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1.  Statistical Approaches for Analyzing Immunologic Data of Repeated Observations: A Practical Guide 
Journal of immunological methods  2013;0:10.1016/j.jim.2013.09.004.
Translational research not only encompasses transitioning from animal to human models but also must address the greater heterogeneity of humans when designing and analyzing experiments. Appropriate study designs can address heterogeneity through a priori data collection, and taking repeated measures can improve the power and efficiency of a study to detect clinically meaningful differences. Although common in other areas of biomedical research, modern statistical methods using repeated measurements on the same subject and accounting for their potential correlations are not widely utilized in immunologic studies. To highlight these analytic issues, we present a practical guide to understanding and applying analytic methods from commonly used T-tests without adjusting for multiple comparisons to mixed models with subject-specific adjustments for correlations using our data on Toll-like receptor-induced cytokine production in monocytes from young and older adults.
PMCID: PMC3840087  PMID: 24055129
Heterogeneity; mixed model; repeated measurement; multiple comparisons
2.  Design and rationale of the comprehensive evaluation of risk factors in older patients with AMI (SILVER-AMI) study 
While older adults (age 75 and over) represent a large and growing proportion of patients with acute myocardial infarction (AMI), they have traditionally been under-represented in cardiovascular studies. Although chronological age confers an increased risk for adverse outcomes, our current understanding of the heterogeneity of this risk is limited. The Comprehensive Evaluation of Risk Factors in Older Patients with AMI (SILVER-AMI) study was designed to address this gap in knowledge by evaluating risk factors (including geriatric impairments, such as muscle weakness and cognitive impairments) for hospital readmission, mortality, and health status decline among older adults hospitalized for AMI.
SILVER-AMI is a prospective cohort study that is enrolling 3000 older adults hospitalized for AMI from a recruitment network of approximately 70 community and academic hospitals across the United States. Participants undergo a comprehensive in-hospital assessment that includes clinical characteristics, geriatric impairments, and health status measures. Detailed medical record abstraction complements the assessment with diagnostic study results, in-hospital procedures, and medications. Participants are subsequently followed for six months to determine hospital readmission, mortality, and health status decline. Multivariable regression will be used to develop risk models for these three outcomes.
SILVER-AMI will fill critical gaps in our understanding of AMI in older patients. By incorporating geriatric impairments into our understanding of post-AMI outcomes, we aim to create a more personalized assessment of risk and identify potential targets for interventions.
Trial registration
Trial registration number: NCT01755052.
PMCID: PMC4239317  PMID: 25370536
Acute myocardial infarction; Aging; Hospital readmission; Health status
JAMA internal medicine  2013;173(19):10.1001/jamainternmed.2013.9063.
Although a serious fall injury is often a devastating event, little is known about the course of disability (i.e. functional trajectories) prior to a serious fall injury or the relationship between these trajectories and those that follow the fall.
To identify distinct sets of functional trajectories in the year immediately before and after a serious fall injury, to evaluate the relationship between the pre-fall and post-fall trajectories, and to determine whether these results differed based on the type of injury.
Design, Setting, and Participants
Prospective cohort study conducted in greater New Haven, Connecticut, from March 1998 to June 2012 of 754 community-living persons aged 70 or older who were initially nondisabled in their basic activities of daily living. Of the 130 participants who subsequently sustained a serious fall injury, 62 had a hip fracture and 68 had another fall-related injury leading to hospitalization.
Main Outcome Measures
Functional trajectories, based on 13 basic, instrumental and mobility activities that were assessed during monthly interviews, were identified in the year before and after the serious fall injury, respectively.
Before the fall, five distinct trajectories were identified: no disability (n=16, 12.3%), mild disability (n=34, 26.2%), moderate disability (n=34, 26.2%), progressive disability (n=23, 17.7%), and severe disability (n=23, 17.7%). After the fall, four distinct trajectories were identified: rapid recovery (n=12, 9.2%), gradual recovery (n=35, 26.9%), little recovery (n=26, 20.0%), and no recovery (n=57, 43.8%). For both hip fractures and other serious fall injuries, the probabilities of the post-fall trajectories were greatly influenced by the pre-fall trajectories, such that rapid recovery was observed only among persons who had no disability or mild disability, and a substantive recovery, defined as rapid or gradual, was highly unlikely among those who had progressive or severe disability. The post-fall trajectories were consistently worse for hip fractures than for the other serious injuries.
