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1.  The rationale, design, and baseline characteristics of the Women’s Health Initiative Memory Study of Younger Women (WHIMS-Y) 
Brain research  2013;1514:3-11.
The Women’s Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women’s Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-54 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-54 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites.
PMCID: PMC3684042  PMID: 23578696
Postmenopausal hormone therapy; Cognitive function; Aging
2.  Sleep Duration, Insomnia, and Coronary Heart Disease Among Postmenopausal Women in the Women's Health Initiative 
Journal of Women's Health  2013;22(6):477-486.
Long and short sleep duration are associated with increased risk for coronary heart disease (CHD) and cardiovascular disease (CVD); however, evidence is inconsistent. We sought to identify whether self-reported sleep duration and insomnia, based on a validated questionnaire, are associated with increased incident CHD and CVD among postmenopausal women.
Women's Health Initiative Observational Study Participants (N=86,329; 50–79 years) who reported on sleep at baseline were followed for incident CVD events. Associations of sleep duration and insomnia with incident CHD and CVD were evaluated using Cox proportional hazards models over 10.3 years.
Women with high insomnia scores had elevated risk of CHD (38%) and CVD (27%) after adjustment for age and race, and in fully adjusted models (hazard ratio [HR]=1.19, 95% confidence interval [CI] 1.09–1.30; 1.11 95% CI 1.03–2.00). Shorter (≤5 hours) and longer (≥10 hours) sleep duration demonstrated significantly higher incident CHD (25%) and CVD (19%) in age- and race-adjusted models, but this was not significant in fully adjusted models. Formal tests for interaction indicated significant interactions between sleep duration and insomnia for risk of CHD (p<0.01) and CVD (p=0.02). Women with high insomnia scores and long sleep demonstrated the greatest risk of incident CHD compared to midrange sleep duration (HR=1.93, 95% CI 1.06—3.51) in fully adjusted models.
Sleep duration and insomnia are associated with CHD and CVD risk, and may interact to cause almost double the risk of CHD and CVD. Additional research is needed to understand how sleep quality modifies the association between prolonged sleep and cardiovascular outcomes.
PMCID: PMC3678565  PMID: 23651054
3.  Long QT Syndrome in African-Americans 
We evaluated the risk factors and clinical course of Long QT syndrome (LQTS) in African-American patients.
The study involved 41 African-Americans and 3,456 Caucasians with a QTc ≥ 450 ms from the U.S. portion of the International LQTS Registry. Data included information about the medical history and clinical course of the LQTS patients with end points relating to the occurrence of syncope, aborted cardiac arrest, or LQTS- related sudden cardiac death from birth through age 40 years. The statistical analyses involved Kaplan-Meier time to event graphs and Cox regression models for multivariable risk factor evaluation.
The QTc was 29ms longer in African-Americans than Caucasians. Multivarite Cox analyses with adjustment for decade of birth revealed that the cardiac event rate was similar in African-Americans and Caucasians with LQTS and that β-blockers were equally effective in reducing cardiac events in the two racial groups.
The clinical course of LQTS in African-Americans is similar to that of Caucasians with comparable risk factors and benefit from β-blocker therapy in the two racial groups.
PMCID: PMC4028024  PMID: 20146785
4.  Mutation and Gender Specific Risk in Type-2 Long QT Syndrome 
Men and women with type-2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2
To risk stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
The risk for life-threatening cardiac events from birth through age 40 (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) years was assessed among 1,166 LQT2 males (n=490) and females (n=676) by the location of the LQTS-causing mutation in the KCNH2 channel (pre-specified in the primary analysis as pore-loop vs. nonpore-loop).
During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; p<0.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (HR=1.20; p=0.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with nonpore-loop mutations (HR=2.18; p=0.01). Consistently, women experienced a high rate of life-threatening events regardless of mutation-location (pore-loop: 35%, nonpore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with nonpore-loop mutations (8%).
Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in type-2 long QT syndrome.
