Efficient estimation of the attributable fraction when there are monotonicity constraints and interactions.

The PAF for an exposure is the fraction of disease cases in a population that can be attributed to that exposure. One method of estimating the PAF involves estimating the probability of having the disease given the exposure and confounding variables. In many settings, the exposure will interact with the confounders and the confounders will interact with each other. Also, in many settings, the probability of having the disease is thought, based on subject matter knowledge, to be a monotone increasing function of the exposure and possibly of some of the confounders. We develop an efficient approach for estimating logistic regression models with interactions and monotonicity constraints, and apply this approach to estimating the population attributable fraction (PAF). Our approach produces substantially more accurate estimates of the PAF in some settings than the usual approach which uses logistic regression without monotonicity constraints.

Bayesian multivariate growth curve latent class models for mixed outcomes.

In many clinical studies, the disease of interest is multifaceted, and multiple outcomes are needed to adequately capture information about the characteristics of the disease or its severity. In the analysis of such diseases, it is often difficult to determine what constitutes improvement because of the multivariate nature of the outcome. Furthermore, when the disease of interest has an unknown etiology and/or is primarily a symptom-defined syndrome, there is potential for the disease population to have distinct subgroups. Identification of population subgroups is of interest as it may assist clinicians in providing appropriate treatment or in developing accurate prognoses. We propose multivariate growth curve latent class models that group subjects on the basis of multiple symptoms measured repeatedly over time. These groups or latent classes are defined by distinctive longitudinal profiles of a latent variable, which is used to summarize the multivariate outcomes at each point. The mean growth curve for the latent variable in each class defines the features of the class. We develop this model for any combination of continuous, binary, ordinal, or count outcomes within a Bayesian hierarchical framework. We use simulation studies to validate the estimation procedures. We apply our model to data from a randomized clinical trial evaluating the efficacy of Bacillus Calmette-Guerin in treating symptoms of interstitial cystitis where we are able to identify a class of subjects for whom treatment is effective.

Economic inequalities in the effectiveness of a primary care intervention for depression and suicidal ideation.

BACKGROUND: Economic disadvantage is associated with depression and suicide. We sought to determine whether economic disadvantage reduces the effectiveness of depression treatments received in primary care. METHODS: We conducted differential-effects analyses of the Prevention of Suicide in Primary Care Elderly: Collaborative Trial, a primary-care-based randomized, controlled trial for late-life depression and suicidal ideation conducted between 1999 and 2001, which included 514 patients with major depression or clinically significant minor depression. RESULTS: The intervention effect, defined as change in depressive symptoms from baseline, was stronger among persons reporting financial strain at baseline (differential effect size = -4.5 Hamilton Depression Rating Scale points across the study period [95% confidence interval = -8.6 to -0.3]). We found similar evidence for effect modification by neighborhood poverty, although the intervention effect weakened after the initial 4 months of the trial for participants residing in poor neighborhoods. There was no evidence of substantial differences in the effectiveness of the intervention on suicidal ideation and depression remission by economic disadvantage. CONCLUSIONS: Economic conditions moderated the effectiveness of primary-care-based treatment for late-life depression. Financially strained individuals benefited more from the intervention; we speculate this was because of the enhanced treatment management protocol, which led to a greater improvement in the care received by these persons. People living in poor neighborhoods experienced only temporary benefit from the intervention. Thus, multiple aspects of economic disadvantage affect depression treatment outcomes; additional work is needed to understand the underlying mechanisms.

Effectiveness of long-term acute care hospitalization in elderly patients with chronic critical illness.