Conclusions and Relevance
The functional trajectories before and after a serious fall injury are quite varied, but highly interconnected, suggesting that the likelihood of recovery is greatly constrained by the pre-fall trajectory.
PMCID: PMC3812391  PMID: 23958741
4.  Outcomes Among Older Adult Liver Transplantation Recipients in the Model of End Stage Liver Disease (MELD) Era 
Since 2002, the Model of End Stage Liver Disease (MELD) score has been the basis of the liver transplant (LT) allocation system. Among older adult LT recipients, short-term outcomes in the MELD era were comparable to the pre-MELD era, but long-term outcomes remain unclear.
This is a retrospective cohort study using the UNOS data on patients age ≥50 years who underwent primary LT from February 27, 2002 until October 31, 2011.
A total of 35,686 recipients met inclusion criteria. The cohort was divided into 5-year interval age groups. Five-year over-all survival rates for ages 50–54, 55–59, 60–64, 65–69, and 70+ were 72.2%, 71.6%, 69.5%, 65.0%, and 57.5%, respectively. Five-year graft survival rates after adjusting for death as competing risk for ages 50–54, 55–59,60–64, 65–69 and 70+ were 85.8%, 87.3%, 89.6%, 89.1% and 88.9%, respectively. By Cox proportional hazard modeling, age ≥60, increasing MELD, donor age ≥60, hepatitis C, hepatocellular carcinoma (HCC), dialysis and impaired pre-transplant functional status (FS) were associated with increased 5-year mortality. Using Fine and Gray sub-proportional hazard modeling adjusted for death as competing risk, 5-year graft failure was associated with donor age ≥60, increasing MELD, hepatitis C, HCC, and impaired pre-transplant FS.
Among older LT recipients in the MELD era, long-term graft survival after adjusting for death as competing risk was improved with increasing age, while over-all survival was worse. Donor age, hepatitis C, and pre-transplant FS represent potentially modifiable risk factors that could influence long-term graft and patient survival.
PMCID: PMC4201657  PMID: 25256592
Age Groups; Liver Transplantation; Patient Outcome Assessment
5.  Association Between Treatment or Usual Care Region and Hospitalization for Fall-Related Traumatic Brain Injury in the Connecticut Collaboration for Fall Prevention 
Most traumatic brain injuries among older persons in the U.S. are attributed to falls. Efforts to prevent falls may also plausibly reduce the incidence of TBIs and resultant costs.
To evaluate the association between the treatment or usual care region of the Connecticut Collaboration for Fall Prevention (CCFP), a clinical intervention for prevention of falls, and the rate of hospitalization for fall-related traumatic brain injury (FR-TBI) among persons ≥ 70 years. The Medicare charges of FR-TBI hospitalizations are also described.
Using a quasi-experimental design, rates of hospitalization for FR-TBI were recorded over an eight year period (2000–2007) in two distinct geographic regions (treatment and usual care) chosen for their similarity in characteristics associated with occurrence of falls.
Over 200,000 persons, 70 years and older, residing in two geographical regions in Connecticut.
Clinicians in the treatment region translated research protocols from Yale FICSIT, a successful fall prevention randomized clinical trial, into discipline- and site-specific fall prevention procedures for integration into their clinical practices.
The rate of hospitalization for fall-related traumatic brain injury among persons 70 years and older
Relative to the usual care region, CCFP’s treatment region exhibited lower rates of hospitalization for FR-TBI; RR= 0.84 with 95% credible interval (0.72 – 0.99).
The significantly lower rate of hospitalization for FR-TBI in CCFP’s treatment region suggests that the engagement of practicing clinicians in the implementation of evidence-based fall-prevention practices may reduce hospitalizations for FR-TBI.
PMCID: PMC3801219  PMID: 24083593
Connecticut Collaboration for Fall Prevention; fall-related traumatic brain injury; hospitalization; Bayesian; spatial model
6.  An examination of effect estimation in factorial and standardly-tailored designs 
Many clinical trials are designed to test an intervention arm against a control arm wherein all subjects are equally eligible for all interventional components. Factorial designs have extended this to test multiple intervention components and their interactions. A newer design referred to as a ‘standardly-tailored’ design, is a multicomponent interventional trial that applies individual interventional components to modify risk factors identified a priori and tests whether health outcomes differ between treatment arms. Standardly-tailored designs do not require that all subjects be eligible for every interventional component. Although standardly-tailored designs yield an estimate for the net effect of the multicomponent intervention, it has not yet been shown if they permit separate, unbiased estimation of individual component effects. The ability to estimate the most potent interventional components has direct bearing on conducting second stage translational research.
