Impact of caregiver and parenting status on time trade-off and standard gamble utility scores for health state descriptions.

BACKGROUND: The purpose of this study was to examine the effect of caregiver status on time trade-off (TTO) and standard gamble (SG) health state utility scores. Respondents were categorized as caregivers if they reported that either children or adults depended on them for care. METHODS: This study was a secondary analysis of data from three studies in which general population samples rated health state descriptions. Study 1: UK; four osteoarthritis health states. Study 2: UK; three adult ADHD health states. Study 3: US; 16 schizophrenia health states. All three studies included time trade-off assessment. Study 1 also included standard gamble. Descriptive statistics were calculated to examine willingness to trade in TTO or gamble in SG. Utilities for caregivers and non-caregivers were compared using t-tests and ANCOVA models. RESULTS: There were 364 respondents including 106 caregivers (n = 30, 47, and 29 in Studies 1, 2, and 3) and 258 non-caregivers. Most caregivers were parents of dependent children (78.3%). Compared to non-caregivers, caregivers had more responses at the ceiling (i.e., utility = 0.95), indicating less willingness to trade time or gamble. All utilities were higher for caregivers than non-caregivers (mean utility difference between groups: 0.07 to 0.16 in Study 1 TTO; 0.03 to 0.17 in Study 1 SG; 0.06 to 0.10 in Study 2 TTO; 0.11 to 0.22 in Study 3 TTO). These differences were statistically significant for at least two health states in each study (p < 0.05). Results of sensitivity analyses with two caregiver subgroups (parents of dependent children and parents of any child regardless of whether the child was still dependent) followed the same pattern as results of the primary analysis. The parent subgroups were generally less willing to trade time or gamble (i.e., resulting in higher utility scores) than comparison groups of non-parents. CONCLUSIONS: Results indicate that caregiver status, including being a parent, influences responses in time trade-off health state valuation. Caregivers (i.e., predominantly parents) were less willing than non-caregivers to trade time, resulting in higher utility scores. This pattern was consistent across multiple health states in three studies. Standard gamble results followed similar patterns, but with less consistent differences between groups. It may be useful to consider parenting/caregiving status when collecting, interpreting, or using utility data because this demographic variable could influence results.

Depressive, functional status, and neuropsychiatric symptom trajectories before an Alzheimer's disease diagnosis.

OBJECTIVES: This short report relied on multiyear data from the National Alzheimer's Coordinating Center - Uniform Data Set (NACC-UDS) to examine whether significant changes occurred in functional status, neuropsychiatric symptoms, and depressive symptoms in the years before receiving an Alzheimer's disease (AD) diagnosis. METHOD: The secondary analysis used a retrospective cohort design. The NACC-UDS is a publicly accessible, longitudinal database that includes standardized data on neuropsychiatric symptoms, functional status, and depressive symptoms for Alzheimer's Disease Center (ADC) participants in the USA based on their annual visits from 2005 to 2011. ADC participants were considered diagnosed with AD if a follow-up data form indicated an affirmative response to whether the ADC participant had 'probable AD (National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)/Alzheimer's Disease and Related Disorders Association (ADRDA))' or 'possible AD (NINCDS/ADRDA).' This yielded an analytic sample of 2478 individuals (139 with an eventual probable AD diagnosis, 109 individuals with an eventual possible AD diagnosis, and 2230 without any AD diagnosis) representing a total of 11,358 visits/points of data. RESULTS: Multilevel linear models revealed significant decreases (p < 0.05) in functional status prior to a probable or possible AD diagnosis and significant increases in depressive symptoms prior to a probable AD diagnosis. DISCUSSION: Changes in functional and depressive symptoms were partly independent of cognitive decline. The longitudinal results lend additional support to conceptual and empirical models of pre-diagnosis declines in AD.

Potential Impact of Slowing Disease Progression in Early Symptomatic Alzheimer's Disease on Patient Quality of Life, Caregiver Time, and Total Societal Costs: Estimates Based on Findings from GERAS-US Study.