BACKGROUND: For patients recovering from severe acute illness, admission to a long-term acute care hospital (LTAC) is an increasingly common alternative to continued management in an intensive care unit (ICU). OBJECTIVE: To examine the effectiveness of LTAC transfer in patients with chronic critical illness. RESEARCH DESIGN: Retrospective cohort study in United States hospitals from 2002 to 2006. SUBJECTS: Medicare beneficiaries with chronic critical illness, defined as mechanical ventilation and at least 14 days of intensive care. MEASURES: Survival, costs, and hospital readmissions. We used multivariate analyses and instrumental variables to account for differences in patient characteristics, the timing of LTAC transfer, and selection bias. RESULTS: A total of 234,799 patients met our definition of chronic critical illness. Of these, 48,416 (20.6%) were transferred to an LTAC. In the instrumental variable analysis, patients transferred to an LTAC experienced similar survival compared with patients who remained in an ICU [adjusted hazard ratio=0.99; 95% confidence interval (CI), 0.96 to 1.01; P=0.27). Total hospital-related costs in the 180 days after admission were lower among patients transferred to LTACs (adjusted cost difference=-$13,422; 95% CI, -26,662 to -223, P=0.046). This difference was attributable to a reduction in skilled nursing facility admissions (adjusted admission rate difference=-0.591; 95% CI, -0.728 to -0.454; P<0.001). Total Medicare payments were higher (adjusted cost difference=$15,592; 95% CI, 6343 to 24,842; P=0.001). CONCLUSIONS: Patients with chronic critical illness transferred to LTACs experience similar survival compared with patients who remain in ICUs, incur fewer health care costs driven by a reduction in postacute care utilization, however, invoke higher overall Medicare payments.

Radical cystectomy versus bladder-preserving therapy for muscle-invasive urothelial carcinoma: examining confounding and misclassification biasin cancer observational comparative effectiveness research.

OBJECTIVES: Radical cystectomy (RC) is the standard treatment for muscle-invasive urothelial carcinoma of the bladder. Trimodality bladder-preserving therapy (BPT) is an alternative to RC, but randomized comparisons of RC versus BPT have proven infeasible. To compare RC versus BPT, we undertook an observational cohort study using registry and administrative claims data from the Surveillance, Epidemiology and End Results-Medicare database. METHODS: We identified patients age 65 years or older diagnosed between 1995 and 2005 who received RC (n = 1426) or BPT (n = 417). We examined confounding and stage misclassification in the comparison of RC and BPT by using multivariable adjustment, propensity score-based adjustment, instrumental variable (IV) analysis, and simulations. RESULTS: Patients who received BPT were older and more likely to have comorbid disease. After propensity score adjustment, BPT was associated with an increased hazard of death from any cause (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.05-1.53) and from bladder cancer (HR 1.31; 95% CI 0.97-1.77). Using the local area cystectomy rate as an instrument, IV analysis demonstrated no differences in survival between BPT and RC (death from any cause HR 1.06; 95% CI 0.78-1.31; death from bladder cancer HR 0.94; 95% CI 0.55-1.18). Simulation studies for stage misclassification yielded results consistent with the IV analysis. CONCLUSIONS: Survival estimates in an observational cohort of patients who underwent RC versus BPT differ by analytic method. Multivariable and propensity score adjustment revealed greater mortality associated with BPT relative to RC, while IV analysis and simulation studies suggest that the two treatments are associated with similar survival outcomes.

Feasibility, acceptability and preliminary effectiveness of patient advocates for improving asthma outcomes in adults.

BACKGROUND: Asthmatic adults from low-income urban neighborhoods have inferior health outcomes which in part may be due to barriers accessing care and with patient-provider communication. We adapted a patient advocate (PA) intervention to overcome these barriers. OBJECTIVE: To conduct a pilot study to assess feasibility, acceptability and preliminary evidence of effectiveness. METHODS: A prospective randomized design was employed with mixed methods evaluation. Adults with moderate or severe asthma were randomized to 16 weeks of PA or a minimal intervention (MI) comparison condition. The PA, a non-professional, modeled preparations for a medical visit, attended the visit and confirmed understanding. The PA facilitated scheduling, obtaining insurance coverage and overcoming barriers to implementing medical advice. Outcomes included electronically-monitored inhaled corticosteroid (ICS) adherence, asthma control, quality of life, FEV1, emergency department (ED) visits and hospitalizations. Mixed-effects models guided an intention-to-treat analysis. RESULTS: 100 adults participated: age 47 ± 14 years, 75% female, 71% African-American, 16% white, baseline FEV1 69% ± 18%, 36% experiencing hospitalizations and 56% ED visits for asthma in the prior year. Ninety-three subjects completed all visits; 36 of 53 PA-assigned had a PA visit. Adherence declined significantly in the control (p = 0.001) but not significantly in the PA group (p = 0.30). Both PA and MI groups demonstrated improved asthma control (p = 0.01 in both) and quality of life (p = 0.001, p = 0.004). Hospitalizations and ED visits for asthma did not differ between groups. The observed changes over time tended to favor the PA group, but this study was underpowered to detect differences between groups. CONCLUSION: The PA intervention was feasible and acceptable and demonstrated potential for improving asthma control and quality of life.