We present statistical issues related to the estimation of individual component effects in trials of geriatric conditions using factorial and standardly-tailored designs. The medical community is interested in second stage translational research involving the transfer of results from a randomized clinical trial to a community setting. Before such research is undertaken, main effects and synergistic and or antagonistic interactions between them should be identified. Knowledge of the relative strength and direction of the effects of the individual components and their interactions facilitates the successful transfer of clinically significant findings and may potentially reduce the number of interventional components needed. Therefore the current inability of the standardly-tailored design to provide unbiased estimates of individual interventional components is a serious limitation in their applicability to second stage translational research.
We discuss estimation of individual component effects from the family of factorial designs and this limitation for standardly-tailored designs. We use the phrase ‘factorial designs’ to describe full-factorial designs and their derivatives including the fractional factorial, partial factorial, incomplete factorial and modified reciprocal designs. We suggest two potential directions for designing multicomponent interventions to facilitate unbiased estimates of individual interventional components.
Full factorial designs and their variants are the most common multicomponent trial design described in the literature and differ meaningfully from standardly-tailored designs. Factorial and standardly-tailored designs result in similar estimates of net effect with different levels of precision. Unbiased estimation of individual component effects from a standardly-tailored design will require new methodology.
Although clinically relevant in geriatrics, previous applications of standardly-tailored designs have not provided unbiased estimates of the effects of individual interventional components.
Future directions to estimate individual component effects from standardly-tailored designs include applying D-optimal designs and creating independent linear combinations of risk factors analogous to factor analysis.
Methods are needed to extract unbiased estimates of the effects of individual interventional components from standardly-tailored designs.
PMCID: PMC3477845  PMID: 18375650
7.  Association of Injurious Falls With Disability Outcomes and Nursing Home Admissions in Community-Living Older Persons 
American Journal of Epidemiology  2013;178(3):418-425.
Little is known about the deleterious effects of injurious falls relative to those of other disabling conditions or whether these effects are driven largely by hip fractures. From a cohort of 754 community-living elders of New Haven, Connecticut, we matched 122 hospitalizations for an injurious fall (59 hip-fracture and 63 other fall-related injuries) to 241 non–fall-related hospitalizations. Participants (mean age: 85.7 years) were evaluated monthly for disability in 13 activities and admission to a nursing home from 1998 to 2010. For both hip-fracture and other fall-related injuries, the disability scores were significantly greater during each of the first 6 months after hospitalization than for the non–fall-related admissions, with adjusted risk ratios at 6 months of 1.5 (95% confidence interval (CI): 1.3, 1.7) for hip fracture and 1.4 (95% CI: 1.2, 1.6) for other fall-related injuries. The likelihood of having a long-term nursing home admission was considerably greater after hospitalization for a hip fracture and other fall-related injury than for a non–fall-related reason, with adjusted odds ratios of 3.3 (95% CI: 1.3, 8.3) and 3.2 (95% CI: 1.3, 7.8), respectively. Relative to other conditions leading to hospitalization, hip-fracture and other fall-related injuries are associated with worse disability outcomes and a higher likelihood of long-term nursing home admissions.
PMCID: PMC3816345  PMID: 23548756
accidental falls; activities of daily living; aged; cohort studies; nursing homes
8.  Long-Term Trajectories of Lower Extremity Function in Older Adults: Estimating Gender Differences While Accounting for Potential Mortality Bias 
Gender-specific trajectories of lower extremity function (LEF) and the potential for bias in LEF estimation due to differences in survival have been understudied.
We evaluated longitudinal data from 690 initially nondisabled adults age 70 or older from the Precipitating Events Project. LEF was assessed every 18 months for 12 years using a modified Short Physical Performance Battery (mSPPB). Hierarchical linear models with adjustments for length-of-survival estimated the intraindividual trajectory of LEF and differences in trajectory intercept and slope between men and women.
LEF declined following a nonlinear trajectory. In the full sample, and among participants with high (mSPPB 10–12) and intermediate (mSPPB 7–9) baseline LEF, the rate-of-decline in mSPPB was slower in women than in men, with no gender differences in baseline mSPPB scores. Among participants with low baseline LEF (mSPPB ≤6), men had a higher starting mSPPB score, whereas women experienced a deceleration in the rate-of-decline over time. In all groups, participants who survived longer had higher starting mSPPB scores and slower rates-of-decline compared with those who died sooner.
