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1.  Pathway-specific polygenic risk scores as predictors of β-amyloid deposition and cognitive function in a sample at increased risk for Alzheimer’s disease 
Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in β-amyloid (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging (PET) in 168 individuals, and cerebrospinal fluid (CSF) Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.
doi:10.3233/JAD-160195
PMCID: PMC5123972  PMID: 27662287
Alzheimer’s disease; Genetics; Polygenic risk scores; Genetic risk scores; Cognitive function; Beta-amyloid; Cerebral spinal fluid; Pittsburgh compound B; WRAP; APOE
2.  Prioritization of family member sequencing for the detection of rare variants 
BMC Proceedings  2016;10(Suppl 7):227-231.
Background
The advent of affordable sequencing has enabled researchers to discover many variants contributing to disease, including rare variants. There are methods for determining the most informative individuals for sequencing, but the application of these methods is more complex when working with families. Sets of large families can be beneficial in finding rare variants, but it may be unfeasible to sequence all members of these family sets.
Methods
Using simulated data from the Genetic Analysis Workshop 19, we apply multiple regression to identify cases and controls. To find the best controls for each case, we used kinship coefficients to match within families. Selected cases and controls were analyzed for rare variants, collapsed by gene, associated with hypertension using the family-based rare variant association test (FARVAT).
Results
The gene with the strongest simulated effect, MAP4, did not meet the Bonferroni corrected significance threshold. However, analysis of cases and controls using our selection method substantially improved the significance of MAP4, despite the reduction in sample size.
Conclusions
Taking the additional steps to select the optimal cases and controls from large family data sets can help ensure that only informative individuals are included in analysis and may improve the ability to detect rare variants.
doi:10.1186/s12919-016-0035-8
PMCID: PMC5133500  PMID: 27980641
3.  Genetic Analysis Workshop 19: methods and strategies for analyzing human sequence and gene expression data in extended families and unrelated individuals 
BMC Proceedings  2016;10(Suppl 7):67-70.
Genetic Analysis Workshop 19 provided a platform for developing and evaluating statistical methods to analyze whole-genome sequence and gene expression data from a pedigree-based sample, as well as whole-exome sequence data from a large cohort of unrelated individuals. In this article we present an overview of the data sets, the GAW experience, and summaries of the contributions arranged into nine methodological themes.
doi:10.1186/s12919-016-0007-z
PMCID: PMC5133501  PMID: 27980613
4.  Transmission and decorrelation methods for detecting rare variants using sequencing data from related individuals 
BMC Proceedings  2016;10(Suppl 7):203-207.
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 p value Optimized Nuisance parameter Score Test Extended to Relatives (MONSTER), which is a decorrelation method that instead attempts to adjust for relatedness using a regression-based method. We also considered family-based association test linear combination (FBAT-LC) and FBAT-Min P, which are slightly older methods that do not allow for the weighting of rare or common variants, but contrast some of the limitations of FBAT-RV.
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.
doi:10.1186/s12919-016-0031-z
PMCID: PMC5133523  PMID: 27980637
5.  Methods for Collapsing Multiple Rare Variants in Whole-Genome Sequence Data 
Genetic epidemiology  2014;38(0 1):S13-S20.
Genetic Analysis Workshop 18 provided whole-genome sequence data in a pedigree-based sample and longitudinal phenotype data for hypertension and related traits, presenting an excellent opportunity for evaluating analysis choices. We summarize the nine contributions to the working group on collapsing methods, which evaluated various approaches for the analysis of multiple rare variants. One contributor defined a variant prioritization scheme, whereas the remaining eight contributors evaluated statistical methods for association analysis. Six contributors chose the gene as the genomic region for collapsing variants, whereas three contributors chose nonoverlapping sliding windows across the entire genome. Statistical methods spanned most of the published methods, including well-established burden tests, variance-components-type tests, and recently developed hybrid approaches. Lesser known methods, such as functional principal components analysis, higher criticism, and homozygosity association, and some newly introduced methods were also used. We found that performance of these methods depended on the characteristics of the genomic region, such as effect size and direction of variants under consideration. Except for MAP4 and FLT3, the performance of all statistical methods to identify rare casual variants was disappointingly poor, providing overall power almost identical to the type I error. This poor performance may have arisen from a combination of (1) small sample size, (2) small effects of most of the causal variants, explaining a small fraction of variance, (3) use of incomplete annotation information, and (4) linkage disequilibrium between causal variants in a gene and noncausal variants in nearby genes. Our findings demonstrate challenges in analyzing rare variants identified from sequence data.