Social inequalities in depression and suicidal ideation among older primary care patients.

PURPOSE: Depression and suicide are major public health concerns, and are often unrecognized among the elderly. This study investigated social inequalities in depressive symptoms and suicidal ideation among older adults. METHODS: Data come from 1,226 participants in PROSPECT (Prevention of Suicide in Primary Care Elderly: Collaborative Trial), a large primary care-based intervention trial for late-life depression. Linear and logistic regressions were used to analyze depressive symptoms and suicidal ideation over the 2-year follow-up period. RESULTS: Mean Hamilton Depression Rating Scale (HDRS) scores were significantly higher among participants in financial strain [regression coefficient (b) = 1.78, 95 % confidence interval (CI) = 0.67-2.89] and with annual incomes below $20,000 (b = 1.67, CI = 0.34-3.00). Financial strain was also associated with a higher risk of suicidal ideation (odds ratio = 2.35, CI = 1.38-3.98). CONCLUSIONS: There exist marked social inequalities in depressive symptoms and suicidal ideation among older adults attending primary care practices, the setting in which depression is most commonly treated. Our results justify continued efforts to understand the mechanisms generating such inequalities and to recognize and provide effective treatments for depression among high-risk populations.

Is public communication about end-of-life care helping to inform all? Cancer news coverage in African American versus mainstream media.

BACKGROUND: Because cancers are a leading cause of death, these diseases receive a great deal of news attention. However, because news media frequently target specific racial or ethnic audiences, some populations may receive different information, and it is unknown whether reporting equally informs all audiences about the options for care at the end of life. This study of news reporting compared "mainstream" (general market) media with African American media, which serves the largest minority group. The specific goal of this study was to determine whether these news media communicate differently about cure-directed cancer treatment and end-of-life alternatives. METHODS: This content analysis included 660 cancer news stories from online and print media that targeted either African American or mainstream audiences. The main outcome measures included whether reporting discussed adverse events of cancer treatment, cancer treatment failure, cancer death/dying, and end-of-life palliative or hospice care. RESULTS: Unadjusted and adjusted analyses indicated that the news stories in the African American media are less likely than those in mainstream media to discuss each of the topics studied. Comparing the proportions of news stories in mainstream versus African American media, 31.6% versus 13.6% discussed adverse events (odds ratio [OR], 2.92; 95% confidence interval [CI], 1.51-5.66; P = .001); 14.1% versus 4.2% mentioned treatment failure (OR, 3.79; 95% CI, 1.45-9.88; P = .006); and 11.9% versus 3.8% focused on death/dying (OR, 3.42; 95% CI, 1.39-8.38; P = .007). Finally, although very few news stories discussed end-of-life hospice or palliative care, all were found in mainstream media (7/396 vs 0/264). CONCLUSION: The African American news media sampled are less likely than mainstream news media to portray negative cancer outcomes and end-of-life care. Given media's segmented audiences, these findings raise concerns that not all audiences are being informed equally well. Because media content is modifiable, there may be opportunities to improve public cancer communication.

The analysis of binary longitudinal data with time-dependent covariates.

