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1.  The Body-Mind Connection in Aging and Dementia 
doi:10.1111/jgs.12257
PMCID: PMC4157467  PMID: 23855848
2.  “Getting off the Bus Closer to Your Destination”: Patients’ Views about Pharmacogenetic Testing 
The Permanente Journal  2015;19(3):21-27.
The authors conducted focus groups with patients prescribed antidepressants (pilot session plus 2 focus groups, n = 27); patients prescribed carbamazepine (2 focus groups, n = 17); and healthy patients (2 focus groups, n = 17). Although participants understood the potential advantages of pharmacogenetic testing, many felt that the risks (discrimination, stigmatization, physician overreliance on genomic results, and denial of certain medications) may outweigh the benefits. These concerns were shared across groups but were more strongly expressed among participants with chronic mental health diagnoses.
Context:
Pharmacogenetic testing, a form of precision medicine, has the potential to optimize medication choice and dosing. Yet, relatively little is known about the views of patients—particularly those with chronic psychiatric conditions—with respect to such testing.
Objective:
To explore patients’ beliefs and attitudes regarding pharmacogenetic testing, with the goal of informing policy development and implementation.
Design:
Qualitative study design using semistructured focus groups with adults enrolled in Group Health Cooperative, a large health maintenance organization in the Pacific Northwest. We conducted focus groups with patients prescribed antidepressants (pilot session plus 2 focus groups, n = 27); patients prescribed carbamazepine (2 focus groups, n = 17); and healthy patients (2 focus groups, n = 17).
Results:
Although participants understood the potential advantages of pharmacogenetic testing, many felt that the risks (discrimination, stigmatization, physician overreliance on genomic results, and denial of certain medications) may outweigh the benefits. These concerns were shared across groups but were more strongly expressed among participants with chronic mental health diagnoses.
Conclusion:
Clinical implementation of pharmacogenetic testing must address patient concerns about privacy, discrimination, quality of care, and erosion of the physician-patient relationship.
doi:10.7812/TPP/15-046
PMCID: PMC4500477  PMID: 26057686
3.  Prospective participant selection and ranking to maximize actionable pharmacogenetic variants and discovery in the eMERGE Network 
Genome Medicine  2015;7(1):67.
Background
In an effort to return actionable results from variant data to electronic health records (EHRs), participants in the Electronic Medical Records and Genomics (eMERGE) Network are being sequenced with the targeted Pharmacogenomics Research Network sequence platform (PGRNseq). This cost-effective, highly-scalable, and highly-accurate platform was created to explore rare variation in 84 key pharmacogenetic genes with strong drug phenotype associations.
Methods
To return Clinical Laboratory Improvement Amendments (CLIA) results to our participants at the Group Health Cooperative, we sequenced the DNA of 900 participants (61 % female) with non-CLIA biobanked samples. We then selected 450 of those to be re-consented, to redraw blood, and ultimately to validate CLIA variants in anticipation of returning the results to the participant and EHR. These 450 were selected using an algorithm we designed to harness data from self-reported race, diagnosis and procedure codes, medical notes, laboratory results, and variant-level bioinformatics to ensure selection of an informative sample. We annotated the multi-sample variant call format by a combination of SeattleSeq and SnpEff tools, with additional custom variables including evidence from ClinVar, OMIM, HGMD, and prior clinical associations.
Results
We focused our analyses on 27 actionable genes, largely driven by the Clinical Pharmacogenetics Implementation Consortium. We derived a ranking system based on the total number of coding variants per participant (75.2±14.7), and the number of coding variants with high or moderate impact (11.5±3.9). Notably, we identified 11 stop-gained (1 %) and 519 missense (20 %) variants out of a total of 1785 in these 27 genes. Finally, we prioritized variants to be returned to the EHR with prior clinical evidence of pathogenicity or annotated as stop-gain for the following genes: CACNA1S and RYR1 (malignant hyperthermia); SCN5A, KCNH2, and RYR2 (arrhythmia); and LDLR (high cholesterol).