Background: Impact of Alzheimer's disease (AD) progression on patient health-related quality of life (HRQoL), caregiver time, and societal costs is not well characterized in early AD. Objective: To assess the association of change in cognition with HRQoL, caregiver time, and societal costs over 36 months, and estimate the impact of slowing disease progression on these outcomes. Methods: This post-hoc analysis included patients with amyloid-positive mild cognitive impairment (MCI) and mild AD dementia (MILD AD) from the 36-month GERAS-US study. Disease progression was assessed using the Mini-Mental State Examination score. Change in outcomes associated with slowing AD progression was estimated using coefficients from generalized linear models. Results: At baseline, 300 patients had MCI and 317 had MILD AD. Observed natural progression over 36 months was associated with: 5.1 point decline in the Bath Assessment of Subjective Quality of Life in Dementia (BASQID) score (for HRQoL), increase in 1,050 hours of total caregiver time, and $8,504 total societal costs for MCI; 6.6 point decline in the BASQID score, increase in 1,929 hours of total caregiver time, and $12,795 total societal costs for MILD AD per person. Slowing AD progression by 30% could result in per person savings in HRQoL decline, total caregiver time, and total societal costs: for MCI: 1.5 points, 315 hours, and $2,638; for MILD AD: 2.0 points, 579 hours, and $3,974. Conclusions: Slowing AD progression over 36 months could slow decline in HRQoL and save caregiver time and societal cost in patients with MCI and MILD AD.

Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework.

Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies-which was statistically significant for the comparison with teriflunomide-this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis.

The role of the FcGRIIIa polymorphism in modifying the association between treatment and outcome in patients with rheumatoid arthritis treated with rituximab versus TNF-α antagonist therapies.

OBJECTIVES: There is an association between the FcGRIIIa polymorphism and the development of rheumatoid arthritis (RA). Studies in non-Hodgkin lymphoma demonstrated a relationship between the FcGRIIIa polymorphism and response to anti-CD20 therapies. However, there are currently no published studies evaluating the relationship between this polymorphism and therapeutic response to treatment with anti-CD20 agents such as rituximab in RA. We conducted a study to identify if the FcGRIIIa polymorphism is associated with rituximab efficacy in patients with RA. METHODS: Subjects with RA treated with rituximab (cases, n=158) or TNF-α antagonist (controls, n=390) were recruited from the Consortium of Rheumatology Researchers of North America. The FcGRIIIa variant was genotyped for all subjects and longitudinal patient outcomes were assessed using the clinical disease activity index (CDAI). We used a linear regression random effects model to estimate CDAI scores over time with multiple time points nested within patient. RESULTS: Similar changes in CDAI were observed across the three FcGRIIIa genotypes for the rituximab treated group (VV [4.56, SD 14.5]), VF (7.44, SD 14.9) and FF (4.75, SD 10.8) (p >0.05)] and the TNF-α antagonist therapy treated group [VV (5.12, SD 14.6), VF (6.77, SD 15.9), and FF (4.36, SD 18.2) (p >0.05). Overall, there were similar changes in CDAI at 6 months for rituximab (-5.91, SD 14.1) and anti-TNFs (-5.77, SD 15.5) (p >0.05). The FcGRIIIa genotype was not significantly associated (p=0.86) with treatment response in rituximab treated RA patients compared with TNF-α antagonist therapy treated patients. Baseline CDAI and number of prior biologics were significant predictors of clinical response over time. CONCLUSIONS: Our finding emphasises the idea that determinants of response to treatment are complex and may be dependent upon genetic and phenotypic interactions. Future studies should analyse the interaction between the FcGRIIIa gene, other neighbouring polymorphisms and other phenotypic and environmental factors.

The longitudinal interplay between negative and positive symptom trajectories in patients under antipsychotic treatment: a post hoc analysis of data from a randomized, 1-year pragmatic trial.