We consider longitudinal studies with binary outcomes that are measured repeatedly on subjects over time. The goal of our analysis was to fit a logistic model that relates the expected value of the outcomes with explanatory variables that are measured on each subject. However, additional care must be taken to adjust for the association between the repeated measurements on each subject. We propose a new maximum likelihood method for covariates that may be fixed or time varying. We also implement and make comparisons with two other approaches: generalized estimating equations, which may be more robust to misspecification of the true correlation structure, and alternating logistic regression, which models association via odds ratios that are subject to less restrictive constraints than are correlations. The proposed estimation procedure will yield consistent and asymptotically normal estimates of the regression and correlation parameters if the correlation on consecutive measurements on a subject is correctly specified. Simulations demonstrate that our approach can yield improved efficiency in estimation of the regression parameter; for equally spaced and complete data, the gains in efficiency were greatest for the parameter associated with a time-by-group interaction term and for stronger values of the correlation. For unequally spaced data and with dropout according to a missing-at-random mechanism, MARK1ML with correctly specified consecutive correlations yielded substantial improvements in terms of both bias and efficiency. We present an analysis to demonstrate application of the methods we consider. We also offer an R function for easy implementation of our approach.

Simulation study of instrumental variable approaches with an application to a study of the antidiabetic effect of bezafibrate.

PURPOSE: We studied the application of the generalized structural mean model (GSMM) of instrumental variable (IV) methods in estimating treatment odds ratios (ORs) for binary outcomes in pharmacoepidemiologic studies and evaluated the bias of GSMM compared to other IV methods. METHODS: Because of the bias of standard IV methods, including two-stage predictor substitution (2SPS) and two-stage residual inclusion (2SRI) with binary outcomes, we implemented another IV approach based on the GSMM of Vansteelandt and Goetghebeur. We performed simulations under the principal stratification setting and evaluated whether GSMM provides approximately unbiased estimates of the causal OR and compared its bias and mean squared error to that of 2SPS and 2SRI. We then applied different IV methods to a study comparing bezafibrate versus other fibrates on the risk of diabetes. RESULTS: Our simulations showed that unlike the standard logistic, 2SPS, and 2SRI procedures, our implementation of GSMM provides an approximately unbiased estimate of the causal OR even under unmeasured confounding. However, for the effect of bezafibrate versus other fibrates on the risk of diabetes, the GSMM and two-stage approaches yielded similarly attenuated and statistically non-significant OR estimates. The attenuation of the OR by the two-stage and GSMM IV approaches suggests unmeasured confounding, although violations of the IV assumptions or differences in the parameters estimated could be playing a role. CONCLUSION: The GSMM IV approach provides approximately unbiased adjustment for unmeasured confounding on binary outcomes when a valid IV is available.

Problem solving to improve adherence and asthma outcomes in urban adults with moderate or severe asthma: a randomized controlled trial.

BACKGROUND: Improving inhaled corticosteroid (ICS) adherence should improve asthma outcomes. OBJECTIVE: In a randomized controlled trial we tested whether an individualized problem-solving (PS) intervention improves ICS adherence and asthma outcomes. METHODS: Adults with moderate or severe asthma from clinics serving urban neighborhoods were randomized to PS (ie, defining specific barriers to adherence, proposing/weighing solutions, trying the best, assessing, and revising) or standard asthma education (AE) for 3 months and then observed for 3 months. Adherence was monitored electronically. Outcomes included the following: asthma control, FEV(1), asthma-related quality of life, emergency department (ED) visits, and hospitalizations. In an intention-to-treat-analysis longitudinal models using random effects and regression were used. RESULTS: Three hundred thirty-three adults were randomized: 49 ± 14 years of age, 72% female, 68% African American, 7% Latino, mean FEV(1) of 66% ± 19%, and 103 (31%) with hospitalizations and 172 (52%) with ED visits for asthma in the prior year. There was no difference between groups in overall change in any outcome (P > .20). Mean adherence (61% ± 27%) decreased significantly (P = .0004) over time by 14% and 10% in the AE and PS groups, respectively. Asthma control improved overall by 15% (P = .002). In both groups FEV(1) and quality of life improved by 6% (P = .01) and 18% (P < .0001), respectively. However, the improvement in FEV(1) only occurred during monitoring but not subsequently after randomization. Rates of ED visits and hospitalizations did not significantly decrease over the study period. CONCLUSION: PS was not better than AE in improving adherence or asthma outcomes. However, monitoring ICS use with provision of medications and attention, which was imposed on both groups, was associated with improvement in FEV(1) and asthma control.