Conclusions
The incorporation of genetics into the EHR for clinical decision support is a complex undertaking for many reasons including lack of prior consent for return of results, lack of biospecimens collected in a CLIA environment, and EHR integration. Our study design accounts for these hurdles and is an example of a pilot system that can be utilized before expanding to an entire health system.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-015-0181-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13073-015-0181-z
PMCID: PMC4517371  PMID: 26221186
4.  TOMM40 intron 6 poly-T length, age-at-onset and neuropathology of AD in individuals with APOE ε3/ε3 
Background
This study investigates the association between TOMM40 poly-T length, age-at-onset, and neuropathology in Alzheimer’s disease (AD) individuals with the APOE ε3/ε3 allele.
Methods
Thirty-two PSEN1 mutation carriers with AD, 27 PSEN2 mutation carriers with AD, 59 participants with late-onset AD (LOAD), and 168 participants with autopsies from a community-based cohort were genotyped for TOMM40 intron 6 poly-T (rs10524523) length using short tandem repeat assays.
Results
Among AD patients with PSEN2 mutations, the presence of a long poly-T was associated with an earlier age-at-onset, whereas there were no such associations for patients with PSEN1 mutations or LOAD. In community-based participants, the presence of a long poly-T was associated with increased neuritic tangles and a higher likelihood of pathologically diagnosed AD.
Conclusions
TOMM40 intron 6 poly-T length may explain some of the variation in age-at-onset in PSEN2 familial AD and may be associated with AD neuropathology in persons with APOE ε3/ε3.
doi:10.1016/j.jalz.2012.06.009
PMCID: PMC3606272  PMID: 23183136
Alzheimer’s disease; age-at-onset; genetic; APOE; TOMM40; PSEN1 mutation; PSEN2 mutation; neuropathology
5.  Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study 
PLoS Medicine  2015;12(6):e1001841.
Background
Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR).
Methods and Findings
We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP–AD associations from the International Genomics of Alzheimer’s Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62–0.91]; p = 3.4 × 10−3). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10−8). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51–0.89]; p = 6.5 × 10−3), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses.
Conclusions
Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure—or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications—may reduce AD risk.
Robert A. Scott and colleagues use genetic instruments to identify causal associations between known risk factors and Alzheimer's disease.
Editors' Summary
Background
Worldwide, about 44 million people have dementia, a group of brain degeneration disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. Dementia mainly affects older people, and because people are living longer, experts estimate that more than 135 million people will have dementia by 2050. The most common form of dementia, which accounts for 60%–70% of cases, is Alzheimer disease (AD). The earliest sign of AD is often increasing forgetfulness. As the disease progresses, affected individuals gradually lose the ability to look after themselves, they may become anxious or aggressive, and they may have difficulty recognizing friends and relatives. People with late stage disease may lose control of their bladder and of other physical functions. At present, there is no cure for AD, although some of its symptoms can be managed with drugs. Most people with AD are initially cared for at home by relatives and other caregivers, but many affected individuals end their days in a care home or specialist nursing home.
Why Was This Study Done?
Researchers are interested in identifying risk factors for AD, particularly modifiable risk factors, because if such risk factors exist, it might be possible to limit the predicted increase in future AD cases. Epidemiological studies (investigations that examine patterns of disease in populations) have identified several potential risk factors for AD, including hypertension (high blood pressure), obesity, smoking, and dyslipidemia (changes in how the body handles fats). However, epidemiological studies cannot prove that a specific risk factor causes AD. For example, people with hypertension might share another characteristic that causes both hypertension and AD (confounding) or AD might cause hypertension (reverse causation). Information on causality is needed to decide which risk factors to target to help prevent AD. Here, the researchers use “Mendelian randomization” to examine whether differences in several epidemiologically identified risk factors for AD have a causal impact on AD risk. In Mendelian randomization, causal associations are inferred from the effects of genetic variants (which predict levels of modifiable risk factors) on the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if hypertension actually causes AD, genetic variants that affect hypertension should be associated with an altered risk of AD.
What Did the Researchers Do and Find?
