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Article ; Online: Findings from a Genetic Sequencing Investigation of Men with Familial and Aggressive Prostate Cancer.

Darst, Burcu F

2020 Volume 79, Issue 3, Page(s) 362–363

MeSH term(s)	Humans ; Male ; Prostatic Neoplasms/genetics
Language	English
Publishing date	2020-09-29
Publishing country	Switzerland
Document type	Editorial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	193790-x
ISSN	1873-7560 ; 1421-993X ; 0302-2838
ISSN (online)	1873-7560 ; 1421-993X
ISSN	0302-2838
DOI	10.1016/j.eururo.2020.09.002
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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: 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: Racial and Ethnic Differences in the Population-Attributable Fractions of Alzheimer Disease and Related Dementias.

Park, Song-Yi / Setiawan, Veronica Wendy / Crimmins, Eileen M / White, Lon R / Wu, Anna H / Cheng, Iona / Darst, Burcu F / Haiman, Christopher A / Wilkens, Lynne R / Le Marchand, Loїc / Lim, Unhee

Neurology

2024 Volume 102, Issue 3, Page(s) e208116

Abstract: Background and objectives: Previous studies estimated that modifiable risk factors explain up to 40% of the dementia cases in the United States and that this population-attributable fraction (PAF) differs by race and ethnicity-estimates of future impact ...

Abstract	Background and objectives: Previous studies estimated that modifiable risk factors explain up to 40% of the dementia cases in the United States and that this population-attributable fraction (PAF) differs by race and ethnicity-estimates of future impact based on the risk factor prevalence in contemporary surveys. The aim of this study was to determine the race-specific and ethnicity-specific PAF of late-onset Alzheimer disease and related dementias (ADRDs) based on the risk factor prevalence and associations observed on the same individuals within a prospective cohort. Methods: Data were from Multiethnic Cohort Study participants (African American, Japanese American, Latino, Native Hawaiian, and White) enrolled in Medicare Fee-for-Service. We estimated the PAF based on the prevalence of risk factors at cohort baseline and their mutually adjusted association with subsequent ADRD incidence. Risk factors included low educational attainment and midlife exposures to low neighborhood socioeconomic status, unmarried status, history of hypertension, stroke, diabetes or heart disease, smoking, physical inactivity, short or long sleep duration, obesity, and low-quality diet, as well as Results: Among 91,881 participants (mean age 59.3 at baseline, 55.0% female participants), 16,507 incident ADRD cases were identified from Medicare claims (1999-2016, mean follow-up 9.3 years). The PAF for nongenetic factors combined was similar in men (24.0% [95% CI 21.3-26.6]) and women (22.8% [20.3-25.2]) but varied across Japanese American (14.2% [11.1-17.2]), White (21.9% [19.0-24.7]), African American (27.8% [22.3-33.0]), Native Hawaiian (29.3% [21.0-36.7]), and Latino (33.3% [27.5-38.5]) groups. The combined PAF was attenuated when accounting for competing risk of death, in both men (10.4%) and women (13.9%) and across racial and ethnic groups (4.7%-25.5%). The combined PAF was also different by age at diagnosis and ADRD subtypes, higher for younger (65-74 years: 43.2%) than older (75-84 years: 32.4%; ≥85 years: 11.3%) diagnoses and higher for vascular or unspecified ADRD than for AD or Lewy body dementia. An additional PAF of 11.8% (9.9-13.6) was associated with Discussion: Known risk factors explained about a third of the ADRD cases but with unequal distributions across racial and ethnic groups.
MeSH term(s)	Male ; Humans ; Female ; Aged ; United States/epidemiology ; Middle Aged ; Alzheimer Disease/epidemiology ; Cohort Studies ; Prospective Studies ; Apolipoprotein E4/genetics ; Medicare
Chemical Substances	Apolipoprotein E4
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000208116
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Article: Transmission and decorrelation methods for detecting rare variants using sequencing data from related individuals.

Darst, Burcu F / Engelman, Corinne D

BMC proceedings

2016 Volume 10, Issue Suppl 7, Page(s) 203–207

Abstract: Background: Advances in whole genome sequencing have enabled the investigation of rare variants, which could explain some of the missing heritability that genome-wide association studies are unable to detect. Most methods to detect associations with ... ...