doi:10.1002/gepi.21820
PMCID: PMC4558905  PMID: 25112183
Genetic Analysis Workshop 18; rare variants; whole-genome sequence; burden tests; nonburden tests
6.  Epidemiologic study of the C-3 epimer of 25-hydroxyvitamin D3 in a population-based sample 
Background & aims
Vitamin D is associated with many health outcomes and the blood concentration of 25-hydroxyvitamin D [25(OH)D] is commonly measured in clinical practice. A C-3 epimer of this compound, 3-epi-25(OH)D3, has recently been detected in blood samples. Few clinical assays currently detect this epimer and its physiological function is unknown, as are the demographic, behavioral, and physiologic factors that may be correlated with it. We sought to determine the correlation between these factors and 3-epi-25(OH)D3.
Methods
We conducted a cross-sectional population-based study of 303 non-Hispanic white participants in the Survey of the Health of Wisconsin. Serum 25(OH)D2, 25(OH)D3 and 3-epi-25(OH)D3 were measured by high-performance liquid chromatography tandem mass spectrometry. We measured vitamin D intake from foods and supplements via a food frequency questionnaire, sun exposure by spectrophotometry, waist circumference during a physical exam, and additional demographic and behavioral factors by questionnaire. We calculated the percent of 3-epi-25(OH)D3 out of the total 25(OH)D3.
Results
Summer P=0.009), higher alcohol intake (season (P=0.007), and higher vitamin D intake from supplements (P=0.0004), but not food (P=0.20), were significantly associated with a higher percent of 3-epi-25(OH)D3 relative to the total 25(OH)D3, although these associations appear to be partially driven by individuals with low 3-epi-25(OH)D3. Moreover, the percent of 3-epi-25(OH)D3 was significantly correlated with the total 25(OH)D3 (r=0.37, P<0.0001).
Conclusions
We report findings from an epidemiologic study of 3-epi-25(OH)D3 and show that individuals with lower total 25(OH)D3 tend to have a lower percent of 3-epi-25(OH)D3 relative to the total. While this is the largest reported sample of adults with measured 3-epi-25(OH)D3, the sample size of 303 is relatively small and replication of our findings is necessary.
doi:10.1016/j.clnu.2013.06.005
PMCID: PMC3884039  PMID: 23831447
3-epi-25(OH)D3; 25(OH)D2; 25(OH)D3; epimer; vitamin D; sun exposure
7.  Investigation of TREM2 variant in the Wisconsin Registry for Alzheimer’s Prevention 
Neurobiology of aging  2013;35(6):1252-1254.
Recent studies have found an association between a variant in TREM2 (rs75932628-T) and both Alzheimer’s disease (AD) and cognitive function in individuals age 80–100. The role of TREM2 in younger, asymptomatic individuals is unknown. We examined this variant in 1,148 participants from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Thirteen individuals carried the T risk allele. Carriers were more likely to have a parental history of AD (100% of carriers versus 70% of non-carriers; p=0.01) and, among the parental history subset, families with a TREM2 carrier had a younger maternal age of AD onset than non-carriers (67.9 versus 75.6 years; p=0.03). There was no significant association between TREM2 carrier status and cognitive function or decline. In conclusion, the association between TREM2 and both parental history of AD and younger maternal age of AD onset provide additional support for the role of TREM2 in AD and illustrate the importance of considering family history in AD study design.
doi:10.1016/j.neurobiolaging.2013.11.013
PMCID: PMC3961539  PMID: 24378087
TREM2; family history; Alzheimer’s disease; memory; cognition; longitudinal
8.  Heritability of Cognitive Traits Among Siblings with a Parental History of Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2015;45(4):1149-1155.
Cognitive decline is one of the hallmark features of Alzheimer’s disease, but many studies struggle to find strong associations between cognitive function and genetic variants. In order to identify which aspects of cognition are more likely to have a strong genetic component, we assessed the heritability of various cognitive functions related to Alzheimer’s in 303 initially asymptomatic middle-aged adult siblings with a parental history of Alzheimer’s from the Wisconsin Registry for Alzheimer’s Prevention. Participants underwent extensive cognitive testing and six cognitive factors were identified via factor analysis. Working Memory and Visual Learning & Memory had the highest heritability (52% and 41%, respectively). Inclusion of APOE allele counts did not notably change heritability estimates, indicating that there are likely additional genetic variants contributing to cognition. These findings suggest that future genetic studies should focus on the cognitive domains of Working Memory and Visual Learning & Memory.
doi:10.3233/JAD-142658
PMCID: PMC4398625  PMID: 25649654
Alzheimer’s Disease; Heritability; Genetics; Cognitive Function; WRAP; APOE
9.  Stressful Events, Social Support, and Cognitive Function in Middle-aged Adults with a Family History of Alzheimer’s Disease 
Journal of aging and health  2013;25(6):944-959.