The researchers identified causal associations between potentially modifiable risk factors and AD risk by analyzing the occurrence of single nucleotide polymorphisms (SNPs, a type of gene variant) known to predict levels of each risk factor, in genetic data from 17,008 individuals with AD and 37,154 cognitively normal elderly controls collected by the International Genomics of Alzheimer’s Project. They report that genetically predicted higher systolic blood pressure (SBP; the pressure exerted on the inside of large blood vessels when the heart is pumping out blood) was associated with lower AD risk (and with a higher probability of taking antihypertensive medication). Predicted smoking quantity was also associated with lower AD risk, but there was no evidence of causal associations between any of the other risk factors investigated and AD risk.
What Do These Findings Mean?
In contrast to some epidemiological studies, these findings suggest that hypertension is associated with lower AD risk. However, because genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication, it could be that exposure to such drugs, rather than having hypertension, reduces AD risk. Like all Mendelian randomization studies, the reliability of these findings depends on the validity of several assumptions made by the researchers and on the ability of the SNPs used in the analyses to explain variations in exposure to the various risk factors. Moreover, because all the participants in the International Genomics of Alzheimer’s Project are of European ancestry, these findings may not be valid for other ethnic groups. Given that hypertension is a risk factor for cardiovascular disease, the researchers do not advocate raising blood pressure as a measure to prevent AD (neither do they advocate that people smoke more cigarettes to lower AD risk). Rather, given the strong association between higher SBP gene scores and the probability of exposure to antihypertensive treatment, they suggest that the possibility that antihypertensive drugs might reduce AD risk independently of their effects on blood pressure should be investigated as a priority.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001841.
The UK National Health Service Choices website provides information (including personal stories) about Alzheimer disease
The UK not-for-profit organization Alzheimer’s Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer disease
The US not-for-profit organization Alzheimer’s Association also provides information for patients and carers about dementia and personal stories about dementia
Alzheimer’s Disease International is the federation of Alzheimer disease associations around the world; it provides links to individual Alzheimer associations, information about dementia, and links to world Alzheimer reports
MedlinePlus provides links to additional resources about Alzheimer disease (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
A PLOS Medicine Research Article by Proitsi et al. describes a Mendelian randomization study that looked for a causal association between dyslipidemia and Alzheimer disease
doi:10.1371/journal.pmed.1001841
PMCID: PMC4469461  PMID: 26079503
6.  ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology 
Acta neuropathologica  2014;127(6):825-843.
Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer’s Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer’s Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer’s Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1–3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4–5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10−9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.
doi:10.1007/s00401-014-1282-2
PMCID: PMC4113197  PMID: 24770881
Oldest old; Neuropathology; KATP; CTAGE5; ADGC; Potassium channel
7.  Neuropathologic Changes Associated With Atrial Fibrillation in a Population-Based Autopsy Cohort 
Background.
Atrial fibrillation (AF) is associated with higher risk of dementia and Alzheimer’s disease. To better understand the mechanism, we examined neuropathologic changes seen with AF.
Methods.
We analyzed data from an autopsy series arising from a population-based, prospective cohort study set within Group Health, an integrated health care delivery system. Participants were people aged 65 and older, community-dwelling, and nondemented at study enrollment, who died during follow-up and underwent autopsy. AF was defined from medical records. Permanent AF was defined as having two or more electrocardiograms showing AF between 6 and 36 months apart with no evidence of sinus rhythm in between. The primary study outcomes were gross infarcts, neuritic plaques, and neurofibrillary tangles, ascertained using consensus guidelines. Adjusted relative risks and 95% CIs were calculated using modified Poisson regression, weighted to account for selection into the autopsy cohort.
Results.
Three hundred and twenty-eight participants underwent autopsy; 134 (41%) had AF. People with AF were more likely to have gross infarcts than those without AF (45% vs 31%; relative risk 1.82, 95% CI 1.23–2.71); in 30%, these infarcts were not clinically recognized before death. Alzheimer’s disease neuropathologic changes were not associated with ever having AF but were more common in people with permanent AF. Adjusted relative risks for frequent neuritic plaques and neurofibrillary tangles were 1.47 (0.96–2.28) and 1.40 (0.79–2.49), respectively, for people with permanent AF versus no AF.
Conclusions.