Abstract	Background: Advances in whole genome sequencing have enabled the investigation of rare variants, which could explain some of the missing heritability that genome-wide association studies are unable to detect. Most methods to detect associations with rare variants are developed for unrelated individuals; however, several methods exist that utilize family studies and could have better power to detect such associations. Methods: Using whole genome sequencing data and simulated phenotypes provided by the organizers of the Genetic Analysis Workshop 19 (GAW19), we compared family-based methods that test for associations between rare and common variants with a quantitative trait. This was done using 2 fairly novel methods: family-based association test for rare variants (FBAT-RV), which is a transmission-based method that utilizes the transmission of genetic information from parent to offspring; and Minimum Results: MONSTER had much higher overall power than FBAT-RV and FBAT-Min P. Interestingly, FBAT-LC had similar overall power as MONSTER. MONSTER had the highest power for a gene accounting for a larger percent of the phenotypic variance, whereas MONSTER and FBAT-LC both had the highest power for a gene accounting for moderate variance. FBAT-LC had the highest power for a gene accounting for the least variance. Conclusions: Based on the simulated data from GAW19, MONSTER and FBAT-LC were the most powerful of the methods assessed. However, there are limitations to each of these methods that should be carefully considered when conducting an analysis of rare variants in related individuals. This emphasizes the need for methods that can incorporate the advantages of each of these methods into 1 family-based association test for rare variants.
Language	English
Publishing date	2016-10-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2411867-9
ISSN	1753-6561
ISSN	1753-6561
DOI	10.1186/s12919-016-0031-z
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Article ; Online: Using recursive feature elimination in random forest to account for correlated variables in high dimensional data.

Darst, Burcu F / Malecki, Kristen C / Engelman, Corinne D

BMC genetics

2018 Volume 19, Issue Suppl 1, Page(s) 65

Abstract: Background: Random forest (RF) is a machine-learning method that generally works well with high-dimensional problems and allows for nonlinear relationships between predictors; however, the presence of correlated predictors has been shown to impact its ... ...

Abstract	Background: Random forest (RF) is a machine-learning method that generally works well with high-dimensional problems and allows for nonlinear relationships between predictors; however, the presence of correlated predictors has been shown to impact its ability to identify strong predictors. The Random Forest-Recursive Feature Elimination algorithm (RF-RFE) mitigates this problem in smaller data sets, but this approach has not been tested in high-dimensional omics data sets. Results: We integrated 202,919 genotypes and 153,422 methylation sites in 680 individuals, and compared the abilities of RF and RF-RFE to detect simulated causal associations, which included simulated genotype-methylation interactions, between these variables and triglyceride levels. Results show that RF was able to identify strong causal variables with a few highly correlated variables, but it did not detect other causal variables. Conclusions: Although RF-RFE decreased the importance of correlated variables, in the presence of many correlated variables, it also decreased the importance of causal variables, making both hard to detect. These findings suggest that RF-RFE may not scale to high-dimensional data.
MeSH term(s)	CpG Islands ; DNA Methylation ; Epigenomics ; Genome-Wide Association Study ; Genotype ; Humans ; Hypertriglyceridemia/drug therapy ; Hypertriglyceridemia/genetics ; Hypoglycemic Agents/therapeutic use ; Machine Learning ; Polymorphism, Single Nucleotide ; Triglycerides/blood
Chemical Substances	Hypoglycemic Agents ; Triglycerides
Language	English
Publishing date	2018-09-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1471-2156
ISSN (online)	1471-2156
DOI	10.1186/s12863-018-0633-8
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Article ; Online: Association of Prostate-Specific Antigen Levels with Prostate Cancer Risk in a Multiethnic Population: Stability Over Time and Comparison with Polygenic Risk Score.

Chou, Alisha / Darst, Burcu F / Wilkens, Lynne R / Marchand, Loïc Le / Lilja, Hans / Conti, David V / Haiman, Christopher A

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2022 Volume 31, Issue 12, Page(s) 2199–2207

Abstract: Background: Studies in men of European ancestry suggest prostate-specific antigen (PSA) as a marker of early prostate cancer development that may help to risk-stratify men earlier in life.: Methods: We examined PSA levels in men measured up to 10+ ... ...

Abstract	Background: Studies in men of European ancestry suggest prostate-specific antigen (PSA) as a marker of early prostate cancer development that may help to risk-stratify men earlier in life. Methods: We examined PSA levels in men measured up to 10+ years before a prostate cancer diagnosis in association with prostate cancer risk in 2,245 cases and 2,203 controls of African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. We also compared the discriminative ability of PSA to polygenic risk score (PRS) for prostate cancer. Results: Excluding cases diagnosed within 2 and 10 years of blood draw, men with PSA above the median had a prostate cancer OR (95% CIs) of 9.12 (7.66-10.92) and 3.52 (2.50-5.03), respectively, compared with men with PSA below the median. A PSA level above the median identified 90% and 75% of cases diagnosed more than 2 and 10 years after blood draw, respectively. The associations were significantly greater for Gleason ≤7 versus 8+ disease. At 10+ years, the association of prostate cancer with PSA was comparable with that with the PRS [OR per SD increase: 1.88 (1.45-2.46) and 2.12 (1.55-2.93), respectively]. Conclusions: We found PSA to be an informative marker of prostate cancer risk at least a decade before diagnosis across multiethnic populations. This association was diminished with increasing time, greater for low grade tumors, and comparable with a PRS when measured 10+ years before diagnosis. Impact: Our multiethnic investigation suggests broad clinical implications on the utility of PSA and PRS for risk stratification in prostate cancer screening practices.
MeSH term(s)	Male ; Humans ; Prostate-Specific Antigen ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/genetics ; Early Detection of Cancer ; Black or African American ; Risk Factors
Chemical Substances	Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2022-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-22-0443
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Article ; Online: Author Correction: Metabolomic epidemiology offers insights into disease aetiology.