Objectives
To examine the associations of stressful experiences and social support with cognitive function in a sample of middle-aged adults with a family history of Alzheimer’s disease (AD).
Methods
Using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP; N=623), we evaluated relationships between stressful events experienced in the past year, as well as social support, and cognitive performance in four domains: speed and flexibility, immediate memory, verbal learning and memory, and working memory. We assessed interactions between psychosocial predictors, and with APOE ε4 status.
Results
Greater number of stressful events was associated with poorer performance on tests of speed and flexibility. Greater social support was associated with better performance in the same domain; this relationship was diminished by presence of the ε4 allele. No associations were seen in the remaining three domains.
Discussion
Psychosocial factors may influence cognition in at-risk individuals; influence varies by cognitive domain and ε4 status.
doi:10.1177/0898264313498416
PMCID: PMC3769466  PMID: 23945762
Cognitive function; geriatrics; social factors; stressful events; gene-environment interaction
10.  Interaction between two cholesterol metabolism genes influences memory: findings from the Wisconsin Registry for Alzheimer’s Prevention 
The strongest genetic factor for late-onset Alzheimer’s disease (AD) is APOE; nine additional susceptibility genes have recently been identified. The effect of these genes is often assumed to be additive and polygenic scores are formed as a summary measure of risk. However, interactions between these genes are likely to be important. We sought to examine the role of interactions between the nine recently identified AD susceptibility genes and APOE in cognitive function and decline in 1,153 participants from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Participants underwent extensive cognitive testing at baseline and up to two additional visits approximately 4 and 6 years later. The influence of the interaction between APOE and each of 14 single nucleotide polymorphisms (SNPs) in the nine recently identified genes on three cognitive factor scores (Verbal Learning and Memory, Working Memory, and Immediate Memory) was examined using linear mixed models adjusting for age, gender and ancestry. Interactions between the APOE ε4 allele and both of the genotyped ABCA7 SNPs, rs3764650 and rs3752246, were associated with all three cognitive factor scores (P-values ≤0.01). Both of these genes are in the cholesterol metabolism pathway leading to AD. This research supports the importance of considering non-additive effects of AD susceptibility genes.
doi:10.3233/JAD-130482
PMCID: PMC3759032  PMID: 23669301
gene-gene interaction; memory; cognition; Alzheimer’s disease; cholesterol
11.  Association between vitamin D status and age-related macular degeneration by genetic risk 
JAMA ophthalmology  2015;133(10):1171-1179.
Importance
Deficient 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with increased odds of age-related macular degeneration (AMD).
Objective
We examined 1) whether this association is modified by genetic risk for AMD and 2) if there is an association between AMD and single nucleotide polymorphisms (SNPs) of genes involved in vitamin D transport, metabolism and genomic function.
Design, Setting and Participants
Women were postmenopausal and participants of the Carotenoids in Age-Related Eye Disease Study (CAREDS) (54 to <75 years) with available serum 25(OH)D concentrations (assessed from 1994–1998), genetic data, and measures of AMD (n=142) assessed at CAREDS baseline from 2001–2004 (n=913).
Main Outcomes and Measures
Prevalent early or late AMD was determined from graded, stereoscopic fundus photographs. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for AMD by the joint effects of 25(OH)D (<30, ≥30 to <50, ≥50 to <75, and ≥75 nmol/L) and risk genotype (noncarrier, one, or two risk alleles). The referent group was noncarriers with adequate vitamin D status (≥75 nmol/L). Joint effect ORs were adjusted for age, smoking, iris pigmentation, self-reported cardiovascular disease, self-reported diabetes status, and hormone use. Additive and multiplicative interactions were assessed using the Synergy Index (SI) and an interaction term, respectively.
Results
We observed a 6.7-fold increased odds of AMD (95% CI=1.6, 28.2) among women with deficient vitamin D status (25(OH)D<30 nmol/L) and two risk alleles for complement factor H (CFH) Y402H (SI for additive interaction=1.4, 95% CI=1.1, 1.7; p for multiplicative interaction=0.25,. A significant additive (SI=1.4, 95% CI=1.1, 1.7) and multiplicative interaction (p=0.02) was observed for deficient women with two high risk complement factor I (CFI) (rs10033900) alleles (OR=6.3, 95% CI=1.6, 24.2). The odds of AMD did not differ by genotype of candidate vitamin D genes.