BACKGROUND: Schizophrenia is a highly heterogeneous disorder with positive and negative symptoms being characteristic manifestations of the disease. While these two symptom domains are usually construed as distinct and orthogonal, little is known about the longitudinal pattern of negative symptoms and their linkage with the positive symptoms. This study assessed the temporal interplay between these two symptom domains and evaluated whether the improvements in these symptoms were inversely correlated or independent with each other. METHODS: This post hoc analysis used data from a multicenter, randomized, open-label, 1-year pragmatic trial of patients with schizophrenia spectrum disorder who were treated with first- and second-generation antipsychotics in the usual clinical settings. Data from all treatment groups were pooled resulting in 399 patients with complete data on both the negative and positive subscale scores from the Positive and Negative Syndrome Scale (PANSS). Individual-based growth mixture modeling combined with interplay matrix was used to identify the latent trajectory patterns in terms of both the negative and positive symptoms. Pearson correlation coefficients were calculated to examine the relationship between the changes of these two symptom domains within each combined trajectory pattern. RESULTS: We identified four distinct negative symptom trajectories and three positive symptom trajectories. The trajectory matrix formed 11 combined trajectory patterns, which evidenced that negative and positive symptom trajectories moved generally in parallel. Correlation coefficients for changes in negative and positive symptom subscale scores were positive and statistically significant (P < 0.05). Overall, the combined trajectories indicated three major distinct patterns: (1) dramatic and sustained early improvement in both negative and positive symptoms (n = 70, 18%), (2) mild and sustained improvement in negative and positive symptoms (n = 237, 59%), and (3) no improvement in either negative or positive symptoms (n = 82, 21%). CONCLUSIONS: This study of symptom trajectories over 1 year shows that changes in negative and positive symptoms were neither inversely nor independently related with each other. The positive association between these two symptom domains supports the notion that different symptom domains in schizophrenia may depend on each other through a unified upstream pathological disease process.

Relationship between muscle mass and muscle strength, and the impact of comorbidities: a population-based, cross-sectional study of older adults in the United States.

BACKGROUND: Loss of muscle mass and muscle strength are natural consequences of the aging process, accompanied by an increased prevalence of chronic health conditions. Research suggests that in the elderly, the presence of comorbidities may impact the muscle mass/strength relationship. The objectives of this study were to characterize the muscle mass/strength relationship in older adults in the USA and to examine the impact of a variety of comorbidities on this relationship. METHODS: Data were obtained from the National Health and Nutrition Examination Survey 1999-2002 databases. Subjects aged 50 years and older were included in the present study. Muscle mass was assessed by height-adjusted appendicular skeleton muscle mass (aASM) in kg/m2, as measured by dual-energy x-ray absorptiometry. Muscle strength was assessed via isokinetic quadriceps strength (IQS) in newton as measured by a dynamometer. The relationship between aASM and IQS was assessed adjusting for age and gender. The effects of a variety of comorbidities on IQS and/or on the relationship between IQS and aASM were assessed using multiple regression models. RESULTS: This study included 2,647 individuals, with a mean age of 62.6 years and 52.9% of whom were female. The mean (SE) aASM (kg/m2) was 7.3 (0.04), and the mean (SE) IQS (newton) was 365.0 (3.00). After adjusting for age and gender, the correlation coefficient between aASM and IQS was 0.365 (P < 0.001). Diabetes, coronary heart disease/congestive heart failure (CHD/CHF), and vision problems were significant predictors of lower muscle strength (P < 0.05) in the multiple regression models that adjusted for age, gender, and aASM, and obesity significantly modified the relationship between aASM and IQS (P < 0.05). CONCLUSIONS: Among individuals aged 50 and older in the US, muscle mass and muscle strength are positively correlated, independent of the associations of age and gender with muscle mass and strength. A variety of comorbid medical conditions serve as independent predictors of lower muscle strength (e.g., diabetes, CHD/CHF, vision problems) and/or modify the relationship between muscle mass and muscle strength (e.g., obesity).