PMCID: PMC4028036  PMID: 21440677
long-QT syndrome; pore-loop mutations; sudden cardiac death; gender
5.  β-Blocker Efficacy in High-Risk Patients with the Congenital Long-QT Syndrome Types 1 and 2 
β-blockers are the mainstay therapy in patients with the congenital long-QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high-risk subsets of these populations.
Methods and Results
Multivariate analysis was carried out to identify age-related gender- and genotype- specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n=549) and LQT2 (n=422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR=1.49, p=0.003) and male gender (HR=1.31, p=0.04) in the 0-14 years age-group; and the LQT2 genotype (HR=1.67, p<0.001) and female gender (HR=2.58, p<0.001) in the 15-40 years age-group. Gender-genotype subset analysis showed enhanced risk among LQT1 males (HR=1.93, p<0.001) and LQT2 females (HR=3.28, p<0.001) in the 2 respective age-groups. β-blocker therapy was associated with a significant risk-reduction in high-risk patients, including a 67% reduction (p=0.02) in LQT1 males and a 71% reduction (p<0.001) in LQT2 females. Life-threatening events (ACA/SCD) rarely occurred as a presenting symptom among β-blocker-treated patients. However, high-risk patients who experienced syncope during β-blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient-years).
The present findings suggest that β-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy.
PMCID: PMC4005824  PMID: 20233272
long QT syndrome; β-blockers; cardiac events; sudden cardiac death
6.  Risk of Cardiac Events in Patients with Asthma and Long QT Syndrome Treated with β2-agonists 
The American journal of cardiology  2008;102(7):871-874.
The clinical course and risk factors associated with β2-agonist therapy for asthma have not been investigated previously in patients with the Long QT Syndrome (LQTS). The risk of a first LQTS-related cardiac event due to β2-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc≥450msec. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent β2-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio (HR) = 2.00, 95% confidence interval 1.26–3.15, p = 0.003) after adjustment for relevant covariates including time-dependent β-blocker use, sex, QTc, and history of asthma. This risk was augmented within the first year after the initiation of β2-agonist therapy (HR = 3.53; p = 0.006). The combined use of β2-agonist and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66; p < 0.01). β-blocker therapy was associated with a reduction in cardiac events in those using β2-agonists (HR = 0.14; P = 0.05). In conclusion, β2-agonist therapy was associated with an increased risk for cardiac events in asthmatic patients with LQTS, and this risk was diminished in patients receiving β-blockers.
PMCID: PMC4005827  PMID: 18805113
7.  Risk Factors for Aborted Cardiac Arrest and Sudden Cardiac Death in Children with the Congenital Long-QT Syndrome 
Circulation  2008;117(17):2184-2191.
The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death (SCD) in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified
Methods and Results
Cox proportional hazards regression modeling was used to identify risk factors for aborted cardiac arrest (ACA) or SCD in 3,015 LQTS children from the International LQTS Registry who were followed up from age 1 through 12 years. The cumulative probability of the combined end point was significantly higher in males (5%) than in females (1%; p<0.001). Risk factors for ACA or SCD during childhood included QTc duration >500 msec (HR=2.72 [95%CI 1.50 - 4.92]; p=0.001) and prior syncope (recent syncope [<2 years]: HR=6.16 [95%CI 3.41 - 11.15], p<0.001; remote syncope [≥2 years]: HR=2.67 [95% CI 1.22 - 5.85], p=0.01) in males, whereas prior syncope was the only significant risk factor among females (recent syncope: HR=27.82 [95%CI 9.72 - 79.60], p<0.001]; remote syncope: HR=12.04 [95%CI 3.79 - 38.26], p<0.001). β-blocker therapy was associated with a significant 53% reduction in the risk of ACA or SCD (p=0.01).
LQTS males experience a significantly higher rate of fatal or near-fatal cardiac events than females during childhood. A QTc duration >500 msec and a history of prior syncope identify risk in males, whereas prior syncope is the only significant risk factor among females. β-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.
PMCID: PMC3944375  PMID: 18427136
long-QT syndrome; risk factors; sudden death
8.  Risk of Life Threatening Cardiac Events among Patients with Long QT Syndrome and Multiple Mutations 
Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.