Conclusions and Relevance
In this study, the odds of AMD was highest in those with deficient vitamin D status and two risk alleles for CFH and CFI genotype suggesting a synergistic effect between vitamin D status and complement cascade protein function. Limited sample size led to wide confidence intervals. Findings may be due to chance or explained by residual confounding.
doi:10.1001/jamaophthalmol.2015.2715
PMCID: PMC4841267  PMID: 26312598
12.  Detecting Multiple Causal Rare Variants in Exome Sequence Data 
Genetic Epidemiology  2011;35(Suppl 1):S18-S21.
Recent advances in sequencing technology have presented both opportunities and challenges, with limited statistical power to detect a single causal rare variant with practical sample sizes. To overcome this, the contributors to Group 1 of Genetic Analysis Workshop 17 sought to develop methods to detect the combined signal of multiple causal rare variants in a biologically meaningful way. The contributors used genes, genome location proximity, or genetic pathways as the basic unit in combining the information from multiple variants. Weaknesses of the exome sequence data and the relative strengths and weaknesses of the five approaches are discussed.
doi:10.1002/gepi.20644
PMCID: PMC3271433  PMID: 22128053
Bayesian; pathways; simulated
13.  Genome-wide association study of vitamin D concentrations in Hispanic Americans: The IRAS Family Study 
Vitamin D deficiency is associated with many adverse health outcomes. There are several well established environmental predictors of vitamin D concentrations, yet studies of the genetic determinants of vitamin D concentrations are in their infancy. Our objective was to conduct a pilot genome-wide association (GWA) study of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations in a subset of 229 Hispanic subjects, followed by replication genotyping of 50 single nucleotide polymorphisms (SNPs) in the entire sample of 1,190 Hispanics from San Antonio, Texas and San Luis Valley, Colorado. Of the 309,200 SNPs that met all quality control criteria, three SNPs in high linkage disequilibrium (LD) with each other were significantly associated with 1,25[OH]2D (rs6680429, rs9970802, and rs10889028) at a Bonferroni corrected P-value threshold of 1.62 × 10−7, however none met the threshold for 25[OH]D. Of the 50 SNPs selected for replication genotyping, five for 25[OH]D (rs2806508, rs10141935, rs4778359, rs1507023, and rs9937918) and eight for 1,25[OH]2D (rs6680429, rs1348864, rs4559029, rs12667374, rs7781309, rs10505337, rs2486443, and rs2154175) were replicated in the entire sample of Hispanics (P < 0.01). In conclusion, we identified several SNPs that were associated with vitamin D metabolite concentrations in Hispanics. These candidate polymorphisms merit further investigation in independent populations and other ethnicities.
doi:10.1016/j.jsbmb.2010.06.013
PMCID: PMC2949505  PMID: 20600896
Vitamin D; 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; genome-wide association study; Hispanic
14.  Shiftwork, Sleep Habits, and Metabolic Disparities: Results from the Survey of the Health of Wisconsin 
Sleep health  2015;1(2):115-120.
Background
With the expanding demand for a 24-hour society, the prevalence of sleep deprivation and other sleep-related health problems is increasing. Shiftwork is an occupational health risk of growing significance because of its high prevalence and because of its potential role as a determinant of socioeconomic-related health disparities.
Aims
The aim of this study was to examine the associations of shiftwork with overweight status and type 2 diabetes, and explore whether a history of sleep problems mediates or modifies these associations.
Participants and Methods
A cross-sectional study was conducted among 1,593 participants in the Survey of the Health of Wisconsin (2008–12) who were employed and reported work characteristics (traditional schedule or shiftwork) and sleep habits and history of sleep problems (insomnia, insufficient sleep, wake time sleepiness). Objective measures of body mass index (BMI) and type 2 diabetes were used.
Results
Shiftworkers were more overweight than traditional-schedule workers (83% vs. 71% with BMI≥25) and reported more sleep problems, such as insomnia symptoms (24% vs. 16%), insufficient sleep (53% vs.43%), and sleepiness (32% vs. 24%). The associations between shiftwork and being overweight or diabetic were stronger among those reporting insufficient sleep, but the interaction was not statistically significant.
