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Article ; Online: Strategies in Aggregation Tests for Rare Variants.

Rajabli, Farid / Kunkle, Brian W

Current protocols

2023 Volume 3, Issue 11, Page(s) e931

Abstract: Genome-wide association studies (GWAS) successfully identified numerous common variants involved in complex diseases, but only limited heritability was explained by these findings. Advances in high-throughput sequencing technology made it possible to ... ...

Abstract	Genome-wide association studies (GWAS) successfully identified numerous common variants involved in complex diseases, but only limited heritability was explained by these findings. Advances in high-throughput sequencing technology made it possible to assess the contribution of rare variants in common diseases. However, study of rare variants introduces challenges due to low frequency of rare variants. Well-established common variant methods were underpowered to identify the rare variants in GWAS. To address this challenge, several new methods have been developed to examine the role of rare variants in complex diseases. These approaches are based on testing the aggregate effect of multiple rare variants in a predefined genetic region. Provided here is an overview of statistical approaches and the protocols explaining step-by-step analysis of aggregations tests with the hands-on experience using R scripts in four categories: burden tests, adaptive burden tests, variance-component tests, and combined tests. Also explained are the concepts of rare variants, permutation tests, kernel methods, and genetic variant annotation. At the end we discuss relevant topics of bioinformatics tools for annotation, family-based design of rare-variant analysis, population stratification adjustment, and meta-analysis. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.
MeSH term(s)	Genome-Wide Association Study/methods ; Disease/genetics ; Genetic Variation
Language	English
Publishing date	2023-11-21
Publishing country	United States
Document type	Journal Article
ISSN	2691-1299
ISSN (online)	2691-1299
DOI	10.1002/cpz1.931
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Article ; Online: An X Chromosome Transcriptome Wide Association Study Implicates ARMCX6 in Alzheimer's Disease.

Zhang, Xueyi / Gomez, Lissette / Below, Jennifer E / Naj, Adam C / Martin, Eden R / Kunkle, Brian W / Bush, William S

Journal of Alzheimer's disease : JAD

2024 Volume 98, Issue 3, Page(s) 1053–1067

Abstract: Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer's disease (AD).: Objective: To model the expression ... ...

Abstract	Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer's disease (AD). Objective: To model the expression of X chromosome genes and evaluate their impact on AD risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF > 0.05) within the cis-regulatory window were used to train tissue-specific models of each gene. We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer's Disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p < 0.05, with only ARMCX6 in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6.
MeSH term(s)	Humans ; Male ; Female ; Alzheimer Disease/genetics ; Transcriptome ; Genetic Predisposition to Disease/genetics ; X Chromosome ; Brain ; Polymorphism, Single Nucleotide/genetics ; Genome-Wide Association Study
Language	English
Publishing date	2024-03-14
Publishing country	Netherlands
Document type	Meta-Analysis ; Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-231075
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Article: Professional and Amateur Pitchers' Perspective on the Ulnar Collateral Ligament Injury Risk.

Vance, Danica D / Alexander, Frank J / Kunkle, Brian W / Littlefield, Mark / Ahmad, Christopher S

Orthopaedic journal of sports medicine

2019 Volume 7, Issue 6, Page(s) 2325967119850777

Abstract: Background: Medial ulnar collateral ligament (UCL) injury is increasingly prevalent in professional baseball pitchers, and significant research has been devoted to understanding the risk factors and prevention strategies associated with it. To date, no ... ...