Over the course of 12 years, older women preserve LEF better than men. Nonadjustment for differences in survival results in overestimating the level and underestimating the rate-of-decline in LEF over time.
PMCID: PMC3674712  PMID: 23160367
Lower extremity function; Trajectories; Gender differences; Survival bias
9.  Antidepressant Use and Cognitive Deficits in Older Men: Addressing Confounding by Indications Using Different Methods 
Annals of epidemiology  2011;22(1):9-16.
Antidepressant use has been associated with cognitive impairment in older persons. This study sought to examine whether this association might reflect an indication bias.
544 community-dwelling hypertensive men aged ≥65 years completed the Hopkins Verbal Learning Test (HVLT) at baseline and one year. Antidepressant medications were ascertained using medical records. Potential confounding by indications was examined by adjusting for depression-related diagnoses and severity of depression symptoms using multiple linear regression (MLR), a propensity-score (PS) and a structural equation model (SEM).
Before adjusting for the indications, a one unit cumulative exposure to antidepressants was associated with −1.00 (95% Confidence Interval (CI): −1.94, −0.06) point lower HVLT score. After adjusting for the indications using MLR or a PS, the association diminished to −0.48 (95% CI: −0.62, 1.58) and −0.58 (95% CI: −0.60, 1.58), respectively. The most clinical interpretable empirical SEM with adequate fit involves both direct and indirect paths of the two indications. Depression-related diagnoses and depression symptoms significantly predict antidepressant use (P <0.05). Their total standardized path coefficients on HVLT score were twice (0.073) or as large (0.034) as the antidepressant use (0.035).
The apparent association between antidepressant use and memory deficit in older persons may be confounded by indications. SEM offers a heuristic empirical method for examining confounding by indications, but not quantitatively superior bias reduction compared to conventional methods.
PMCID: PMC4054866  PMID: 22037381
Antidepressant use; confounding by indication; structural equation modeling; elderly; cognitive deficit; multiple linear regression
10.  Accounting for the Hierarchical Structure in Veterans Health Administration Data: Differences in Healthcare Utilization between Men and Women Veterans 
Women currently constitute 15% of active United States of America military service personnel, and this proportion is expected to double in the next 5 years. Previous research has shown that healthcare utilization and costs differ in women US Veterans Health Administration (VA) patients compared to men. However, none have accounted for the potential effects of clustering on their estimates of healthcare utilization. US Women Veterans are more likely to serve in specific military branches (e.g. Army), components (e.g. National Guard), and ranks (e.g. officer) than men. These factors may confer different risk and protection that can affect subsequent healthcare needs. Our study investigates the effects of accounting for the hierarchical structure of data on estimates of the association between gender and VA healthcare utilization. The sample consisted of data on 406,406 Veterans obtained from VA's Operation Enduring Freedom/Operation Iraqi Freedom roster provided by Defense Manpower Data Center — Contingency Tracking System Deployment File. We compared three statistical models, ordinary, fixed and random effects hierarchical logistic regression, in order to assess the association of gender with healthcare utilization, controlling for branch of service, component, rank, age, race, and marital status. Gender was associated with utilization in ordinary logistic and, but not in fixed effects hierarchical logistic or random effects hierarchical logistic regression models. This point out that incomplete inference could be drawn by ignoring the military structure that may influence combat exposure and subsequent healthcare needs. Researchers should consider modeling VA data using methods that account for the potential clustering effect of hierarchy.
PMCID: PMC4047985  PMID: 24910720
Hierarchical Logistics Models; Random Effects; GLIMMIX; GENMOD; Generalized Estimating Equations; Gender Differences; Veterans
11.  Gerontologic Biostatistics: The Statistical Challenges of Clinical Research with Older Study Participants 
The medical and personal circumstances of older persons present challenges for designing and analyzing clinical research studies in which they participate. These challenges presented by elderly study samples are not unique but they are sufficiently distinctive to warrant deliberate and systematic attention. Their distinctiveness originates in the multifactorial etiologies of geriatric health syndromes and the multiple morbidities accruing with aging at the end of life. The objective of this article is to identify a set of statistical challenges arising in research with older persons that should be considered conjointly in the practice of clinical research and that should be addressed systematically in the training of biostatisticians intending to work with gerontologists, geriatricians, and older study participants. The statistical challenges include design and analytical strategies for multicomponent interventions, multiple outcomes, state transition models, floor and ceiling effects, missing data, and mixed methods. The methodological and pedagogical themes of this article will be integrated by a description of a proposed subdiscipline of “gerontologic biostatistics” and supported by the introduction of new set of statistical resources for researchers working in this area. These conceptual and methodological resources have been developed in the context of several collaborating Claude D. Pepper Older Americans Independence Centers.