AF is associated with gross infarcts. Permanent AF may contribute to Alzheimer’s disease neuropathologic changes, but more study is needed.
doi:10.1093/gerona/glt141
PMCID: PMC3991149  PMID: 24077599
Alzheimer's; Cardiac arrhythmias; Stroke; Brain aging; Cardiovascular.
8.  Cumulative Use of Strong Anticholinergic Medications and Incident Dementia 
JAMA internal medicine  2015;175(3):401-407.
IMPORTANCE
Many medications have anticholinergic effects. The general view is that anticholinergic-induced cognitive impairment is reversible upon medication discontinuation. However, a few studies suggest that anticholinergic medications may be associated with increased dementia risk.
OBJECTIVE
To examine whether cumulative anticholinergic medication use is associated with a higher risk of incident dementia.
DESIGN
Prospective population-based cohort study using data from the Adult Changes in Thought Study.
SETTING
Group Health, an integrated health-care delivery system, Seattle, Washington
PARTICIPANTS
3,434 participants aged 65 and older with no dementia at study entry. Initial recruitment occurred between 1994 and 1996 or 2000 and 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants received follow-up every two years.
EXPOSURE
Using computerized pharmacy dispensing data, cumulative anticholinergic exposure was defined as the total standardized daily doses (TSDD) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was time-varying.
MAIN OUTCOMES AND MEASURES
Incident dementia and Alzheimer’s disease using standard diagnostic criteria. Statistical analyses used Cox proportional hazards models, adjusted for demographic, health behaviors and health status including comorbidities.
RESULTS
The most common anticholinergic drug classes used were tricyclic antidepressants, first generation antihistamines and bladder antimuscarinics. Over a mean follow-up of 7.3 years, 797 participants (23%) developed dementia (637 developed Alzheimer’s). A 10-year cumulative dose-response relationship was observed for both dementia and Alzheimer’s disease (test for trend, p<0.001). For dementia, adjusted hazard ratios (HRs) and 95% confidence interval (CI) for cumulative anticholinergic use was 0.92 (95% CI, 0.74-1.16) for 1-90 TSDD; 1.19 (CI, 0.94-1.51) for 91-365 TSDD; 1.23 (CI, 0.94-1.62) for 366-1095 TSDD; and 1.54 (95% CI, 1.21-1.96) for >1095 TSDD, compared to non-use. A similar pattern of results was noted for Alzheimer’s disease. Results were robust to secondary, sensitivity and post-hoc analyses.
CONCLUSION AND RELEVANCE
Higher cumulative anticholinergic medication use is associated with an increased risk for dementia. Efforts to increase awareness among health professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.
doi:10.1001/jamainternmed.2014.7663
PMCID: PMC4358759  PMID: 25621434
dementia; Alzheimer disease; pharmacoepidemiology; cohort study; anticholinergic medication use; aged
9.  Interpreting treatment effects from clinical trials in the context of real-world risk information: the example of end-stage renal disease prevention in older adults 
JAMA internal medicine  2014;174(3):391-397.
Importance
Older adults are often excluded from clinical trials. The benefit of preventive interventions tested in younger trial populations may be reduced when applied to older adults in the clinical setting if they are less likely to survive long enough to experience those outcomes targeted by the intervention.
Objective
To extrapolate a treatment effect similar to those reported in major randomized controlled clinical trials of ACE inhibitors and ARBs for end-stage renal disease (ESRD) prevention to a real-world population of older patients with chronic kidney disease (CKD).
Design and Setting
Simulation study in a retrospective cohort; Department of Veterans Affairs (VA).
Participants
371,470 VA patients aged ≥ 70 years with chronic kidney disease (CKD). Main outcomes and measures: Among members of this cohort, we evaluated the expected effect of a 30% reduction in relative risk on the number needed to treat (NNT) to prevent one case of ESRD over a three year period. These parameters were selected to mimic the treatment effect achieved in major trials of ACE inhibitors and ARBs for ESRD prevention which have reported relative risk reductions of between 23% and 56% over observation periods of 2.6 to 3.4 years yielding NNTs to prevent one case of ESRD of between 9 and 25.