The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.
The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.
Patients with multiple mutations (n = 57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; p = 0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p < 0.001). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (p = 0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (p = 0.010) whereas the risk associated with multiple mutation status involving > 1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, p = 0.26).
LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.
PMCID: PMC3690288  PMID: 23174487
Aborted cardiac arrest; Long QT syndrome; Mutation; Risk factor; Sudden cardiac death
9.  Self-reported Snoring and Risk of Cardiovascular Disease among Postmenopausal Women (From the Women’s Health Initiative) 
The American journal of cardiology  2012;111(4):540-546.
Habitual snoring may be associated with cardiovascular disease (CVD); however limited evidence exists among women. We investigated whether frequent snoring is a predictor of coronary heart disease (CHD) and stroke among 42,244 postmenopausal women participating in the Women’s Health Initiative Observational Study. Participants provided self-reported information regarding snoring habits at baseline (1993-1998) and were followed for outcomes through August 2009. Physician adjudicators confirmed CHD, defined as MI, CHD death, revascularization procedures, or hospitalized angina, and confirmed ischemic stroke. Cox proportional hazards models were used to evaluate whether snoring frequency is a significant predictor of adjudicated outcomes. We observed 2,401 incident cases of CHD over 437,899 person-years of follow up. After adjusting for age and race, frequent snoring was associated with incident CHD (HR=1.54, 95% CI 1.39-1.70) and stroke (HR=1.41, 95% CI 1.19-1.66), and all CVD (HR=1.46, 95% CI 1.34-1.60). In fully adjusted models that included CVD risk factors such as obesity, hypertension, and diabetes, frequent snoring was associated with a more modest increase in incident CHD (HR=1.14 95% CI 1.01-1.28), stroke (HR=1.19, 95% CI 1.02-1.40) and CVD (HR=1.12, 95% CI 1.01-1.24). In conclusion, snoring is associated with a modest increased risk of incident CHD, stroke and CVD after adjustment for CVD risk factors. Additional studies are needed to elucidate the mechanisms in which snoring may be associated with CVD risk factors and outcomes.
PMCID: PMC3563849  PMID: 23219175
Snoring; Cardiovascular Disease; Coronary Heart Disease; Menopause
10.  Influence of Type 2 Diabetes on Brain Volumes and Changes in Brain Volumes 
Diabetes Care  2012;36(1):90-97.
To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function.
Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72–89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined.
The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits.
Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.
PMCID: PMC3526228  PMID: 22933440
11.  Changes in GABA and glutamate concentrations during memory tasks in patients with Parkinson’s disease undergoing DBS surgery 
Until now direct neurochemical measurements during memory tasks have not been accomplished in the human basal ganglia. It has been proposed, based on both functional imaging studies and psychometric testing in normal subjects and in patients with Parkinson’s disease (PD), that the basal ganglia is responsible for the performance of feedback-contingent implicit memory tasks. To measure neurotransmitters, we used in vivo microdialysis during deep brain stimulation (DBS) surgery. We show in the right subthalamic nucleus (STN) of patients with PD a task-dependent change in the concentrations of glutamate and GABA during an implicit memory task relative to baseline, while no difference was found between declarative memory tasks. The five patients studied had a significant decrease in the percent concentration of GABA and glutamate during the performance of the weather prediction task (WPT). We hypothesize, based on current models of basal ganglia function, that this decrease in the concentration is consistent with expected dysfunction in basal ganglia networks in patients with PD.
PMCID: PMC3945932  PMID: 24639638
microdialysis; STN; Parkinson disease; implicit memory; DBS; GABA; glutamate; WPT
12.  Statins, Angiotensin-Converting Enzyme Inhibitors and Physical Performance in Older Women 
Angiotensin-converting enzyme (ACE) inhibitor and statin medications may preserve skeletal muscle. We examined associations between each medication class and baseline and mean annual change in physical performance measures and muscle strength in older women.