Abstract	Background: Medial ulnar collateral ligament (UCL) injury is increasingly prevalent in professional baseball pitchers, and significant research has been devoted to understanding the risk factors and prevention strategies associated with it. To date, no study has investigated what the players themselves believe causes and prevents the injury. Purpose: To evaluate the opinions of UCL injuries among pitchers, including professional athletes. Study design: Cross-sectional study. Methods: A total of 214 baseball pitchers (45 high school/college, 169 Major League Baseball [MLB]/Minor League Baseball) completed a 52-item questionnaire designed to evaluate their opinions on the cause of UCL injuries, injury prevention, and Tommy John surgery. Overall, 51 of the 214 pitchers had previously experienced a UCL injury. The frequency of the selection of each answer option was measured. Additionally, chi-square tests were used to compare (1) responses between professional and nonprofessional pitchers and (2) responses between pitchers with and without a previous UCL injury. Results: Only 45% of pitchers thought that UCL injuries are avoidable in MLB. Additionally, 55% of pitchers with a UCL injury had a history of elbow injuries as an adolescent/child, compared with 18% in the uninjured group ( Conclusion: Pitchers with a previous childhood elbow injury had a significantly higher incidence of UCL injuries during their adult career, suggesting possible predisposition to UCL injury and warranting further research. Fatigue and inadequate rest were of greatest concern among all pitchers for an increased risk of UCL injuries. Understanding and acknowledging the opinions that players have regarding UCL injuries are important to improve UCL education, prevention, and treatment.
Language	English
Publishing date	2019-06-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2706251-X
ISSN	2325-9671
ISSN	2325-9671
DOI	10.1177/2325967119850777
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Article ; Online: Genetic analyses in multiplex families confirms chromosome 5q35 as a risk locus for Alzheimer's Disease in individuals of African Ancestry.

Nuytemans, Karen / Rajabli, Farid / Jean-Francois, Melissa / Kurup, Jiji Thulaseedhara / Adams, Larry D / Starks, Takiyah D / Whitehead, Patrice L / Kunkle, Brian W / Caban-Holt, Allison / Haines, Jonathan L / Cuccaro, Michael L / Vance, Jeffery M / Byrd, Goldie S / Beecham, Gary W / Reitz, Christiane / Pericak-Vance, Margaret A

Neurobiology of aging

2023 Volume 133, Page(s) 125–133

Abstract: There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint ... ...

Abstract	There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint linkage analyses in 51 multi-generational AA AD families ascertained through the Research in African American Alzheimer Disease Initiative (REAAADI) and the National Institute on Aging Late Onset Alzheimer's disease (NIA-LOAD) Family Based Study. Variants were prioritized on minor allele frequency (<0.01), functional potential of coding and noncoding variants, co-segregation with AD and presence in multi-ancestry ADSP release 3 WGS data. We identified a significant linkage signal on chromosome 5q35 (HLOD=3.3) driven by nine families. Haplotype segregation analysis in the family with highest LOD score identified a 3'UTR variant in INSYN2B with the most functional evidence. Four other linked AA families harbor within-family shared variants located in INSYN2B's promoter or enhancer regions. This AA family-based finding shows the importance of diversifying population-level genetic data to better understand the genetic determinants of AD on a global scale.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Alzheimer Disease/epidemiology ; Lod Score ; Genetic Linkage/genetics ; Haplotypes ; Chromosomes ; Genetic Predisposition to Disease/genetics
Language	English
Publishing date	2023-10-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2023.10.010
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Article ; Online: Manifestations of Alzheimer's disease genetic risk in the blood are evident in a multiomic analysis in healthy adults aged 18 to 90.

Heath, Laura / Earls, John C / Magis, Andrew T / Kornilov, Sergey A / Lovejoy, Jennifer C / Funk, Cory C / Rappaport, Noa / Logsdon, Benjamin A / Mangravite, Lara M / Kunkle, Brian W / Martin, Eden R / Naj, Adam C / Ertekin-Taner, Nilüfer / Golde, Todd E / Hood, Leroy / Price, Nathan D

Scientific reports

2022 Volume 12, Issue 1, Page(s) 6117

Abstract: Genetics play an important role in late-onset Alzheimer's Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have ...