Factors predicting change in frequency of heavy drinking days among alcohol-dependent participants in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

AIMS: To discover the predictors of change in the frequency of heavy drinking (HD) over a 4-year period in alcohol dependent (AD)-individuals identified in the general population, namely, among participants of the US National Epidemiologic Survey on Alcohol and Related Conditions interviewed at Wave 1 (2001-2002) and at Wave 2 (2004-2005). METHODS: The study cohort included subjects meeting DSM-IV criteria for AD in the past year at Wave 1 (n = 1484), who were present at Wave 2 (n = 1172) and had complete data on factors of interest (n = 1123). Frequency of HD was defined as the number of HD days (HDD) (≥5 drinks per day for men and ≥4 for women). Change in frequency of HDD from baseline (Wave 1) to ~3 years later (Wave 2) was determined. An analysis of covariance model (ANCOVA), adjusting for baseline HDD, was used to examine individual factors associated with change in frequency of HDD, while a multivariable regression model was employed to assess factors associated with change in frequency of HDD simultaneously. RESULTS: Overall, there was a decrease in mean (SE) HDD [from 119.4 (1.8) at Wave 1 to 82.5 (2.1) at Wave 2, P < 0.0001]. Compared with smokers, non-smokers had a mean (SE) HDD reduction of 13.4 (6.7), P < 0.05. AD criteria of tolerance was significantly associated (P < 0.05) with less reduction in HDD. Change in depression/dysthymia status was associated with greater reduction in HDD in the ANCOVA model, but not the fully adjusted multivariable model. CONCLUSION: Findings from this study suggest that smoking and AD criteria of tolerance are important factors for long-term follow-up of AD patients and they should influence the selection of the kinds of interventions required for AD patients to achieve maximal therapeutic benefit.

Factors associated with treatment of women with osteoporosis or osteopenia from a national survey.

BACKGROUND: Health outcomes could be improved if women at high risk for osteoporotic fracture were matched to effective treatment. This study determined the extent to which treatment for osteoporosis/osteopenia corresponded to the presence of specific risk factors for osteoporotic fracture. METHODS: This retrospective analysis of the United States 2007 National Health and Wellness Survey included women age ≥ 40 years who reported having a diagnosis of osteoporosis (69% of 3276) or osteopenia (31% of 3276). Patients were stratified by whether they were or were not taking prescription treatment for osteoporosis/osteopenia. Using 34 patient characteristics as covariates, logistic regression was used to determine factors associated with treatment. RESULTS: Current prescription treatment was reported by 1800 of 3276 (54.9%) women with osteoporosis/osteopenia. The following factors were associated with receiving prescription treatment: patient-reported diagnosis of osteoporosis (versus osteopenia); previous bone mineral density test; ≥ 2 fractures since age 50; older age; lower body mass index; better physical functioning; postmenopausal status; family history of osteoporosis; fewer comorbidities; prescription insurance coverage; higher total prescription count; higher ratio of prescription costs to monthly income; higher income; single status; previous visit to a rheumatologist or gynecologist; and 1 or 2 outpatient visits to healthcare provider (vs. none) in the prior 6 months. Glucocorticoid, tobacco, and daily alcohol use were risk factors for fracture that were not associated with treatment. CONCLUSIONS: There is a mismatch between those women who could benefit from treatment for osteoporosis and those who are actually treated. For example, self-reported use of glucocorticoids, tobacco, and alcohol were not associated with prescription treatment of osteoporosis. Other clinical and socioeconomic factors were associated with treatment (e.g. prescription drug coverage and higher income) or not (e.g. comorbid osteoarthritis and anxiety) and could be opportunities to improve care.

Demonstration of Clinical Meaningfulness of the Integrated Alzheimer's Disease Rating Scale (iADRS): Association Between Change in iADRS Scores and Patient and Caregiver Health Outcomes.