Prospective cohort study
Participants from the Women’s Health Initiative Clinical Trials who were aged 65–79 at baseline and had physical performance measures, self-report of health insurance and no prior history of stroke or congestive heart failure were included (n=5777). Women were recruited between 1993 and 1998.
Medication use was ascertained through a baseline inventory. Physical performance measures (timed 6-meter walk, repeated chair stands in 15 seconds) and grip strength were assessed at baseline and follow-up years 1, 3 and 6. Multivariable adjusted linear repeated- measures models adjusted for demographic and health characteristics.
ACE inhibitor use was negatively associated with mean grip strength at baseline (22.40 kg, 95% confidence interval [CI] 21.89, 22.91 versus 23.18 kg, 95% CI 23.02, 23.34; P = .005) and a greater mean annual change in number of chair stands (−.182, 95% CI −.217, −.147 versus −.145, 95% CI −.156, −.133; P = .05) compared to non-use. Statin use was not significantly associated with baseline or mean annual change for any outcome. A subgroup analysis suggested that statin use was associated with less mean annual change in chair stands (P = .006) in the oldest women.
These results do not support an association of statin or ACE inhibitor use with slower decline in physical performance or muscle strength, and thus do not support the use of these medications for preserving functional status in older adults.
PMCID: PMC3521070  PMID: 23176078
ACE inhibitors; statins; physical performance; grip strength
13.  Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study 
Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.
Methods and Results
Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.
CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.
PMCID: PMC3886762  PMID: 24351701
cardiovascular diseases; cognitive decline; postmenopausal women
14.  Toward a Positive Aging Phenotype for Older Women: Observations From the Women’s Health Initiative 
To develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living.
Data from Women’s Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services).
We identified a multidimensional phenotype of positive aging that included two factors: Physical–Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical–Social Functioning was the strongest predictor. Each standard deviation of increase in Physical–Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living.
Physical–Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical–Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.
PMCID: PMC3667695  PMID: 22518819
Positive aging; Phenotypes; Women's health; Healthy life span
15.  A Tool to Assess Student Performance in a Clostridium difficile Infection Simulation Scenario 
Objective. To develop and validate an evaluation tool to assess student pharmacists' performance in a simulation scenario involving a patient with Clostridium difficile infection (CDI).
Methods. The authors used an expert panel review process to establish content validity of the tool. Four faculty members used the tool to evaluate student pharmacist groups during 2011 and tested a modified version of the tool in 2012. The authors analyzed the results for each year to determine internal consistency and inter-rater reliability.
Results. The 2011 tool demonstrated sound internal consistency, but several items had poor inter-rater agreement. The revised 2012 tool demonstrated acceptable internal consistency and good to excellent inter-rater agreement for all items except one.
Conclusions. The tool facilitated reliable assessment of student pharmacists' clinical decision-making during simulation performance involving a patient with CDI.
PMCID: PMC3776903  PMID: 24052652
assessment; simulation; evaluation tool; validation; clostridium difficile infection
16.  Clinical Utility of Lp-PLA2 for Cardiovascular Disease Prediction in a Multiethnic Cohort of Women 
Clinical chemistry  2012;58(9):1352-1363.
Findings regarding the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass with incident cardiovascular disease (CVD) have been inconsistent, and their role in risk prediction is uncertain.
A case-cohort sample from the Women’s Health Initiative Observational Study (WHI-OS) comprised 1,821 CVD cases and a subcohort of 1,992. Cox regression models with inverse sampling weights assessed the association of Lp-PLA2 mass and activity with CVD (myocardial infarction [MI], stroke, and CVD mortality).
Subcohort means were 184.3 mmol/min/mL for Lp-PLA2 activity and 499.2 ng/mL for Lp-PLA2 mass, with 99% having mass above 200 ng/mL, the clinically recommended cut-point. Both activity and mass were positively associated with incident CVD in age- and race/ethnicity-adjusted analyses. Following adjustment by CVD risk factors, the association with activity became null (hazard ratio [HR] = 1.02 for top vs. bottom quartile, 95% confidence interval [CI] = 0.79-1.33, p-trend=0.65), but the association with mass remained (HR = 1.84, 95% CI = 1.45-2.34, p-trend <0.0001). In contrast to blood pressure, HDL, and hsCRP, reclassification statistics for Lp-PLA2 mass did not suggest improvement for overall CVD after full adjustment.