Conclusions
Shiftworkers face disparities in metabolic health, particularly those with insufficient sleep. Improved understanding of the relationship between sleep and metabolic states can inform healthcare providers’ and employers’ efforts to screen high-risk individuals and intervene with workplace wellness initiatives to address these disparities.
doi:10.1016/j.sleh.2015.04.014
PMCID: PMC4755509  PMID: 26894229
shiftwork; insufficient sleep; obesity; type 2 diabetes; health disparities
15.  Detecting Gene-Environment Interactions in Genome-Wide Association Data 
Genetic epidemiology  2009;33(Suppl 1):S68-S73.
Despite the importance of gene-environment (G×E) interactions in the etiology of common diseases, little work has been done to develop methods for detecting these types of interactions in genome-wide association study data. This was the focus of Genetic Analysis Workshop 16 Group 10 contributions, which introduced a variety of new methods for the detection of G×E interactions in both case-control and family-based data using both cross-sectional and longitudinal study designs. Many of these contributions detected significant G×E interactions. Although these interactions have not yet been confirmed, the results suggest the importance of testing for interactions. Issues of sample size, quantifying the environmental exposure, longitudinal data analysis, family-based analysis, selection of the most powerful analysis method, population stratification, and computational expense with respect to testing G×E interactions are discussed.
doi:10.1002/gepi.20475
PMCID: PMC2924567  PMID: 19924704
GAW; case-control; family-based; cross-sectional; longitudinal; rheumatoid arthritis; Framingham Heart Study
16.  Association of 25-hydroxyvitamin D with Blood Pressure in Predominantly 25-hydroxyvitamin D Deficient Hispanic and African Americans 
American journal of hypertension  2009;22(8):867-870.
Background
Several observational studies have recently suggested an inverse association of circulating levels of vitamin D with blood pressure. These findings have been based mainly on Caucasian populations; whether this association also exists among Hispanic and African Americans has yet to be definitively determined. This study investigates the association of 25-hydroxyvitamin D (25[OH]D) with blood pressure in Hispanic and African Americans.
Methods
The data source for this study is the Insulin Resistance Atherosclerosis Family Study (IRASFS), which consists of Hispanic- and African-American families from three U.S. recruitment centers (n=1334). A variance components model was used to analyze the association of plasma 25[OH]D levels with blood pressure.
Results
An inverse association was found between 25[OH]D and both systolic (β for 10 ng/mL difference= −2.05; p<0.01) and diastolic (β for 10 ng/mL difference= −1.35; p<0.001) blood pressure in all populations combined, after adjusting for age, sex, ethnicity and season of blood draw. Further adjustment for body mass index (BMI) weakened this association (β for 10 ng/mL difference= −0.94; p=0.14 and β for 10 ng/mL difference = −0.64; p=0.09, respectively).
Conclusions
25[OH]D levels are significantly inversely associated with blood pressure in Hispanic and African Americans from the IRASFS. However, this association was not significant after adjustment for BMI. Further research is needed to determine the role of BMI in this association. Large, well-designed prospective studies of the effect of vitamin D supplementation on blood pressure may be warranted.
doi:10.1038/ajh.2009.88
PMCID: PMC2865679  PMID: 19444222
Vitamin D; 25-hydroxyvitamin D; blood pressure; hypertension; race; ethnic groups; Hispanic; African American
17.  Association Between Informal Caregiving and Cellular Aging in the Survey of the Health of Wisconsin: The Role of Caregiving Characteristics, Stress, and Strain 
American Journal of Epidemiology  2014;179(11):1340-1352.
The pathophysiological consequences of caregiving have not been fully elucidated. We evaluated how caregiving, stress, and caregiver strain were associated with shorter relative telomere length (RTL), a marker of cellular aging. Caregivers (n = 240) and some noncaregivers (n = 98) in the 2008–2010 Survey of the Health of Wisconsin, comprising a representative sample of Wisconsin adults aged 21–74 years, reported their sociodemographic, health, and psychological characteristics. RTL was assayed from blood or saliva samples. Median T and S values were used to determine the telomere-to-single copy gene ratio (T/S) for each sample, and log(T/S) was used as the dependent variable in analyses. Multivariable generalized additive models showed that RTL did not differ between caregivers and noncaregivers (difference in log(T/S) = −0.03; P > 0.05), but moderate-to-high levels of stress versus low stress were associated with longer RTL (difference = 0.15; P = 0.04). Among caregivers, more hours per week of care, caring for a young person, and greater strain were associated with shorter RTL (P < 0.05). Caregivers with discordant levels of stress and strain (i.e., low perceived stress/high strain) compared with low stress/low strain had the shortest RTL (difference = −0.24; P = 0.02, Pinteraction = 0.13), corresponding to approximately 10–15 additional years of aging. Caregivers with these characteristics may be at increased risk for accelerated aging. Future work is necessary to better elucidate these relationships and develop interventions to improve the long-term health and well-being of caregivers.
doi:10.1093/aje/kwu066
PMCID: PMC4036217  PMID: 24780842
caregivers; caregiver strain; population-based studies; stress, psychological; Survey of the Health of Wisconsin
18.  Reproductive windows, genetic loci and breast cancer risk. 
Annals of epidemiology  2014;24(5):376-382.