Abstract	Genetics play an important role in late-onset Alzheimer's Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.
MeSH term(s)	ATP-Binding Cassette Transporters/genetics ; Adult ; Alzheimer Disease/genetics ; Apolipoprotein E2/genetics ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomics ; Humans ; Male ; Polymorphism, Single Nucleotide
Chemical Substances	ATP-Binding Cassette Transporters ; Apolipoprotein E2
Language	English
Publishing date	2022-04-12
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-09825-2
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Article ; Online: Reverse engineering of modified genes by Bayesian network analysis defines molecular determinants critical to the development of glioblastoma.

Kunkle, Brian W / Yoo, Changwon / Roy, Deodutta

PloS one

2013 Volume 8, Issue 5, Page(s) e64140

Abstract: In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of ... ...

Abstract	In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and 'key genes' within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated). These 10 genes were able to predict tumor status with 96-100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential 'hubs of activity'. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several 'key genes' may be required for the development of glioblastoma. Further studies are needed to validate these 'key genes' as useful tools for early detection and novel therapeutic options for these tumors.
MeSH term(s)	Bayes Theorem ; Carcinogenesis/genetics ; Computational Biology/methods ; Disease Progression ; Female ; Gene Regulatory Networks ; Genes, Neoplasm/genetics ; Glioblastoma/genetics ; Glioblastoma/pathology ; Humans ; Male ; Markov Chains ; Meta-Analysis as Topic ; Neoplasm Grading ; Reproducibility of Results ; Transcriptome
Language	English
Publishing date	2013-05-30
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0064140
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Article ; Online: Hadoop and PySpark for reproducibility and scalability of genomic sequencing studies.

Wheeler, Nicholas R / Benchek, Penelope / Kunkle, Brian W / Hamilton-Nelson, Kara L / Warfe, Mike / Fondran, Jeremy R / Haines, Jonathan L / Bush, William S

Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing

2019 Volume 25, Page(s) 523–534

Abstract: Modern genomic studies are rapidly growing in scale, and the analytical approaches used to analyze genomic data are increasing in complexity. Genomic data management poses logistic and computational challenges, and analyses are increasingly reliant on ... ...

Abstract	Modern genomic studies are rapidly growing in scale, and the analytical approaches used to analyze genomic data are increasing in complexity. Genomic data management poses logistic and computational challenges, and analyses are increasingly reliant on genomic annotation resources that create their own data management and versioning issues. As a result, genomic datasets are increasingly handled in ways that limit the rigor and reproducibility of many analyses. In this work, we examine the use of the Spark infrastructure for the management, access, and analysis of genomic data in comparison to traditional genomic workflows on typical cluster environments. We validate the framework by reproducing previously published results from the Alzheimer's Disease Sequencing Project. Using the framework and analyses designed using Jupyter notebooks, Spark provides improved workflows, reduces user-driven data partitioning, and enhances the portability and reproducibility of distributed analyses required for large-scale genomic studies.
MeSH term(s)	Base Sequence ; Chromosome Mapping ; Computational Biology/methods ; Diagnostic Tests, Routine ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Reproducibility of Results ; Sequence Analysis, DNA ; Software ; Workflow
Language	English
Publishing date	2019-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2335-6936
ISSN (online)	2335-6936
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Article ; Online: Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer's disease.

Zhang, Lanyu / Silva, Tiago C / Young, Juan I / Gomez, Lissette / Schmidt, Michael A / Hamilton-Nelson, Kara L / Kunkle, Brian W / Chen, Xi / Martin, Eden R / Wang, Lily

Nature communications

2020 Volume 11, Issue 1, Page(s) 6114

Abstract: DNA methylation differences in Alzheimer's disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. Using a ... ...