BACKGROUND: The integrated Alzheimer's Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures. OBJECTIVE: To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study. METHODS: Analysis of covariate (ANCOVA) models were used to estimate the relationship between 18-month change on the iADRS and changes on health outcome measures (related to cost, quality of life, and caregiver burden). The regression coefficients for the iADRS were used to compute impact of natural disease progression and disease-modifying treatment on health outcomes. Additional ANCOVAs were conducted to understand whether cognition and/or function was the underlying explanation of any association between iADRS and health outcome change. RESULTS: Across datasets and disease stages, a worsening on the iADRS was significantly associated with increased societal costs, caregiver burden (time and distress) and worsening in measures of patient quality of life. CONCLUSION: Decline on the iADRS was associated with worsening in health outcome measures. These findings suggest that the iADRS can be used in clinical trials as a proxy measure of clinically meaningful outcomes of AD progression.

Assessing the Cost-effectiveness of a Hypothetical Disease-modifying Therapy With Limited Duration for the Treatment of Early Symptomatic Alzheimer Disease.

PURPOSE: Clinical trials have produced promising results for disease-modifying therapies (DMTs) for Alzheimer's disease (AD); however, the evidence on their potential cost-effectiveness is limited. This study assesses the cost-effectiveness of a hypothetical DMT with a limited treatment duration in AD. METHODS: We developed a Markov state-transition model to estimate the cost-effectiveness of a hypothetical DMT plus best supportive care (BSC) versus BSC alone among Americans living with mild cognitive impairment (MCI) due to AD or mild AD. AD states included MCI due to AD, mild AD, moderate AD, severe AD, and death. A hypothetical DMT was assumed to confer a 30% reduction in progression from MCI and mild AD. The base case annual drug acquisition cost was assumed to be $56,000. Other medical and indirect costs were obtained from published literature or list prices. Utilities for patients and caregivers were obtained from the published literature and varied by AD state and care setting (community care or long-term care). We considered 3 DMT treatment strategies: (1) treatment administered until patients reached severe AD (continuous strategy), (2) treatment administered for a maximum duration of 18 months or when patients reached severe AD (fixed-duration strategy), and (3) 40% of patients discontinuing treatment at 6 months because of amyloid plaque clearance and the remaining patients continuing treatment until 18 months or until they reached severe AD (test-and-discontinue strategy). Incremental cost-effectiveness ratios (ICERs) were calculated as the incremental cost per quality-adjusted life-year (QALY) gained. FINDINGS: From the health care sector perspective, continuous treatment with a hypothetical DMT versus BSC resulted in an ICER of $612,354 per QALY gained. The ICER decreased to $157,288 per QALY gained in the fixed-duration strategy, driven by large reductions in treatment costs. With 40% of patients discontinuing treatment at 6 months (test-and-discontinue strategy), the ICER was $125,631 per QALY gained. In sensitivity and scenario analyses, the ICER was the most sensitive to changes in treatment efficacy, treatment cost, and the initial population AD state distribution. From the modified societal perspective, ICERs were 6.3%, 20.4%, and 25.1% lower than those from the health care sector perspective for the continuous, fixed-duration, and test-and-discontinue strategies, respectively. IMPLICATIONS: Under a set of assumptions for annual treatment costs and the magnitude and duration of treatment efficacy, DMTs used for a limited duration may deliver value consistent with accepted US cost-effectiveness thresholds.

Does caregiver burden mediate the effects of behavioral disturbances on nursing home admission?