PMCID: PMC2918405  PMID: 20533963
clinical research; statistics; aging; study design
12.  Restricting Symptoms in the Last Year of Life 
JAMA internal medicine  2013;173(16):1534-1540.
Freedom from symptoms is an important determinant of a good death, but little is known about symptom occurrence during the last year of life.
To evaluate the monthly occurrence of physical and psychological symptoms leading to restrictions in daily activities (ie, restricting symptoms) among older persons during the last year of life and to determine the associations of demographic and clinical factors with symptom occurrence.
Prospective cohort study. Comprehensive assessments were completed every 18 months, and monthly interviews were conducted to assess the presence of restricting symptoms. Of 1002 nondisabled community-dwelling individuals 70 years or older in greater New Haven, Connecticut, eligible to participate, 754 agreed and were enrolled between 1998 and 1999.
The primary outcome was the monthly occurrence of restricting symptoms as a dichotomous outcome. The monthly mean count of restricting symptoms was a secondary outcome.
Among the 491 participants who died after their first interview and before June 30, 2011, mean age at death was 85.8 years, 61.9% were women, and 9.0% were nonwhite. The mean number of comorbid conditions was 2.4, and 73.1% had multimorbidity. The monthly occurrence of restricting symptoms was fairly constant from 12 months before death (20.4%) until 5 months before death (27.4%), when it began to increase rapidly, reaching 57.2% in the month before death. In multivariable analysis, age younger than 85 years (odds ratio [OR], 1.30 [95% CI, 1.07–1.57]), multimorbidity (OR, 1.38 [95% CI, 1.09–1.75]), and proximity to time of death (OR, 1.14 per month [95% CI, 1.11–1.16]) were significantly associated with the monthly occurrence of restricting symptoms. Participants who died of cancer had higher monthly symptom occurrence (OR, 1.80 [95% CI, 1.03–3.14]) than participants who died of sudden death, although this difference was only marginally significant (P = .04). Symptom burden did not otherwise differ substantially according to condition leading to death.
Restricting symptoms are common during the last year of life, increasing substantially approximately 5 months before death. Our results highlight the importance of assessing and managing symptoms in older patients, particularly those with multimorbidity.
PMCID: PMC4041035  PMID: 23836056
Across the lifespan, women live longer than men but experience higher rates of disability. To more completely evaluate these gender differences, the current study set out to compare the trajectories and burden of disability over an extended period of time between older men and women.
Prospective, longitudinal study with 13.5 years of follow-up.
Greater New Haven, Connecticut.
754 persons, aged 70 years or older, who were initially community-living and nondisabled in their basic activities of daily living.
Disability in 13 basic, instrumental and mobility activities was assessed during monthly interviews, while demographic and clinical covariates were measured during comprehensive assessments every 18 months.
Five distinct trajectories were identified over successive 18-month intervals: independent, mild disability, mild to moderate disability, moderate disability, and severe disability. Women were more likely than men to experience the moderate and severe disability trajectories, but were less likely to transition from the independent trajectory to a worse disability trajectory during the subsequent 18-month interval. Women were also less likely to die after each of the five trajectories, and these differences were at least marginally significant for all but the independent trajectory. Over the entire duration of follow-up, women suffered from a greater burden of disability than men, but these differences were greatly attenuated after adjustment for the baseline levels of disability.
Gender differences in disability over an extended period of time can be explained, at least in part, by the higher mortality experienced by older men and the higher initial levels of disability among older women. These results suggest the need to take a life-course approach to better understand gender differences in disability.
PMCID: PMC3615123  PMID: 23294968
disability assessment; longitudinal study; gender differences
14.  When Parents Matter to Their Adult Children: Filial Reliance Associated With Parents’ Depressive Symptoms 
A neglected topic in aging depression research is the potential role of the parent–adult child relationship. In this study we examined whether adult children’s reports of having relied upon parents for instrumental and expressive support are associated with parents’ depressive symptoms. The sample included 304 parents (aged 50–72 years), matched to a randomly selected adult offspring, from the University of Southern California Longitudinal Study of Generations. We measured parents’ depressive symptoms by using the Center for Epidemiologic Studies Depression Scale at baseline and 3 and 6 years later. The final longitudinal analysis showed that, when we adjusted for relevant variables including age, gender, income, self-rated health, and child’s depressive symptoms, the adult child’s reliance on instrumental support was associated with fewer parental depressive symptoms (p = .036). Expressive support did not show the same pattern. Thus, adult children’s reliance on instrumental support might contribute to their parents’ mental health.