In the WHI-OS Lp-PLA2 mass, but not activity, was independently associated with CVD. However, model fit did not significantly improve with Lp-PLA2, and assay calibration remains a clinical concern.
PMCID: PMC3621122  PMID: 22859728
17.  Genetic Determinants of Macular Pigments in Women of the Carotenoids in Age-Related Eye Disease Study 
To investigate genetic determinants of macular pigment optical density in women from the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women's Health Initiative Observational Study.
1585 of 2005 CAREDS participants had macular pigment optical density (MPOD) measured noninvasively using customized heterochromatic flicker photometry and blood samples genotyped for 440 single nucleotide polymorphisms (SNPs) in 26 candidate genes related to absorption, transport, binding, and cleavage of carotenoids directly, or via lipid transport. SNPs were individually tested for associations with MPOD using least-squares linear regression.
Twenty-one SNPs from 11 genes were associated with MPOD (P ≤ 0.05) after adjusting for dietary intake of lutein and zeaxanthin. This includes variants in or near genes related to zeaxanthin binding in the macula (GSTP1), carotenoid cleavage (BCMO1), cholesterol transport or uptake (SCARB1, ABCA1, ABCG5, and LIPC), long-chain omega-3 fatty acid status (ELOVL2, FADS1, and FADS2), and various maculopathies (ALDH3A2 and RPE65). The strongest association was for rs11645428 near BCMO1 (βA = 0.029, P = 2.2 × 10−4). Conditional modeling within genes and further adjustment for other predictors of MPOD, including waist circumference, diabetes, and dietary intake of fiber, resulted in 13 SNPs from 10 genes maintaining independent association with MPOD. Variation in these single gene polymorphisms accounted for 5% of the variability in MPOD (P = 3.5 × 10−11).
Our results support that MPOD is a multi-factorial phenotype associated with variation in genes related to carotenoid transport, uptake, and metabolism, independent of known dietary and health influences on MPOD.
In 1585 postmenopausal women of the Carotenoids in Age-Related Eye Disease Study sample, common genetic variants in or near genes involved in carotenoid transport, uptake, and metabolism were associated with density of lutein and zeaxanthin in the macula, independent of other known predictors, including dietary intake of carotenoids.
PMCID: PMC3626525  PMID: 23404124
18.  Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events: Implications for Mutation-Specific Response to Beta-Blocker Therapy in Type-1 Long QT Syndrome 
Circulation  2012;125(16):1988-1996.
β-adrenergic stimulation is the main trigger for cardiac events in type-1 long QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location.
Methods and Results
The study sample comprised 860 patients with genetically-confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C-loops), membrane spanning domain, C/N-terminus, and non-missense mutations. There were 27 aborted cardiac arrest [ACA] and 78 sudden cardiac death [SCD] events from birth through age 40 years. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for ACA or SCD (hazard ratio [95% confidence interval] vs. non-missense mutations = 2.75 [1.29-5.86, P=0.009]). β-blocker therapy was associated with a significantly greater reduction in the risk of ACA or SCD among patients with C-loop mutations than among all other patients (hazard ratios = 0.12 [0.02-0.73, P=0.02] and 0.82 [0.31-2.13, P=0.68], respectively; P-for interaction = 0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation.
Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high-risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation following sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
PMCID: PMC3690492  PMID: 22456477
beta-blockers; ion channels; long QT syndrome; mutation
19.  Risk of Syncope in Family Members Who Are Genotype Negative for a Family-Associated Long QT Syndrome Mutation 
Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families.
Methods and Results
Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 msec (interquartile-range: 402–442 msec). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) experienced ACA and none died suddenly during follow-up. Independent risk factors for syncope in genotype negative subjects included female gender (HR 1.60, p = 0.002), prolonged QTc (HR = 1.63 per 100 msec increment, p = 0.02), family history of ACA or SCD (HR = 1.89, p = 0.002), and LQT2 vs. LQT1 family mutation (HR = 1.41, p = 0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (p = 0.001) increase in the risk of recurrent syncope in genotype negative subjects.
Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.
PMCID: PMC3690290  PMID: 21831960
gene mutation; genetic polymorphisms; long-QT syndrome; sudden cardiac death arrhythmia; syncope
20.  Fronto-Temporal Dysregulation in Asymptomatic Bipolar I Patients: A Paired Associate Functional MRI Study 
Human brain mapping  2010;31(7):1041-1051.
Bipolar disorder is associated with persistent declarative memory disturbances, but the neural basis of these deficits is not well understood. We used fMRI to investigate brain activity during performance on a face-name paired associate task, which allows for the dissociation of encoding and recall-related memory processes. Fifteen clinically remitted bipolar I disorder patients and 24 demographically matched healthy comparison subjects were scanned during task performance. At the voxel level, bipolar patients showed reduced cortical activation, relative to controls, in multiple task-related brain regions during encoding. During recognition, bipolar patients under-activated left hippocampal and parahippocampal regions, despite adequate task performance. Region of interest analyses indicated that, during encoding, bipolar patients had greater bilateral dorsolateral prefrontal (DLPFC) activity than healthy subjects. In contrast, during recognition patients showed hypo-activation relative to controls in the right, but not the left, DLPFC. Although hippocampal activity did not differ between groups during encoding, bipolar patients failed to activate hippocampal regions to the same extent as healthy subjects during recognition. Finally, while better task performance was associated with recognition-related hippocampal activity in healthy subjects, bipolar patients showed an inverse relationship between task performance and hippocampal activity. Remitted bipolar patients over-engaged dorsolateral prefrontal regions when learning face-name pairs, but relative hypoactivation in both prefrontal and medial temporal regions during recognition. These findings suggest a neural basis for the long-term memory deficits consistently observed in patients with bipolar disorder; further, as these patterns appear in symptomatically remitted patients, they are unlikely to be an artifact of mood symptoms.
PMCID: PMC3660318  PMID: 20063304
Hippocampus; declarative memory; long-term memory; bipolar disorder; fMRI; frontal cortex
21.  Self-perceived physical health predicts cardiovascular disease incidence and death among postmenopausal women 
BMC Public Health  2013;13:468.
Physical and Mental Component Summary (PCS, MCS, respectively) scales of SF- 36 health-related-quality-of-life have been associated with all-cause and cardiovascular disease (CVD) mortality. Their relationships with CVD incidence are unclear. This study purpose was to test whether PCS and/or MCS were associated with CVD incidence and death.
Postmenopausal women (aged 50–79 years) in control groups of the Women’s Health Initiative clinical trials (n = 20,308) completed the SF-36 and standardized questionnaires at trial entry. Health outcomes, assessed semi-annually, were verified with medical records. Cox regressions assessed time to selected outcomes during the trial phase (1993–2005).
A total of 1075 incident CVD events, 204 CVD-specific deaths, and 1043 total deaths occurred during the trial phase. Women with low versus high baseline PCS scores had less favorable health profiles at baseline. In multivariable models adjusting for baseline confounders, participants in the lowest PCS quintile (reference = highest quintile) exhibited 1.8 (95%CI: 1.4, 2.3), 4.7 (95%CI: 2.3, 9.4), and 2.1 (95%CI: 1.7, 2.7) times greater risk of CVD incidence, CVD-specific death, and total mortality, respectively, by trial end; whereas, MCS was not significantly associated with CVD incidence or death.
Physical health, assessed by self-report of physical functioning, is a strong predictor of CVD incidence and death in postmenopausal women; similar self-assessment of mental health is not. PCS should be evaluated as a screening tool to identify older women at high risk for CVD development and death.
PMCID: PMC3706392  PMID: 23672763
Physical component summary; Mental component summary; Cardiovascular disease; All-cause death
22.  Comparison of the Framingham and Reynolds Risk Scores for Global Cardiovascular Risk Prediction in the Multiethnic Women’s Health Initiative 
Circulation  2012;125(14):1748-1756.