Results
The NNT to prevent one case of ESRD among members of this cohort ranged from 16 in patients with the highest baseline risk (estimated glomerular filtration rate (eGFR) 15–29 ml/min/1.73 m2 and ≥ 2+ proteinuria) to 2,500 for those with the lowest baseline risk (eGFR 45–59 ml/min/1.73 m2 and negative/trace proteinuria and eGFR ≥ 60 ml/min/1.73 m2 and 1+proteinuria). Most patients belonged to groups with an NNT >100. This was true even when the exposure time was extended over 10 years and in all sensitivity analyses.
Conclusion and relevance
Differences in baseline risk and life expectancy between trial subjects and real-world populations of older adults with CKD may reduce the marginal benefit to individual patients of interventions to prevent ESRD.
doi:10.1001/jamainternmed.2013.13328
PMCID: PMC4119007  PMID: 24424348
elderly; chronic kidney disease; end-stage renal disease; prevention; ACE inhibitor; ARB; number needed to treat
10.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
Importance
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
Objectives
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Results
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
doi:10.1001/jamaneurol.2014.1491
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
11.  Prospects for delaying the rising tide of worldwide, late-life dementias 
International psychogeriatrics / IPA  2010;22(8):1196-1202.
Worldwide, lifespan is lengthening. Concomitantly, late-life dementias are increasingly common, challenging both personal and public health internationally. After age 65, rates of dementia tend to double every five years in developed countries and every seven in developing ones. The late-life dementias, particularly Alzheimer’s disease, have profound effects on aging individuals and their caregivers. Multidisciplinary research has explored the potential for various approaches to prevent or delay the onset of late-life dementias. Outlining that research, including our team’s Adult Changes in Thought and Kame studies, this review concludes that delaying these dementias’ onset appears feasible, although absolute prevention may not be. Today the most promising methods appear to include controlling vascular risk factors like hypertension and engaging in physical exercise—and possibly mental exercise—on and off the job. If people can delay the onset of dementias, they can lead more fulfilling lives for longer—spending less time suffering from dementia and letting their families spend less time coping with the disease. It is possible that trends toward more knowledge-based societies, where cognitive health is so vital, may increasingly exert evolutionary pressure favoring larger and healthier brains—and a “compression of cognitive morbidity”—well into old age. Public health’s great triumph, increased lifespan, should give more of the world’s people the reward of many years of dementia-free life—rather than the personal difficulties and public health burdens of many years of functional impairment, dependency, and suffering with dementia some interventions may delay the onset of Alzheimer’s disease and other dementias.
doi:10.1017/S1041610210001080
PMCID: PMC3164829  PMID: 20594386
Alzheimer’s disease; prevention; lifestyle risk factors; aging; exercise; demographics; evolution
12.  A Genome- and Phenome-Wide Association Study to Identify Genetic Variants Influencing Platelet Count and Volume and their Pleiotropic Effects 
Human genetics  2013;133(1):10.1007/s00439-013-1355-7.
Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized association of variants influencing MPV and PLT using functional, pathway and disease enrichment analysis assess pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic (eMERGE) network had data for PLT and 6,291 participants had data for MPV. We identified 5 chromosomal regions associated with PLT and 8 associated with MPV at genome-wide significance (P<5E-8). In addition, we replicated 20 SNPs (out of 56 SNPs (α: 0.05/56=9E-4)) influencing PLT and 22 SNPs (out of 29 SNPs (α: 0.05/29=2E-3)) influencing MPV in a meta-analysis of GWAS of PLT and MPV. While our GWAS did not reveal any novel associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1368 diagnoses (0.05/1368=3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.
doi:10.1007/s00439-013-1355-7
PMCID: PMC3880605  PMID: 24026423
14.  Genetic Variants Associated with Serum Thyroid Stimulating Hormone (TSH) Levels in European Americans and African Americans from the eMERGE Network 
PLoS ONE  2014;9(12):e111301.
Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10−17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10−6, β = −0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = −0.09), VEGFA (rs11755845 p = 0.01, β = −0.13), and NFIA (rs334699 p = 1.50×10−3, β = −0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.
doi:10.1371/journal.pone.0111301
PMCID: PMC4249871  PMID: 25436638
15.  A Template for Authoring and Adapting Genomic Medicine Content in the eMERGE Infobutton Project 
The Electronic Medical Records and Genomics (eMERGE) Network is a national consortium that is developing methods and best practices for using the electronic health record (EHR) for genomic medicine and research. We conducted a multi-site survey of information resources to support integration of pharmacogenomics into clinical care. This work aimed to: (a) characterize the diversity of information resource implementation strategies among eMERGE institutions; (b) develop a master template containing content topics of important for genomic medicine (as identified by the DISCERN-Genetics tool); and (c) assess the coverage of content topics among information resources developed by eMERGE institutions. Given that a standard implementation does not exist and sites relied on a diversity of information resources, we identified a need for a national effort to efficiently produce sharable genomic medicine resources capable of being accessed from the EHR. We discuss future areas of work to prepare institutions to use infobuttons for distributing standardized genomic content.
PMCID: PMC4419923  PMID: 25954402
16.  Longitudinal Associations between Self-Rated Health and Performance-Based Physical Function in a Population-Based Cohort of Older Adults 
PLoS ONE  2014;9(11):e111761.
Background
Although self-rated health (SRH) and performance-based physical function (PPF) are both strong predictors of mortality, little research has investigated the relationships between them. The objective of this study was to evaluate longitudinal, bi-directional associations between SRH and PPF.
Methods
We evaluated longitudinal associations between SRH and PPF in 3,610 adults aged 65–89 followed for an average of 4.8 (standard deviation [SD]: 4.4) years between 1994 and July 2011 in the Adult Changes in Thought study, a population-based cohort in the Seattle area. SRH was assessed with a single-item question in the ACT study. Participants were asked at each evaluation to rate their health as “excellent”, “very good”, “good”, “fair”, or “poor” in response to the question “In general, how would you rate your health at this time”. PPF scores (ranging from 0–16, with higher indicating better performance) included walking speed, chair rises, grip strength, and balance.
Results
At the baseline visit, participants averaged 74.5 (SD: 5.8) years of age and 2,115 (58.6%) were female. In multivariable linear mixed models, PPF declined with age, with more rapid decreases associated with very good, good, and fair (vs. excellent) baseline SRH. Adjusted annual change in PPF was −0.17 points (95% confidence interval [CI]: −0.19, −0.15) for individuals with excellent baseline SRH and −0.21 points (95% CI: −0.22, −0.19) for participants with fair SRH. In multivariable generalized linear mixed models, lower baseline PPF quartiles were associated with lower odds of excellent/very good/good SRH at age 75, however, differences between baseline PPF quartiles diminished with age.
Conclusions
These results suggest that less than excellent SRH predicts decline in physical functioning, however, poor physical functioning may not predict change in SRH in a reciprocal fashion. SRH provides a simple assessment tool for identifying individuals at increased risk for decline in physical function.
doi:10.1371/journal.pone.0111761
PMCID: PMC4218810  PMID: 25365288
17.  Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias 
PLoS Genetics  2014;10(9):e1004606.
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Author Summary
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.
doi:10.1371/journal.pgen.1004606
PMCID: PMC4154667  PMID: 25188341
18.  Frailty and Incident Dementia 
Background.
We sought to examine whether frailty is associated with dementia, Alzheimer’s disease (AD), and non-AD dementia risk.
Methods.
This is a prospective population-based cohort derived from an integrated health maintenance organization. The sample consisted of 2,619 participants aged 65 and older without dementia at baseline followed from 1994 to 2010. Frailty was defined as having at least 3 of the following criteria: weakness (grip strength), slowness (walking speed), weight loss, low physical activity, and self-reported exhaustion. Follow-up occurred every 2 years to identify incident dementia, possible or probable AD, and non-AD dementia using standard research criteria. Covariates came from self-report and study measures. We used adjusted Cox proportional hazards models to examine the association between frailty and each outcome.
Results.