Purpose
The reproductive windows between age at menarche and first childbirth (standardized AFB) and from menarche to menopause (reproductive lifespan) may interact with genetic variants in association with breast cancer risk.
Methods
We assessed this hypothesis in 6131 breast cancer cases and 7274 controls who participated in the population-based Collaborative Breast Cancer Study. Risk factor information was collected through telephone interviews and DNA samples were collected on a sub-sample (N=1484 cases, 1307 controls) to genotype for 13 genome-wide association study-identified loci. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated and P-values for the interaction between reproductive windows and genotypes were obtained by adding cross-product terms to statistical models.
Results
For standardized AFB, the OR was 1.52 (CI:1.36-1.71) comparing the highest to lowest quintile. Carrier status for rs10941679 (5p12) and rs10483813 (RAD51B) appeared to modify this relationship (P=0.04 and P=0.02, respectively). For reproductive lifespan, the OR comparing the highest and lowest quintiles was 1.62 (CI:1.35-1.95). No interactions were detected between genotype and reproductive lifespan (all P>0.05). All results were similar regardless of ductal versus lobular breast cancer subtype.
Conclusions
Our results suggest reproductive windows are associated with breast cancer risk, and that associations may vary by genetic variants.
doi:10.1016/j.annepidem.2014.02.007
PMCID: PMC4164346  PMID: 24792587
breast neoplasms; epidemiology; menarche; menopause; genetic loci; histology
19.  PREDICTORS OF DISCORDANCE BETWEEN PERCEIVED AND OBJECTIVE NEIGHBORHOOD DATA 
Annals of epidemiology  2013;24(3):214-221.
Purpose
Pathways by which the social and built environments affect health can be influenced by differences between perception and reality. This discordance is an important for understanding health impacts of the built environment. This study examines associations between perceived and objective measures of 12 non-residential destinations, as well as previously unexplored sociodemographic, lifestyle, neighborhood and urbanicity predictors of discordance.
Methods
Perceived neighborhood data were collected from participants of the Survey of the Health of Wisconsin (SHOW), using a self-administered questionnaire. Objective data were collected using the Wisconsin Assessment of the Social and Built Environment, an audit-based instrument assessing built environment features around each participant’s residence.
Results
Overall, there was relatively high agreement, ranging from 50% for proximity to parks to >90% for golf courses. Education, positive neighborhood perceptions, and rurality were negatively associated with discordance. Associations between discordance and depression, disease status, and lifestyle factors appeared to be modified by urbanicity level.
Conclusions
These data show perceived and objective neighborhood environment data are not interchangeable and the level of discordance is associated with or modified by individual and neighborhood factors, including level of urbanicity. These results suggest that consideration should be given to including both types of measures in future studies.
doi:10.1016/j.annepidem.2013.12.007
PMCID: PMC3947547  PMID: 24467991
Epidemiological methods; Environment Design; Obesity; Perception; Validity (Epidemiology); Rural Population; Urban Population
20.  The Wisconsin Assessment of the Social and Built Environment (WASABE): a multi-dimensional objective audit instrument for examining neighborhood effects on health 
BMC Public Health  2014;14:1165.
Background
Growing evidence suggests that mixed methods approaches to measuring neighborhood effects on health are needed. The Wisconsin Assessment of the Social and Built Environment (WASABE) is an objective audit tool designed as an addition to a statewide household-based health examination survey, the Survey of the Health of Wisconsin (SHOW), to objectively measure participant’s neighborhoods.
Methods
This paper describes the development and implementation of the WASABE and examines the instrument’s ability to capture a range of social and built environment features in urban and rural communities. A systematic literature review and formative research were used to create the tool. Inter-rater reliability parameters across items were calculated. Prevalence and density of features were estimated for strata formed according to several sociodemographic and urbanicity factors.