Framingham-based and Reynolds risk scores for cardiovascular disease (CVD) prediction have not been directly compared in an independent validation cohort.
Methods and Results
We selected a case-cohort sample of the multi-ethnic Women’s Health Initiative Observational Cohort, comprising 1722 cases of major CVD (752 MIs, 754 ischemic strokes, and 216 other CVD deaths) and a random subcohort of 1994 women without prior CVD. We estimated risk using the ATP-III score, the Reynolds risk score, and the Framingham CVD model, reweighting to reflect cohort frequencies. Predicted 10-year risk varied widely between models, with 10% or higher risk in 6%, 10%, and 41% of women using the ATP-III, Reynolds, and Framingham CVD models, respectively. Calibration was adequate for the Reynolds model, but the ATP-III and Framingham CVD models over-estimated risk for CHD and major CVD, respectively. After recalibration, the Reynolds model demonstrated improved discrimination over the ATP-III model through a higher c-statistic (0.765 vs. 0.757, p=0.03), positive net reclassification improvement (NRI) (4.9%, p=0.02) and positive integrated discrimination improvement (IDI) (4.1%, p<0.0001) overall, excluding diabetics (NRI=4.2%, p=0.01), and in white (NRI=4.3%, p=0.04) and black (NRI=11.4, p=0.13) women. The Reynolds (NRI=12.9, p<0.0001) and ATP-III (NRI=5.9%, p=0.0001) models demonstrated better discrimination than the Framingham CVD model.
The Reynolds Risk Score was better calibrated than the Framingham-based models in this large external validation cohort. The Reynolds score also showed improved discrimination overall and in black and white women. Large differences in risk estimates exist between models, with clinical implications for statin therapy.
PMCID: PMC3324658  PMID: 22399535
cardiovascular disease risk factors; models; prediction; risk score; statins
23.  Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained 
Wu, Ying | Waite, Lindsay L. | Jackson, Anne U. | Sheu, Wayne H-H. | Buyske, Steven | Absher, Devin | Arnett, Donna K. | Boerwinkle, Eric | Bonnycastle, Lori L. | Carty, Cara L. | Cheng, Iona | Cochran, Barbara | Croteau-Chonka, Damien C. | Dumitrescu, Logan | Eaton, Charles B. | Franceschini, Nora | Guo, Xiuqing | Henderson, Brian E. | Hindorff, Lucia A. | Kim, Eric | Kinnunen, Leena | Komulainen, Pirjo | Lee, Wen-Jane | Le Marchand, Loic | Lin, Yi | Lindström, Jaana | Lingaas-Holmen, Oddgeir | Mitchell, Sabrina L. | Narisu, Narisu | Robinson, Jennifer G. | Schumacher, Fred | Stančáková, Alena | Sundvall, Jouko | Sung, Yun-Ju | Swift, Amy J. | Wang, Wen-Chang | Wilkens, Lynne | Wilsgaard, Tom | Young, Alicia M. | Adair, Linda S. | Ballantyne, Christie M. | Bůžková, Petra | Chakravarti, Aravinda | Collins, Francis S. | Duggan, David | Feranil, Alan B. | Ho, Low-Tone | Hung, Yi-Jen | Hunt, Steven C. | Hveem, Kristian | Juang, Jyh-Ming J. | Kesäniemi, Antero Y. | Kuusisto, Johanna | Laakso, Markku | Lakka, Timo A. | Lee, I-Te | Leppert, Mark F. | Matise, Tara C. | Moilanen, Leena | Njølstad, Inger | Peters, Ulrike | Quertermous, Thomas | Rauramaa, Rainer | Rotter, Jerome I. | Saramies, Jouko | Tuomilehto, Jaakko | Uusitupa, Matti | Wang, Tzung-Dau | Boehnke, Michael | Haiman, Christopher A. | Chen, Yii-Der I. | Kooperberg, Charles | Assimes, Themistocles L. | Crawford, Dana C. | Hsiung, Chao A. | North, Kari E. | Mohlke, Karen L.