Over a mean follow-up of 6.5 years, 521 participants developed dementia (of which 448 developed AD). In the model adjusted for age, sex, education, and race, the hazard ratio for frailty was 1.78 (95% confidence interval [CI] 1.32–2.40). In the fully adjusted models, the hazard ratio for frailty was 1.20 for all-cause dementia (95% CI 0.85–1.69), 1.08 for AD (95% CI 0.74–1.57), and 2.57 for non-AD dementia (95% CI 1.08–6.11). For all-cause dementia, we found an interaction between baseline cognitive score and frailty (p = .02); hazard ratio for frailty was 1.78 for those with higher global cognition (95% CI 1.14–2.78) and 0.79 for those with lower global cognition (95% CI 0.50–1.26).
Conclusion.
Frailty was associated with dementia when adjusting only for demographic variables but not in the fully adjusted model. Frailty was associated with higher risk of developing non-AD dementia but not AD. Although frailty was not associated with all-cause dementia in the entire sample, an association did exist in participants with higher cognitive scores. Mechanisms underlying these associations remain to be elucidated.
doi:10.1093/gerona/glt013
PMCID: PMC3738027  PMID: 23419778
Dementia; Alzheimer’s disease; Frailty; Epidemiology
19.  New Insights into the Dementia Epidemic 
The New England journal of medicine  2013;369(24):2275-2277.
doi:10.1056/NEJMp1311405
PMCID: PMC4130738  PMID: 24283198
20.  Phenome-wide association studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index 
Frontiers in Genetics  2014;5:250.
Phenome-wide association studies (PheWAS) have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR)-based PheWAS to explore pleiotropy of genetic variants in the fat mass and obesity associated gene (FTO), some of which have been previously associated with obesity and type 2 diabetes (T2D). We used a population of 10,487 individuals of European ancestry with genome-wide genotyping from the Electronic Medical Records and Genomics (eMERGE) Network and another population of 13,711 individuals of European ancestry from the BioVU DNA biobank at Vanderbilt genotyped using Illumina HumanExome BeadChip. A meta-analysis of the two study populations replicated the well-described associations between FTO variants and obesity (odds ratio [OR] = 1.25, 95% Confidence Interval = 1.11–1.24, p = 2.10 × 10−9) and FTO variants and T2D (OR = 1.14, 95% CI = 1.08–1.21, p = 2.34 × 10−6). The meta-analysis also demonstrated that FTO variant rs8050136 was significantly associated with sleep apnea (OR = 1.14, 95% CI = 1.07–1.22, p = 3.33 × 10−5); however, the association was attenuated after adjustment for body mass index (BMI). Novel phenotype associations with obesity-associated FTO variants included fibrocystic breast disease (rs9941349, OR = 0.81, 95% CI = 0.74–0.91, p = 5.41 × 10−5) and trends toward associations with non-alcoholic liver disease and gram-positive bacterial infections. FTO variants not associated with obesity demonstrated other potential disease associations including non-inflammatory disorders of the cervix and chronic periodontitis. These results suggest that genetic variants in FTO may have pleiotropic associations, some of which are not mediated by obesity.
doi:10.3389/fgene.2014.00250
PMCID: PMC4134007  PMID: 25177340
PheWAS; genetic association; pleiotropy; Exome chip; FTO; BMI
21.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Background
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
doi:10.1371/journal.pone.0094661
PMCID: PMC4055488  PMID: 24922517
22.  To Prevent, React, and Rebuild: Health Research and the Prevention of Genocide 
Health Services Research  2004;39(6 Pt 2):2027-2051.
Objective
To develop an approach to the primary prevention of genocide, based on established public health-based violence prevention methods derived from a variety of high-risk settings.
Data Sources
(1) Peer-reviewed literature in the fields of public health, violence/injury prevention, medicine, economics, sociology, psychology, history, and genocide studies, (2) demographic and health data bases made available by governments and international organizations, (3) reports on recent episodes of genocide published by international and nongovernmental organizations, (4) newspaper and journalistic accounts of recent and past genocides, (5) archival testimonies of genocide victims and perpetrators, and (6) court transcripts of international genocide prosecutions.
