Article ; Online: A Hierarchical Approach Using Marginal Summary Statistics for Multiple Intermediates in a Mendelian Randomization or Transcriptome Analysis.

Jiang, Lai / Xu, Shujing / Mancuso, Nicholas / Newcombe, Paul J / Conti, David V

American journal of epidemiology

2021 Volume 190, Issue 6, Page(s) 1148–1158

Abstract: Previous research has demonstrated the usefulness of hierarchical modeling for incorporating a flexible array of prior information in genetic association studies. When this prior information consists of estimates from association analyses of single- ... ...

Abstract	Previous research has demonstrated the usefulness of hierarchical modeling for incorporating a flexible array of prior information in genetic association studies. When this prior information consists of estimates from association analyses of single-nucleotide polymorphisms (SNP)-intermediate or SNP-gene expression, a hierarchical model is equivalent to a 2-stage instrumental or transcriptome-wide association study (TWAS) analysis, respectively. We propose to extend our previous approach for the joint analysis of marginal summary statistics to incorporate prior information via a hierarchical model (hJAM). In this framework, the use of appropriate estimates as prior information yields an analysis similar to Mendelian randomization (MR) and TWAS approaches. hJAM is applicable to multiple correlated SNPs and intermediates to yield conditional estimates for the intermediates on the outcome, thus providing advantages over alternative approaches. We investigated the performance of hJAM in comparison with existing MR and TWAS approaches and demonstrated that hJAM yields an unbiased estimate, maintains correct type-I error, and has increased power across extensive simulations. We applied hJAM to 2 examples: estimating the causal effects of body mass index (GIANT Consortium) and type 2 diabetes (DIAGRAM data set, GERA Cohort, and UK Biobank) on myocardial infarction (UK Biobank) and estimating the causal effects of the expressions of the genes for nuclear casein kinase and cyclin dependent kinase substrate 1 and peptidase M20 domain containing 1 on the risk of prostate cancer (PRACTICAL and GTEx).
MeSH term(s)	Amidohydrolases/analysis ; Bias ; Body Mass Index ; Data Interpretation, Statistical ; Diabetes Mellitus, Type 2/genetics ; Female ; Gene Expression Profiling/methods ; Genome-Wide Association Study ; Humans ; Male ; Mendelian Randomization Analysis/methods ; Models, Genetic ; Myocardial Infarction/genetics ; Nuclear Proteins/analysis ; Phosphoproteins/analysis ; Polymorphism, Single Nucleotide ; Prostatic Neoplasms/genetics
Chemical Substances	NUCKS1 protein, human ; Nuclear Proteins ; Phosphoproteins ; Amidohydrolases (EC 3.5.-) ; PM20D1 protein, human (EC 3.5.-)
Language	English
Publishing date	2021-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2937-3
ISSN	1476-6256 ; 0002-9262
ISSN (online)	1476-6256
ISSN	0002-9262
DOI	10.1093/aje/kwaa287
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Article ; Online: Inverted genomic regions between reference genome builds in humans impact imputation accuracy and decrease the power of association testing.

Sheng, Xin / Xia, Lucy / Cahoon, Jordan L / Conti, David V / Haiman, Christopher A / Kachuri, Linda / Chiang, Charleston W K

HGG advances

2022 Volume 4, Issue 1, Page(s) 100159

Abstract: Over the last two decades, the human reference genome has undergone multiple updates as we complete a linear representation of our genome. Two versions of human references are currently used in the biomedical literature, GRCh37/hg19 and GRCh38. ... ...

Abstract	Over the last two decades, the human reference genome has undergone multiple updates as we complete a linear representation of our genome. Two versions of human references are currently used in the biomedical literature, GRCh37/hg19 and GRCh38. Conversions between these versions are critical for quality control, imputation, and association analysis. In the present study, we show that single-nucleotide variants (SNVs) in regions inverted between different builds of the reference genome are often mishandled bioinformatically. Depending on the array type, SNVs are found in approximately 2-5 Mb of the genome that are inverted between reference builds. Coordinate conversions of these variants are mishandled by both the TOPMed imputation server as well as routine in-house quality control pipelines, leading to underrecognized downstream analytical consequences. Specifically, we observe that undetected allelic conversion errors for palindromic (i.e., A/T or C/G) variants in these inverted regions would destabilize the local haplotype structure, leading to loss of imputation accuracy and power in association analyses. Though only a small proportion of the genome is affected, these regions include important disease susceptibility variants that would be affected. For example, the p value of a known locus associated with prostate cancer on chromosome 10 (chr10) would drop from 2.86 × 10
MeSH term(s)	Male ; Humans ; Genome-Wide Association Study ; Genomics ; Genome, Human/genetics ; Haplotypes/genetics ; Black or African American
Language	English
Publishing date	2022-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2666-2477
ISSN (online)	2666-2477
DOI	10.1016/j.xhgg.2022.100159
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