A difference-in-differences analysis of health, safety, and greening vacant urban space.

Greening of vacant urban land may affect health and safety. The authors conducted a decade-long difference-in-differences analysis of the impact of a vacant lot greening program in Philadelphia, Pennsylvania, on health and safety outcomes. "Before" and "after" outcome differences among treated vacant lots were compared with matched groups of control vacant lots that were eligible but did not receive treatment. Control lots from 2 eligibility pools were randomly selected and matched to treated lots at a 3:1 ratio by city section. Random-effects regression models were fitted, along with alternative models and robustness checks. Across 4 sections of Philadelphia, 4,436 vacant lots totaling over 7.8 million square feet (about 725,000 m(2)) were greened from 1999 to 2008. Regression-adjusted estimates showed that vacant lot greening was associated with consistent reductions in gun assaults across all 4 sections of the city (P < 0.001) and consistent reductions in vandalism in 1 section of the city (P < 0.001). Regression-adjusted estimates also showed that vacant lot greening was associated with residents' reporting less stress and more exercise in select sections of the city (P < 0.01). Once greened, vacant lots may reduce certain crimes and promote some aspects of health. Limitations of the current study are discussed. Community-based trials are warranted to further test these findings.

Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report.

AIMS: This is a multisite, 12-week, open-label trial of lamotrigine augmentation in 57 older adults (≥ 60 years; mean ± SD age = 66.5 ± 6.7 years) with either type I or type II bipolar depression. METHODS: Primary outcome measure was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcome measures included Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression-Bipolar version (CGI-BP), and the WHO-Disability Assessment Schedule II (WHO-DAS II). The Udvalg for Kliniske Undersøgelser (UKU) was used to assess side effects. RESULTS: A total of 77.2% of the study subjects had bipolar I disorder. The mean (SD) lamotrigine dose was 150.9 (68.5) mg/day. There was significant improvement in the MADRS, HAM-D, CGI-BP, and in most domains on the WHO-DAS II. For patients for whom final MADRS score was available: 31 (57.4%) met remission criteria and 35 (64.8%) met response criteria. There were 19/57 (33.3%) who dropped out of the study prematurely, with 6 dropouts due to adverse events (4 cases of rash, 1 manic switch, and 1 hyponatremia). Two cases of rash were possibly drug related and were resolved with drug discontinuation. The most common UKU adverse effects were reduced sleep duration (n = 14, 24.6%), weight loss (n = 12, 21.1%), increased dream activity (n = 12, 21.1%), polyuria/polydipsia (n = 11, 19.3%), weight gain (n = 9, 15.8%), diminished sexual desire (n = 9, 15.8%), increased sleep (n = 9, 15.8%), lassitude/fatigue (n = 8, 14%), and unsteady gait (n = 8, 14%). No significant changes in electrocardiogram or laboratory tests were observed. CONCLUSIONS: In bipolar depressed elders, lamotrigine was associated with improvement in depression, psychopathology, and functional status. There was a moderate number of adverse events, although relationship of adverse events (particularly falls) to study medication could not be clearly determined in this uncontrolled trial. Controlled studies are needed to further evaluate efficacy and tolerability of lamotrigine therapy in geriatric bipolar depression.

A latent class model for testing for linkage and classifying families when the sample may contain segregating and non-segregating families.

In a quantitative trait locus (QTL) study, it is usually not feasible to select families with offspring that simultaneously display variability in more than one phenotype. When multiple phenotypes are of interest, the sample will, with high probability, contain 'non-segregating' families, i.e. families with both parents homozygous at the QTL. These families potentially reduce the power of regression-based methods to detect linkage. Moreover, follow-up studies in individual families will be inefficient, and potentially even misleading, if non-segregating families are selected for the study. Our work extends Haseman-Elston regression using a latent class model to account for the mixture of segregating and non-segregating families. We provide theoretical motivation for the method using an additive genetic model with two distinct functions of the phenotypic outcome, squared difference (SqD) and mean-corrected product (MCP). A permutation procedure is developed to test for linkage; simulation shows that the test is valid for both phenotypic functions. For rare alleles, the method provides increased power compared to a 'marginal' approach that ignores the two types of families; for more common alleles, the marginal approach has better power. These results appear to reflect the ability of the algorithm to accurately assign families to the two classes and the relative weights of segregating and non-segregating families to the test of linkage. An application of Bayes rule is used to estimate the family-specific probability of segregating. High predictive value positive values for segregating families, particularly for MCP, suggest that the method has considerable value for identifying segregating families. The method is illustrated for gene expression phenotypes measured on 27 candidate genes previously demonstrated to show linkage in a sample of 14 families.