Fuller, Harriett / Zhu, Yiwen / Nicholas, Jayna / Chatelaine, Haley A / Drzymalla, Emily M / Sarvestani, Afrand K / Julián-Serrano, Sachelly / Tahir, Usman A / Sinnott-Armstrong, Nasa / Raffield, Laura M / Rahnavard, Ali / Hua, Xinwei / Shutta, Katherine H / Darst, Burcu F

Nature metabolism

2024 Volume 6, Issue 1, Page(s) 187

Language	English
Publishing date	2024-01-08
Publishing country	Germany
Document type	Published Erratum
ISSN	2522-5812
ISSN (online)	2522-5812
DOI	10.1038/s42255-023-00967-9
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Article ; Online: Integrated analysis of genomics, longitudinal metabolomics, and Alzheimer's risk factors among 1,111 cohort participants.

Darst, Burcu F / Lu, Qiongshi / Johnson, Sterling C / Engelman, Corinne D

Genetic epidemiology

2019 Volume 43, Issue 6, Page(s) 657–674

Abstract: Although Alzheimer's disease (AD) is highly heritable, genetic variants are known to be associated with AD only explain a small proportion of its heritability. Genetic factors may only convey disease risk in individuals with certain environmental ... ...

Abstract	Although Alzheimer's disease (AD) is highly heritable, genetic variants are known to be associated with AD only explain a small proportion of its heritability. Genetic factors may only convey disease risk in individuals with certain environmental exposures, suggesting that a multiomics approach could reveal underlying mechanisms contributing to complex traits, such as AD. We developed an integrated network to investigate relationships between metabolomics, genomics, and AD risk factors using Wisconsin Registry for Alzheimer's Prevention participants. Analyses included 1,111 non-Hispanic Caucasian participants with whole blood expression for 11,376 genes (imputed from dense genome-wide genotyping), 1,097 fasting plasma metabolites, and 17 AD risk factors. A subset of 155 individuals also had 364 fastings cerebral spinal fluid (CSF) metabolites. After adjusting each of these 12,854 variables for potential confounders, we developed an undirected graphical network, representing all significant pairwise correlations upon adjusting for multiple testing. There were many instances of genes being indirectly linked to AD risk factors through metabolites, suggesting that genes may influence AD risk through particular metabolites. Follow-up analyses suggested that glycine mediates the relationship between carbamoyl-phosphate synthase 1 and measures of cardiovascular and diabetes risk, including body mass index, waist-hip ratio, inflammation, and insulin resistance. Further, 38 CSF metabolites explained more than 60% of the variance of CSF levels of tau, a detrimental protein that accumulates in the brain of AD patients and is necessary for its diagnosis. These results further our understanding of underlying mechanisms contributing to AD risk while demonstrating the utility of generating and integrating multiple omics data types.
MeSH term(s)	Alzheimer Disease/blood ; Alzheimer Disease/cerebrospinal fluid ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Biomarkers/blood ; Biomarkers/cerebrospinal fluid ; Female ; Genomics/methods ; Humans ; Longitudinal Studies ; Male ; Metabolome ; Middle Aged ; Prognosis ; Risk Factors ; Transcriptome
Chemical Substances	Biomarkers
Language	English
Publishing date	2019-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	605785-8
ISSN	1098-2272 ; 0741-0395
ISSN (online)	1098-2272
ISSN	0741-0395
DOI	10.1002/gepi.22211
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Article ; Online: Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival.

Saunders, Edward J / Dadaev, Tokhir / Brook, Mark N / Wakerell, Sarah / Govindasami, Koveela / Rageevakumar, Reshma / Hussain, Nafisa / Osborne, Andrea / Keating, Diana / Lophatananon, Artitaya / Muir, Kenneth R / Darst, Burcu F / Conti, David V / Haiman, Christopher A / Antoniou, Antonis C / Eeles, Rosalind A / Kote-Jarai, Zsofia

European urology oncology

2024 Volume 7, Issue 2, Page(s) 248–257

Abstract: Background: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less ... ...

Abstract	Background: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. Objective: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). Design, setting, and participants: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. Outcome measurements and statistical analysis: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. Results and limitations: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10 Conclusions: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. Patient summary: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms/pathology ; Prostate/pathology ; Genes, BRCA2 ; Mutation
Language	English
Publishing date	2024-03-07
Publishing country	Netherlands
Document type	Journal Article
ISSN	2588-9311
ISSN (online)	2588-9311
DOI	10.1016/j.euo.2024.02.003
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