PMCID: PMC3971430  PMID: 18332193
Depression; Mental Health; Social support; Intergenerational; Parent–adult child relationship
15.  Cumulative Anticholinergic Exposure Is Associated with Poor Memory and Executive Function in Older Men 
To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men.
Prospective cohort study.
A Department of Veterans Affairs primary care clinic.
Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension.
The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anti-cholinergic score.
Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI) = 0.05–0.58) and 0.10-point (95% CI = 0.04–0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI = 0.01–0.56) and executive function (0.08, 95% CI = 0.02–0.15) after further adjustment for concomitant non-anticholinergic medications.
Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects.
PMCID: PMC3952110  PMID: 19093918
anticholinergic score; medication use; cognitive test; cohort study; older men; polypharmacy
16.  Modeling repeated time-to-event health conditions with discontinuous risk intervals: an example of a longitudinal study of functional disability among older persons 
Researchers have often used rather simple approaches to analyze repeated time-to-event health conditions that either examine time to the first event or treat multiple events as independent. More sophisticated models have been developed, although previous applications have focused largely on such outcomes having continuous risk intervals. Limitations of applying these models include their difficulty in implementation without careful attention to forming the data structures.
We first review time-to-event models for repeated events that are extensions of the Cox model and frailty models. Next, we develop a way to efficiently set up the data structures with discontinuous risk intervals for such models, which are more appropriate for many applications than the continuous alternatives. Finally, we apply these models to a real dataset to investigate the effect of gender on functional disability in a cohort of older persons. For comparison, we demonstrate modeling time to the first event.
The GEE Poisson, the Cox counting process, and the frailty models provided similar parameter estimates of gender effect on functional disability, that is, women had increased risk of bathing disability and other disability (disability in walking, dressing, or transferring) as compared to men. These results, especially for other disability, were quite different from those provided by an analysis of the first-event outcomes. However, the effect of gender was no longer significant in the counting process model fully adjusted for covariates.
Modeling time to the first event only may not be adequate. After properly setting up the data structures, repeated event models that account for the correlation between multiple events within subjects, can be easily implemented with common statistical software packages.
PMCID: PMC2735569  PMID: 18338081
recurrent event; modeling; data structure; disability
17.  Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging 
Aging (Albany NY)  2014;6(2):131-139.
Aging is associated with a progressive decline in immune function (immunosenescence) resulting in an increased susceptibility to viral and bacterial infections. Here we show reduced expression of Toll-like receptor 1 (TLR1) in polymorphonuclear leukocytes (PMN) and an underlying age-dependent deficiency in PMN bioenergetics. In older (>65 years) adults, stimulation through TLR1 led to lower activation of integrins (CD11b and CD18), lower production of the chemokine IL-8, and lower levels of the phosphorylated signaling intermediate p38 MAP kinase than in PMN from younger donors (21-30 years). In addition, loss of CD62L, a marker of PMN activation, was reduced in PMN of older adults stimulated through multiple pathways. Rescue of PMN from apoptosis by stimulation with TLR1 was reduced in PMN from older adults. In seeking an explanation for effects of aging across multiple pathways, we examined PMN energy utilization and found that glucose uptake after stimulation through TLR1 was dramatically lower in PMN of older adults. Our results demonstrate a reduction in TLR1 expression and TLR1-mediated responses in PMN with aging, and reduced efficiency of bioenergetics in PMN. These changes likely contribute to reduced PMN efficiency in aging through multiple aspects of PMN function and suggest potential therapeutic opportunities.
PMCID: PMC3969281  PMID: 24595889
neutrophils; Toll-like receptors; p38 Map kinase signaling; aging; bioenergetics; integrins
18.  Motor Deficits and Altered Striatal Gene Expression in aphakia(ak) Mice 
Brain research  2007;1185:283-292.