PLoS Genetics  2013;9(3):e1003379.
Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10−4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
Author Summary
Lipid traits are heritable, but many of the DNA variants that influence lipid levels remain unknown. In a genomic region, more than one variant may affect gene expression or function, and the frequencies of these variants can differ across populations. Genotyping densely spaced variants in individuals with different ancestries may increase the chance of identifying variants that affect gene expression or function. We analyzed high-density genotyped variants for association with TG, HDL-C, and LDL-C in African Americans, East Asians, and Europeans. At several genomic regions, we provide evidence that two or more variants can influence lipid traits; across loci, these additional signals increase the proportion of trait variation that can be explained by genes. At some association signals shared across populations, combining data from individuals of different ancestries narrowed the set of likely functional variants. At PCSK9 and APOA5, the data suggest that different variants influence trait levels in different populations. Variants previously reported to alter gene expression or function frequently exhibited the strongest association at those signals. The multiple signals and population-specific characteristics of the loci described here may be shared by genetic loci for other complex traits.
PMCID: PMC3605054  PMID: 23555291
24.  Diabetes in rural towns: effectiveness of continuing education and feedback for healthcare providers in altering diabetes outcomes at a population level: protocol for a cluster randomised controlled trial 
Type 2 diabetes is one of the fastest growing chronic diseases internationally. The health complications associated with type 2 diabetes can be prevented, delayed, or improved via early diagnosis and effective management. This research aims to examine the impact of a primarily web-based educational intervention on the diabetes care provided by general practitioners (GPs) in rural areas, and subsequent patient outcomes. A population-level approach to outcome assessment is used, via whole-town de-identified pathology records.
The study uses a cluster randomised controlled trial with rural communities as the unit of analysis. Towns from four Australian states were selected and matched on factors including rurality, population size, proportion of the population who were Indigenous Australians, and socio-economic status. Eleven pairs of towns from two states were suitable for the trial, and one town from each pair was randomised to the experimental group. GPs in the towns allocated to the experimental group are offered an intervention package comprising education on best practice diabetes care via an on-line active learning module, a moderated discussion forum, access to targeted and specialist advice through an on-line request form, and town-based performance feedback on diabetes monitoring and outcomes. The package is offered via repeated direct mail.
The benefits of the outcomes of the trial are described along with the challenges and limitations associated with the methodology.
Trial registration
Australian New Zealand Clinical Trials Registry: ACTRN12611000553976
PMCID: PMC3600674  PMID: 23497486
Type 2 diabetes mellitus; Cluster randomised controlled trial; Internet; Medical education; General practitioner
25.  The functional connectivity of the human caudate: An application of meta-analytic connectivity modeling with behavioral filtering 
Neuroimage  2011;60(1):117-129.
Meta-analysis based techniques are emerging as powerful, robust tools for developing models of connectivity in functional neuroimaging. Here, we apply meta-analytic connectivity modeling to the human caudate to 1) develop a model of functional connectivity, 2) determine if meta-analytic methods are sufficiently sensitive to detect behavioral domain specificity within region-specific functional connectivity networks, and 3) compare meta-analytic driven segmentation to structural connectivity parcellation using diffusion tensor imaging. Results demonstrate strong coherence between meta-analytic and data-driven methods. Specifically, we found that behavioral filtering resulted in cognition and emotion related structures and networks primarily localized to the head of the caudate nucleus, while perceptual and action specific regions localized to the body of the caudate, consistent with early models of nonhuman primate histological studies and postmortem studies in humans. Diffusion tensor imaging (DTI) revealed support for meta-analytic connectivity modeling's (MACM) utility in identifying both direct and indirect connectivity. Our results provide further validation of meta-analytic connectivity modeling, while also highlighting an additional potential, namely the extraction of behavioral domain specific functional connectivity.
PMCID: PMC3288226  PMID: 22197743
meta-analytic connectivity modeling; functional connectivity; MACM; DTI; caudate

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