Acute alcohol consumption, alcohol outlets, and gun suicide.

A case-control study of 149 intentionally self-inflicted gun injury cases (including completed gun suicides) and 302 population-based controls was conducted from 2003 to 2006 in a major US city. Two focal independent variables, acute alcohol consumption and alcohol outlet availability, were measured. Conditional logistic regression was adjusted for confounding variables. Gun suicide risk to individuals in areas of high alcohol outlet availability was less than the gun suicide risk they incurred from acute alcohol consumption, especially to excess. This corroborates prior work but also uncovers new information about the relationships between acute alcohol consumption, alcohol outlets, and gun suicide. Study limitations and implications are discussed.

Exposure to community violence is associated with asthma hospitalizations and emergency department visits.

BACKGROUND: Exposure to community violence (ECV) has been associated with asthma morbidity of children living in inner-city neighborhoods. OBJECTIVE: To examine with prospective longitudinal data whether ECV is independently associated with asthma-related health outcomes in adults. METHODS: Adults with moderate-severe asthma, recruited from clinics serving inner-city neighborhoods, completed questionnaires covering sociodemographics, asthma severity, and ECV and were followed for 26 weeks. Longitudinal models were used to assess unadjusted and adjusted associations of subsequent asthma outcomes (emergency department [ED] visits, hospitalizations, FEV(1), quality of life). RESULTS: A total of 397 adults, 47 +/- 14 years old, 73% women, 70% African American, 7% Latino, mean FEV(1) 66% +/- 19%, 133 with hospitalizations and 222 with ED visits for asthma in the year before entry, were evaluated. Ninety-one reported ECV. Controlling for age, sex, race/ethnicity, and household income, those exposed to violence had 2.27 (95% CI, 1.32-3.90) times more asthma-related ED visits per month and 2.49 (95% CI, 1.11-5.60) times more asthma-related hospitalizations per month over the 26-week study period compared with those unexposed. Violence-exposed participants also had 1.71 (95% CI, 1.14-2.56) times more overall ED visits per month and 1.72 (95% CI, 0.95-3.11) times more overall hospitalizations per month from any cause. Asthma-related quality of life was lower in the violence-exposed participants (-0.40; 95% CI, -0.77 to -0.025; P = .04). Effect modification by depressive symptoms was only statistically significant for the ECV association with overall ED visits and quality-of-life outcomes (P < .01). CONCLUSION: In adults, ECV is associated with increased asthma hospitalizations and emergency care for asthma or any condition and with asthma-related quality of life.

Emotional and behavioral functioning of offspring of African American mothers with depression.

Extensive research demonstrates the negative impact of maternal depression on their offspring. Unfortunately, few studies have been explored in African American families. This study examined emotional and behavioral functioning among children of African American mothers with depression. African American mothers (n = 63), with a past year diagnosis of a depressive disorder, and one of their children (ages 7-14) completed behavioral rating scales in a cross-sectional design. Results showed that 6.5 and 15% scored within the clinical range for depression and anxiety symptoms, respectively. Approximately a third of the offspring reported suicidal ideation. Based on mothers' report, 25.4 and 20.6% of the offspring exhibited internalizing and externalizing symptoms in the clinical range, respectively. Offspring whose mothers were in treatment exhibited higher levels of self-reported anxiety symptoms. Offspring of African American mothers with depression were exhibiting socioemotional problems in ways that are similar to offspring of European American mothers with depression.