Like humans with Parkinsons disease (PD), the ak mouse lacks the majority of the substantia nigra pars compacta (SNc) and experiences striatal denervation. The purpose of this study was to test whether motor abnormalities in the ak mouse progress over time, and whether motor function could be associated with temporal alterations in the striatal transcriptome. Ak and wt mice (28 to 180 days old) were tested using paradigms sensitive to nigrostriatal dysfunction. Results were analyzed using a linear mixed model. Ak mice significantly underperformed wt controls in rotarod, balance beam, string test, pole test and cotton shred tests at all ages examined. Motor performance in ak mice remained constant over the first 6 months of life, with the exception of the cotton shred test, in which ak mice exhibited marginal decline in performance. Dorsal striatal semi-quantitative RT-PCR for 19 dopaminergic, cholinergic, glutaminergic and catabolic genes was performed in 1 and 6 month old groups of ak and wt mice. Preproenkephalin levels in ak mice were elevated in both age groups. Drd1, 3 and 4 levels declined over time, in contrast to increasing Drd2 expression. Additional findings included decreased Chrnα6 expression and elevated VGluT1 expression at both time points in ak mice, and elevated AchE expression in young ak mice only. Results confirm that motor ability does not decline significantly for the first 6 months of life in ak mice. Their striatal gene expression patterns are consistent with dopaminergic denervation, and change over time, despite relatively unaltered motor performance.
PMCID: PMC3904435  PMID: 17949697
Aphakia; Denervation; Dopaminergic; Motor; Parkinson’s; Striatum
19.  Results Differ by Applying Distinctive Multiple Imputation Approaches on the Longitudinal Cardiovascular Health Study Data 
Experimental aging research  2013;39(1):27-43.
To examine sequential and simultaneous approaches to multiple imputation of missing data in a longitudinal dataset where losses due to death were common.
Comparison of results from analyses and simulations of time to incident difficulty of activities of daily living (ADL) in the Cardiovascular Health Study when missing data were imputed simultaneously or sequentially.
Results differed with imputation methods. The largest proportional differences in 12 risk factor parameter estimates were: heart failure by 106%, social support by 33%, and arthritis by 27%.
Decedents’ final characteristics were influential on future imputations of those with missing values.
PMCID: PMC3547387  PMID: 23316735
20.  Age-associated Decrease in Toll-like Receptor Function in Primary Human Dendritic Cells Predicts Influenza Vaccine Response1 
Journal of immunology (Baltimore, Md. : 1950)  2010;184(5):10.4049/jimmunol.0901022.
We evaluated Toll-like receptor (TLR) function in primary human dendritic cells from 104 young (age 21–30) and older (≥ 65 years) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid (mDC) and plasmacytoid (pDC) DCs and found substantial decreases in older, compared to young individuals in TNF-α, IL-6 and/or IL-12 (p40) production in mDCs and in TNF-α and IFN-α production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g. gender, race, body mass index [BMI], number of comorbid medical conditions) using mixed effect statistical modeling. Studies of surface and intracellular expression of TLR proteins, and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and post-transcriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older, compared to young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in dendritic cells; notably, defects in cytokine production were strongly associated with poor antibody response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.
PMCID: PMC3867271  PMID: 20100933
21.  The Effect of Psychosocial Support Intervention on Depression in Patients with Dementia and Their Family Caregivers: An Assessor-Blinded Randomized Controlled Trial 
A three-component tailored psychosocial 12-month assessor-blinded randomized controlled trial to reduce depression in people with dementia (PWD) and carers was conducted.
A total of 230 home-dwelling dyads of PWD and their carers were randomized to usual care or intervention consisting of three components over 12 months. Primary outcomes were the difference between the baseline and 12-month score on the Cornell Scale of Depression in Dementia (CSDD) in the PWD and on the Geriatric Depression Scale (GDS) in the carers.
The intent-to-treat difference between the baseline and 12-month change score was not significant between the intervention and control groups for the CSDD (p = 0.95) or GDS (p = 0.82).
The trial did not show a significant difference between usual care and the intervention on depressive symptoms in PWD or their family caregivers.
© 2013 S. Karger AG, Basel
PMCID: PMC3843914  PMID: 24348500
Dementia; Caregiver; Psychosocial intervention; Depression; Clinical trial

22.  Contribution of Individual Diseases to Death in Older Adults with Multiple Diseases 
To determine empirically the diseases contributing most commonly and strongly to death in older adults, accounting for coexisting diseases.
United States
Twenty two thousand eight hundred ninety Medicare Current Beneficiary Survey participants, a national representative sample of Medicare beneficiaries, enrolled during 2002 – 2006.
Chronic and acute diseases were ascertained from Medicare claims data. Diseases contributing to death during follow-up were identified empirically via regression models among all diseases with a frequency of ≥ 1% and hazard ratio for death of > 1. The additive contributions of these diseases, adjusting for co-existing diseases, were calculated using a longitudinal extension of average attributable fraction; 95% confidence intervals were estimated from bootstrapping.