OBJECTIVES: The primary objective of this study was to determine whether caregiving burden mediated the relationship between specific behavior disturbances and time to nursing home admission (NHA) for persons with dementia (i.e., Alzheimer disease or a related disorder). DESIGN: The study used secondary longitudinal data from the Medicare Alzheimer's Disease Demonstration, a Medicare-covered home care benefit and case management program for family caregivers of persons with dementia. Primary caregivers of persons with dementia were assessed via in-person and telephone interviews every 6 months over a 3-year period. SETTING: Dementia caregivers were recruited from eight catchment areas throughout the United States. PARTICIPANTS: The baseline sample included 5,831 dementia caregivers. Just more than 40% (43.9%; N = 2,556) of persons with dementia permanently entered a nursing home during the 3-year study period. MEASUREMENTS: Individual behavior problems were measured with the Memory and Behavior Problem Checklist. Caregiving burden was assessed with a short version of the Zarit Burden Inventory. Key covariates, including sociodemographic background, functional status, and service utilization, were also considered. RESULTS: Event history analyses revealed that time-varying measures of caregiver burden fully mediated the relationship between four behavioral disturbances (episodes of combativeness, property destruction, repetitive questions, and reliving the past) and NHA. CONCLUSIONS: The findings highlight the multifaceted, complex pathway to NHA for persons with dementia and their family caregivers. The results emphasize the need for comprehensive treatment approaches that incorporate the burden of caregivers and the behavioral/psychiatric symptoms of persons with dementia simultaneously.

A Review of Interventional Trials in Youth-Onset Type 2 Diabetes: Challenges and Opportunities.

INTRODUCTION: In recent decades, the dramatic rise of obesity among youth in the US has been accompanied by a rise in the prevalence of type 2 diabetes (T2D) in this population. This alarming trend underscores the importance of conducting trials to evaluate new therapies in children with T2D. METHODS: A targeted review of peer-reviewed literature and trials registered on www.clinicaltrials.gov was conducted in January 2021 to identify pharmaceutical interventional studies in youth with T2D. Information regarding enrollment data, study design elements, subjects' baseline characteristics, and key treatment outcomes was documented. RESULTS: Among the 16 clinical studies included in this review, only five appeared to meet projected enrollment targets in < 4 years. Although three other studies met recruitment targets, two took approximately 5 years to complete and the third took nearly 10 years. CONCLUSIONS: Despite legislation requiring evaluation of pharmaceutical treatments in pediatric populations, surprisingly few interventional studies have been conducted in children with T2D. This review highlights that recruitment challenges may be impeding the conduct and completion of interventional studies. Consequently, few pharmaceutical treatments have been proven to be effective and approved for children with T2D. Metformin and liraglutide remain the only non-insulin treatments formally approved in the US for use in this population. More clinical research is needed to support regulatory decision-making as well as treatment decisions for children with T2D in clinical settings. Sponsors and investigators will need to implement strategies for improving trial enrollment as well as work with regulatory agencies to develop novel study designs that may require fewer patients.

Prevalence and cardiometabolic correlates of ketohexokinase gene variants among UK Biobank participants.

Essential fructosuria (EF) is a benign, asymptomatic, autosomal recessive condition caused by loss-of-function variants in the ketohexokinase gene and characterized by intermittent appearance of fructose in the urine. Despite a basic understanding of the genetic and molecular basis of EF, relatively little is known about the long-term clinical consequences of ketohexokinase gene variants. We examined the frequency of ketohexokinase variants in the UK Biobank sample and compared the cardiometabolic profiles of groups of individuals with and without these variants alone or in combination. Study cohorts consisted of groups of participants defined based on the presence of one or more of the five ketohexokinase gene variants tested for in the Affymetrix assays used by the UK Biobank. The rs2304681:G>A (p.Val49Ile) variant was present on more than one-third (36.8%) of chromosomes; other variant alleles were rare (<1%). No participants with the compound heterozygous genotype present in subjects exhibiting the EF phenotype in the literature (Gly40Arg/Ala43Thr) were identified. The rs2304681:G>A (p.Val49Ile), rs41288797 (p.Val188Met), and rs114353144 (p.Val264Ile) variants were more common in white versus non-white participants. Otherwise, few statistically or clinically significant differences were observed after adjustment for multiple comparisons. These findings reinforce the current understanding of EF as a rare, benign, autosomal recessive condition.