Results
The tool is highly reliable with over 81% of 115 derived items having percent agreement above 95%. It captured variance in neighborhood features in for a diverse sample of SHOW participants. Sidewalk density in neighborhoods surrounding households of participants living at less than 100% of the poverty level was 67% (95% confidence interval, 55-80%) compared to 34% (25-44%) for those living at greater than 400% of the poverty level. Walking and biking trails were present in 29% (19-39%) of participant buffer in urban areas compared to only 7% (2-12%) in rural communities. Significant environmental differences were also observed for white versus non-white, high versus low income, and college graduates versus individuals with lower level of education.
Conclusions
The WASABE has strong inter-rater reliability and validity properties. It builds on previous work to provide a rigorous and standardized method for systematically gathering objective built and social environmental data in a number of geographic settings. Findings illustrate the complex milieu of built environment features found in participants neighborhoods and have relevance for future research, policy, and community engagement purposes.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1165) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-1165
PMCID: PMC4289353  PMID: 25391283
Neighborhoods; Built environment; Social environment; Population health; Measurement; Urban; Rural; Chronic disease; Prevention; Physical activity; Methods; Audit tool
21.  Telomere length varies by DNA extraction method: Implications for epidemiologic research 
Background
Both shorter and longer telomeres in peripheral blood leukocyte (PBL) DNA have been associated with cancer risk. However, associations remain inconsistent across studies of the same cancer type. This study compares DNA preparation methods to determine telomere length from colorectal cancer patients.
Methods
We examined PBL relative telomere length (RTL) measured by quantitative PCR (qPCR) in 1,033 colorectal cancer patients and 2,952 healthy controls. DNA was extracted with Phenol/Chloroform, PureGene or QIAamp.
Results
We observed differences in RTL depending on DNA extraction method (p<0.001). Phenol/Chloroform extracted DNA had a mean RTL (T/S ratio) of 0.78 (range 0.01-6.54) ) compared to PureGene extracted DNA (mean RTL of 0.75; range 0.00-12.33). DNA extracted by QIAamp yielded a mean RTL of 0.38 (range 0.02-3.69). We subsequently compared RTL measured by qPCR from an independent set of 20 colorectal cancer cases and 24 normal controls in PBL DNA extracted by each of the three extraction methods. The range of RTL measured by qPCR from QIAamp-extracted DNA (0.17-0.58-) was smaller than from either PureGene or Phenol/Chloroform (ranges:0.04-2.67 and 0.32-2.81, respectively).
Conclusions
RTL measured by qPCR from QIAamp-extracted DNA was smaller than from either PureGene or Phenol/Chloroform (p<0.001).
Impact
Differences in DNA extraction method may contribute to the discrepancies between studies seeking to find an association between the risk of cancer or other diseases and RTL.
doi:10.1158/1055-9965.EPI-13-0409
PMCID: PMC3827976  PMID: 24019396
Telomere length; extraction methods; colorectal cancer
22.  The associations between a polygenic score, reproductive and menstrual risk factors and breast cancer risk 
We evaluated whether 13 single nucleotide polymorphisms (SNPs) identified in genome-wide association studies interact with one another and with reproductive and menstrual risk factors in association with breast cancer risk. DNA samples and information on parity, breastfeeding, age at menarche, age at first birth, and age at menopause were collected through structured interviews from 1484 breast cancer cases and 1307 controls who participated in a population-based case-control study conducted in three U.S. states. A polygenic score was created as the sum of risk allele copies multiplied by the corresponding log odds estimate. Logistic regression was used to test associations between SNPs, the score, reproductive and menstrual factors and breast cancer risk. Nonlinearity of the score was assessed by the inclusion of a quadratic term for polygenic score. Interactions between the aforementioned variables were tested by including a cross-product term in models. We confirmed associations between rs13387042 (2q35), rs4973768 (SLC4A7), rs10941679 (5p12), rs2981582 (FGFR2), rs3817198 (LSP1), rs3803662 (TOX3) and rs6504950 (STXBP4) with breast cancer. Women in the score’s highest quintile had 2.2-fold increased risk when compared to women in the lowest quintile (95% confidence interval:1.67–2.88). The quadratic polygenic score term was not significant in the model (p=0.85), suggesting established breast cancer loci are not associated with increased risk more than the sum of risk alleles. Modifications of menstrual and reproductive risk factors associations with breast cancer risk by polygenic score were not observed. Our results suggest interactions between breast cancer susceptibility loci and reproductive factors are not strong contributors to breast cancer risk.
doi:10.1007/s10549-013-2646-3
PMCID: PMC3799826  PMID: 23893088
Epidemiology; reproductive and menstrual factors; breast cancer; breast cancer susceptibility loci
23.  Genetic Evidence for Role of Carotenoids in Age-Related Macular Degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS) 
Purpose.