Invited commentary: pushing the mediation envelope.

The very insightful and clear paper by VanderWeele and Vansteelandt in this issue of the Journal (Am J Epidemiol. 2010;172(12):1339-1348) bridges the gap between biostatistics methodologists focusing on causal methods for mediation analyses and the practitioners of mediational analyses to the benefit of both groups. In an effort to continue the bridging of this gap, this invited commentary relates the important issue of "natural direct effects" to the well-known epidemiologic method of direct standardization. Additionally, attention is paid to the importance of temporal sequencing to help substantiate the mediation relations among the exposure, mediation, and outcome. A crucial mathematical distortion under the logistics model, called "absence of collapsibility," is noted in motivating VanderWeele and Vansteelandt's use of the log-linear model for comparing the effect of exposure adjusted for the mediator with the effect of exposure unadjusted for the mediator. It is also noted that this issue applies to one approach to assessing confounding. Finally, some issues are raised for consideration when testing the interaction between the exposure and mediator before assessing mediation.

The relationship of bipolar disorder lifetime duration and vascular burden to cognition in older adults.

OBJECTIVES: We describe the cognitive function of older adults presenting with bipolar disorder (BD) and mania and examine whether longer lifetime duration of BD is associated with greater cognitive dysfunction. We also examine whether there are negative, synergistic effects between lifetime duration of BD and vascular disease burden on cognition. METHODS: A total of 87 nondemented individuals with bipolar I disorder, age 60 years and older, experiencing manic, hypomanic, or mixed episodes, were assessed with the Dementia Rating Scale (DRS) and the Framingham Stroke Risk Profile (FSRP) as a measure of vascular disease burden. RESULTS: Subjects had a mean (SD) age of 68.7 (7.1) years and 13.6 (3.1) years of education; 50.6% (n = 44) were females, 89.7% (n = 78) were white, and 10.3% (n = 9) were black. They presented with overall and domain-specific cognitive impairment in memory, visuospatial ability, and executive function compared to age-adjusted norms. Lifetime duration of BD was not related to DRS total score, any other subscale scores, or vascular disease burden. FSRP scores were related to the DRS memory subscale scores, but not total scores or any other domain scores. A negative interactive effect between lifetime duration of BD and FSRP was only observed with the DRS construction subscale. CONCLUSIONS: In this study, lifetime duration of BD had no significant relationship with overall cognitive function in older nondemented adults. Greater vascular disease burden was associated with worse memory function. There was no synergistic relationship between lifetime duration of BD and vascular disease burden on overall cognition function. Addressing vascular disease, especially early in the course of BD, may mitigate cognitive impairment in older age.

Conceptual and methodological issues in designing a randomized, controlled treatment trial for geriatric bipolar disorder: GERI-BD.

AIM: This report considers the conceptual and methodological concerns confronting clinical investigators seeking to generate knowledge regarding the tolerability and benefits of pharmacotherapy in geriatric bipolar disorder (BD) patients. METHOD: There is continuing need for evidence-based guidelines derived from randomized controlled trials that will enhance drug treatment of geriatric BD patients. Therefore, we present the complex conceptual and methodological choices encountered in designing a multisite clinical trial and the decisions reached by the investigators with the intention that study findings be pertinent to, and can facilitate, routine treatment decisions. RESULTS: Guided by a literature review and input from peers, the tolerability and antimanic effects of lithium and valproate were judged to be the key mood stabilizers to investigate with regard to treating bipolar I disorder manic, mixed, and hypomanic states. The patient selection criteria are intended to generate a sample that not only experiences common treatment needs but also represents the variety of older patients seen in university-based clinical settings. The clinical protocol guides titration of lithium and valproate to target serum concentrations, with lower levels allowed when necessitated by limited tolerability. The protocol emphasizes initial monotherapy. However, augmentation with risperidone is permitted after three weeks when indicated by operational criteria. CONCLUSIONS: A randomized, controlled trial that both investigates commonly prescribed mood stabilizers and maximizes patient participation can meaningfully address high-priority clinical concerns directly relevant to the routine pharmacologic treatment of geriatric BD patients.