Study Design
The research was conducted as a medical-historical policy analysis synthesizing data within the following framework: (1) Assessment of current violence and injury prevention models for suitability in the prevention of extreme, population-wide violence, (2) analysis of morbidity and mortality data to quantify the impact of genocide on the health of populations, (3) making an inventory of the known societal risk factors for genocidal violence, (4) identification of the theorized, modifiable attitudinal risk factors for genocidal behavior within a population health model, and (5) assessment of existing projects targeting primary violence and injury prevention in high risk jurisdictions, for future adaptation within a structured, public health approach.
Principal Findings
Mortality rates due to genocidal violence are far in excess of other public health emergencies including malaria and HIV/AIDS. The immediate and long-range health consequences of genocide include the sequelae of infectious diseases, organ system failure, and psychiatric disorders, conferring an increased burden of disease on affected populations for multiple subsequent generations. The impact of genocide on local health economies is catastrophic, and the opportunity costs of diverting scarce global health dollars toward ameliorating genocide related outcomes are substantial. Structural risk factors for genocide within societies include: totalitarian government, exclusionary ideologies, armed conflict, economic hardship, and inaction of bystander nations. Proposed psychological risk factors for genocidal behavior include: moral exclusion, authority orientation, action in self-interest, desensitization, and compartmentalized thinking. Violence and injury prevention models, incorporating what is currently known about the societal and behavioral risk factors for genocide in high-risk populations, may be modified to address the primary prevention of catastrophic violence on a population-wide scale. A number of existent global peace building initiatives may serve as models for the design of future prevention initiatives in high-risk, pre-genocide jurisdictions.
Conclusions
Our analysis suggests that genocide is one of the most pressing threats to the health of populations in the twenty-first century. Recent advances in the public health discipline of violence prevention provide a blueprint for approaches to primary genocide prevention based on epidemiological methods.
doi:10.1111/j.1475-6773.2004.00331.x
PMCID: PMC1361111  PMID: 15544643
Violence/prevention; human rights; public health; public policy; health promotion/organization
23.  Sustaining Research Networks: the Twenty-Year Experience of the HMO Research Network 
eGEMs  2014;2(2):1067.
Purpose:
As multi-institutional research networks assume a central role in clinical research, they must address the challenge of sustainability. Despite its importance, the concept of network sustainability has received little attention in the literature, and the sustainability strategies of durable scientific networks have not been described.
Innovation:
The Health Maintenance Organization Research Network (HMORN) is a consortium of 18 research departments in integrated health care delivery systems with over 15 million members in the United States and Israel. The HMORN has coordinated federally funded scientific networks and studies since 1994. This case study describes the HMORN approach to sustainability, proposes an operational definition of network sustainability, and identifies 10 essential elements that can enhance sustainability.
Credibility:
The sustainability framework proposed here is drawn from prior publications on organizational issues by HMORN investigators and from the experience of recent HMORN leaders and senior staff.
Conclusion and Discussion:
Network sustainability can be defined as (1) the development and enhancement of shared research assets to facilitate a sequence of research studies in a specific content area or multiple areas, and (2) a community of researchers and other stakeholders who reuse and develop those assets. Essential elements needed to develop the shared assets of a network include: network governance; trustworthy data and processes for sharing data; shared knowledge about research tools; administrative efficiency; physical infrastructure; and infrastructure funding. The community of researchers within a network is enhanced by: a clearly defined mission, vision and values; protection of human subjects; a culture of collaboration; and strong relationships with host organizations. While the importance of these elements varies based on the membership and goals of a network, this framework for sustainability can enhance strategic planning within the network and can guide relationships with external stakeholders.
PMCID: PMC4371441  PMID: 25848605
Clinical research; comparative effectiveness research; health maintenance organization; organizational change; program sustainability; data systems
24.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
doi:10.1038/ng.2802
PMCID: PMC3896259  PMID: 24162737
25.  Genetic variation associated with circulating monocyte count in the eMERGE Network 
Human Molecular Genetics  2013;22(10):2119-2127.
With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(−16), β = −0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(−7), β = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(−16), β = −0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(−7), β = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(−17), β = −0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
doi:10.1093/hmg/ddt010
PMCID: PMC3633369  PMID: 23314186

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