Abstract	DNA methylation differences in Alzheimer's disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. Using a uniform analysis pipeline, we identified 3751 CpGs and 119 differentially methylated regions (DMRs) significantly associated with Braak stage. Our analysis identified differentially methylated genes such as MAMSTR, AGAP2, and AZU1. The most significant DMR identified is located on the MAMSTR gene, which encodes a cofactor that stimulates MEF2C. Notably, MEF2C cooperates with another transcription factor, PU.1, a central hub in the AD gene network. Our enrichment analysis highlighted the potential roles of the immune system and polycomb repressive complex 2 in pathological AD. These results may help facilitate future mechanistic and biomarker discovery studies in AD.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Alzheimer Disease/immunology ; Alzheimer Disease/metabolism ; Brain ; Carrier Proteins/genetics ; DNA Methylation/physiology ; Epigenesis, Genetic/genetics ; Epigenesis, Genetic/physiology ; Female ; GTP-Binding Proteins/genetics ; GTPase-Activating Proteins/genetics ; Gene Regulatory Networks ; Genome-Wide Association Study ; Humans ; Immunity/genetics ; Immunity/physiology ; MEF2 Transcription Factors/genetics ; Prefrontal Cortex/physiology ; Transcription Factors/genetics ; Tumor Suppressor Proteins/genetics
Chemical Substances	Carrier Proteins ; GTPase-Activating Proteins ; MEF2 Transcription Factors ; MEF2C protein, human ; TACC2 protein, human ; Transcription Factors ; Tumor Suppressor Proteins ; AGAP2 protein, human (EC 3.6.1.-) ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2020-11-30
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; 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	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-19791-w
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Article: Large-scale sequencing studies expand the known genetic architecture of Alzheimer's disease.

Xue, Diane / Bush, William S / Renton, Alan E / Marcora, Edoardo A / Bis, Joshua C / Kunkle, Brian W / Boerwinkle, Eric / DeStefano, Anita L / Farrer, Lindsay / Goate, Alison / Mayeux, Richard / Pericak-Vance, Margaret / Schellenberg, Gerard / Seshadri, Sudha / Wijsman, Ellen / Haines, Jonathan L / Blue, Elizabeth E

Alzheimer's & dementia (Amsterdam, Netherlands)

2021 Volume 13, Issue 1, Page(s) e12255

Abstract: Introduction: Genes implicated by genome-wide association studies and family-based studies of Alzheimer's disease (AD) are largely discordant. We hypothesized that genes identified by sequencing studies like the Alzheimer's Disease Sequencing Project ( ... ...

Abstract	Introduction: Genes implicated by genome-wide association studies and family-based studies of Alzheimer's disease (AD) are largely discordant. We hypothesized that genes identified by sequencing studies like the Alzheimer's Disease Sequencing Project (ADSP) may bridge this gap and highlight shared biological mechanisms. Methods: We performed structured literature review of genes prioritized by ADSP studies, genes underlying familial dementias, and genes nominated by genome-wide association studies. Gene set enrichment analyses of each list identified enriched pathways. Results: The genes prioritized by the ADSP, familial dementia studies, and genome-wide association studies minimally overlapped. Each gene set identified dozens of enriched pathways, several of which were shared (e.g., regulation of amyloid beta clearance). Discussion: Alternative study designs provide unique insights into AD genetics. Shared pathways enriched by different genes highlight their relevance to AD pathogenesis, while the patterns of pathway enrichment unique to each gene set provide additional targets for functional studies.
Language	English
Publishing date	2021-12-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832898-X
ISSN	2352-8729
ISSN	2352-8729
DOI	10.1002/dad2.12255
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Article ; Online: Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans.

Alzheimer's & dementia : the journal of the Alzheimer's Association

2022 Volume 19, Issue 6, Page(s) 2538–2548

Abstract: Background: This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions.: Methods! ...

Abstract	Background: This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions. Methods: We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes. Results: Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10 Discussion: Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus. Highlights: We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.
MeSH term(s)	Humans ; Genetic Predisposition to Disease/genetics ; Black or African American/genetics ; Alzheimer Disease/genetics ; Chromosome Mapping/methods ; Genotype ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide/genetics ; Kinesins/genetics ; Protein Serine-Threonine Kinases/genetics
Chemical Substances	KIF1C protein, human ; Kinesins (EC 3.6.4.4) ; MINK1 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.12865
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