We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS).
Methods.
Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid-related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC).
Results.
A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0–4.9).
Conclusions.
Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD.
In this study of over 1600 postmenopausal women of the CAREDS, we describe the first evidence that variation in multiple genes related to carotenoid status in the blood and macula are associated with age-related macular degeneration (AMD).
doi:10.1167/iovs.13-13216
PMCID: PMC3908680  PMID: 24346170
macular degeneration; carotenoids; genes
24.  Perceived neighborhood quality, sleep quality, and health status: Evidence from the Survey of the Health of Wisconsin 
Why does living in a disadvantaged neighborhood predict poorer mental and physical health? Recent research focusing on the Southwestern United States suggests that disadvantaged neighborhoods favor poor health, in part, because they undermine sleep quality. Building on previous research, we test whether this process extends to the Midwestern United States. Specifically, we use cross-sectional data from the Survey of the Health of Wisconsin (SHOW), a statewide probability sample of Wisconsin adults, to examine whether associations among perceived neighborhood quality (e.g., perceptions of crime, litter, and pleasantness in the neighborhood) and health status (overall self-rated health and depression) are mediated by overall sleep quality (measured as self-rated sleep quality and physician diagnosis of sleep apnea). We find that perceptions of low neighborhood quality are associated with poorer self-rated sleep quality, poorer self-rated health, and more depressive symptoms. We also observe that poorer self-rated sleep quality is associated with poorer self-rated health and more depressive symptoms. Our mediation analyses indicate that self-rated sleep quality partially mediates the link between perceived neighborhood quality and health status. Specifically, self-rated sleep quality explains approximately 20% of the association between neighborhood quality and self-rated health and nearly 19% of the association between neighborhood quality and depression. Taken together, these results confirm previous research and extend the generalizability of the indirect effect of perceived neighborhood context on health status through sleep quality.
doi:10.1016/j.socscimed.2012.07.021
PMCID: PMC3733364  PMID: 22901794
Sleep; Sleep quality; Neighborhood context; Neighborhood quality; Self-rated health; Depression; Wisconsin; USA
25.  Correlation of Chromosomal Instability, Telomere Length and Telomere Maintenance in Microsatellite Stable Rectal Cancer: A Molecular Subclass of Rectal Cancer 
PLoS ONE  2013;8(11):e80015.
Introduction
Colorectal cancer (CRC) tumor DNA is characterized by chromosomal damage termed chromosomal instability (CIN) and excessively shortened telomeres. Up to 80% of CRC is microsatellite stable (MSS) and is historically considered to be chromosomally unstable (CIN+). However, tumor phenotyping depicts some MSS CRC with little or no genetic changes, thus being chromosomally stable (CIN-). MSS CIN- tumors have not been assessed for telomere attrition.
Experimental Design
MSS rectal cancers from patients ≤50 years old with Stage II (B2 or higher) or Stage III disease were assessed for CIN, telomere length and telomere maintenance mechanism (telomerase activation [TA]; alternative lengthening of telomeres [ALT]). Relative telomere length was measured by qPCR in somatic epithelial and cancer DNA. TA was measured with the TRAPeze assay, and tumors were evaluated for the presence of C-circles indicative of ALT. p53 mutation status was assessed in all available samples. DNA copy number changes were evaluated with Spectral Genomics aCGH.
Results
Tumors were classified as chromosomally stable (CIN-) and chromosomally instable (CIN+) by degree of DNA copy number changes. CIN- tumors (35%; n=6) had fewer copy number changes (<17% of their clones with DNA copy number changes) than CIN+ tumors (65%; n=13) which had high levels of copy number changes in 20% to 49% of clones. Telomere lengths were longer in CIN- compared to CIN+ tumors (p=0.0066) and in those in which telomerase was not activated (p=0.004). Tumors exhibiting activation of telomerase had shorter tumor telomeres (p=0.0040); and tended to be CIN+ (p=0.0949).
Conclusions
MSS rectal cancer appears to represent a heterogeneous group of tumors that may be categorized both on the basis of CIN status and telomere maintenance mechanism. MSS CIN- rectal cancers appear to have longer telomeres than those of MSS CIN+ rectal cancers and to utilize ALT rather than activation of telomerase.
doi:10.1371/journal.pone.0080015
PMCID: PMC3836975  PMID: 24278232

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