Fifteen diseases and acute events contributed significantly to death, together accounting for nearly 70% of death. Heart failure (20.0%), dementia (13.6%), chronic lower respiratory disease (12.4%), and pneumonia (5.3%) made the largest contributions to death. Cancers, including lung, colorectal, lymphoma, and head and neck, together contributed to 5.6% of death. The other disease and events included acute kidney injury, stroke, septicemia, liver disease, myocardial infarction, and unintentional injuries.
The extent of the contribution of some diseases such as dementia and respiratory disease to death in older adults may be underappreciated, while the contribution of other diseases may be overestimated, with methods that focus on determining a single underlying cause. Current conceptualization of a single underlying cause may not account adequately for the contribution to death of coexisting diseases experienced by older adults.
PMCID: PMC3419332  PMID: 22734792
death; coexisting diseases; multiple chronic conditions
23.  Dysregulation of Human Toll-like Receptor Function in Aging 
Ageing research reviews  2010;10(3):346-353.
Studies addressing immunosenescence in the immune system have expanded to focus on the innate as well as the adaptive responses. In particular, aging results in alterations in the function of Toll-like receptors (TLRs), the first described pattern recognition receptor family of the innate immune system. Recent studies have begun to elucidate the consequences of aging on TLR function in human cohorts and add to existing findings performed in animal models. In general, these studies show that human TLR function is impaired in the context of aging, and in addition there is evidence for inappropriate persistence of TLR activation in specific systems. These findings are consistent with an overarching theme of age-associated dysregulation of TLR signaling that likely contributes to the increased morbidity and mortality from infectious diseases found in geriatric patients.
PMCID: PMC3633557  PMID: 21074638
24.  A Method for Partitioning the Attributable Fraction of Multiple Time-Dependent Coexisting Risk Factors for an Adverse Health Outcome 
American journal of public health  2012;103(1):177-182.
We decomposed the total effect of coexisting diseases on a timed occurrence of an adverse outcome into additive effects from individual diseases.
In a cohort of older adults enrolled in the Precipitating Events Project in New Haven County, Connecticut, we assessed a longitudinal extension of the average attributable fraction method (LE-AAF) to estimate the additive and order-free contributions of multiple diseases to the timed occurrence of a health outcome, with right censoring, which may be useful when relationships among diseases are complex. We partitioned the contribution to death into additive LE-AAFs for multiple diseases.
The onset of heart failure and acute episodes of pneumonia during follow-up contributed the most to death, with the overall LE-AAFs equal to 13.0% and 12.1%, respectively. The contribution of preexisting diseases decreased over the years, with a trend of increasing contribution from new onset of diseases.
LE-AAF can be useful for determining the additive and order-free contribution of individual time-varying diseases to a time-to-event outcome.
PMCID: PMC3518339  PMID: 22515873
25.  Health Outcome Priorities Among Competing Cardiovascular, Fall Injury, and Medication-Related Symptom Outcomes 
To determine the priority that older adults with coexisting hypertension and fall risk give to optimizing cardiovascular outcomes versus fall- and medication symptom-related outcomes.
One hundred twenty-three cognitively intact persons aged 70 and older with hypertension and fall risk.
Discrete choice task was used to elicit the relative importance placed on reducing the risk of three outcomes: cardiovascular events, serious fall injuries, and medication symptoms. Risk estimates with and without antihypertensive medications were obtained from the literature. Participants chose between 11 pairs of options that displayed lower risks for one or two outcomes and a higher risk for the other outcome(s), versus the reverse. Results were used to calculate relative importance scores for the three outcomes. These scores, which sum to 100, reflect the relative priority participants placed on the difference between the risk estimates of each outcome.
Sixty-two participants (50.4%) placed greater importance on reducing risk of cardiovascular events than reducing risk of the combination of fall injuries and medication symptoms; 61 participants did the converse. A lower percentage of participants with chronic obstructive pulmonary disease (P =.02), unsteadiness (P =.02), functional dependency (P =.04), lower cognition (P =.02) and depressive symptoms (P =.03) prioritized cardiovascular outcomes over fall injuries and medication symptoms than did participants without these characteristics.
Interindividual variability in the face of competing outcomes supports individualizing decision-making to individual priorities. In the current example, this may mean forgoing antihypertensive medications or compromising on blood pressure reduction for some individuals.
PMCID: PMC3494099  PMID: 18662210
competing outcomes; fall injuries; hypertension; patient priorities

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