The effects of incident and persistent behavioral problems on change in caregiver burden and nursing home admission of persons with dementia.

BACKGROUND: The individual contributions of behavior problems to key and related outcomes in dementia, such as nursing home admission (NHA) or caregiver burden, remain unclear. OBJECTIVES: This study sought to determine the ramifications of temporal change in individual behavior problems when accounting for increases in caregiver burden and time to NHA. Although burden is sometimes conceptualized as an antecedent to NHA, it has also emerged as a relevant outcome in dementia caregiving research. METHODS: A sample of 4545 dementia caregivers who participated in the Medicare Alzheimer disease Demonstration Evaluation was selected for this secondary analysis. Various patterns of change in individual behavior problems were considered as predictors of increases in caregiver burden and time to NHA over a 3-year period via mixed effects and Cox proportional hazards models, respectively. RESULTS: Caregivers who did not indicate a care recipient's dangerous behavior initially but did so subsequently (ie, an "incident" behavior problem) were more likely to experience increases in burden (P < 0.0026). Alternatively, the persistent occurrence of behavior disturbances (particularly memory problems) emerged as the strongest predictors of time to NHA. DISCUSSION: The findings of this study suggest the benefit of examining temporal patterns of individual behavioral disturbances, and that incident and persistent problems account for different dementia outcomes over time. Considering the temporal ramifications and potency of specific behavior problems can facilitate the targeted and timely delivery of effective clinical interventions.

ADHD and anger contexts: electronic diary mood reports from mothers and children.

OBJECTIVE: Using electronic diaries (eDiaries), this study examined temporal links between child and maternal anger, as well as positive mood and perceived stress, in children with attention-deficit/hyperactivity disorder (ADHD) versus comparison peers. METHODS: Across 7 days, half-hourly eDiaries were completed independently by mothers and their 8-12-year-old children (51 receiving medication for ADHD and 58 comparison peers). RESULTS: Cross-informant analyses revealed systematic patterns of negative maternal moods in relation to child anger in both groups along with evidence of slower recovery in the ADHD group. Analogously, for both groups, children's anger reports increased and good-mood reports decreased in relation to maternal anger, whereas elevated stress in relation to maternal anger was restricted to children with ADHD. CONCLUSIONS: The findings indicate that a negative affective climate is more likely to persist in ADHD than in comparison families. They also affirm the utility of child as well as parent eDiary reports and suggest that children may be willing to report low positive mood when reluctant to report negative mood. The promise of incorporating real-time data on mood patterning into tailored treatments for children with ADHD and their families is discussed.

A retrospective claims analysis of combination therapy in the treatment of adult attention-deficit/hyperactivity disorder (ADHD).

BACKGROUND: Combination therapy in managing psychiatric disorders is not uncommon. While combination therapy has been documented for depression and schizophrenia, little is known about combination therapy practices in managing attention-deficit/hyperactivity disorder (ADHD). This study seeks to quantify the combination use of ADHD medications and to understand predictors of combination therapy. METHODS: Prescription dispensing events were drawn from a U.S. national claims database including over 80 managed-care plans. Patients studied were age 18 or over with at least 1 medical claim with a diagnosis of ADHD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 314.0), a pharmacy claim for ADHD medication during the study period July 2003 to June 2004, and continuous enrollment 6 months prior to and throughout the study period. Dispensing events were grouped into 6 categories: atomoxetine (ATX), long-acting stimulants (LAS), intermediate-acting stimulants (IAS), short-acting stimulants (SAS), bupropion (BUP), and Alpha-2 Adrenergic Agonists (A2A). Events were assigned to calendar months, and months with combined use from multiple categories within patient were identified. Predictors of combination therapy for LAS and for ATX were modeled for patients covered by commercial plans using logistic regression in a generalized estimating equations framework to adjust for within-patient correlation between months of observation. Factors included age, gender, presence of the hyperactive component of ADHD, prior diagnoses for psychiatric disorders, claims history of recent psychiatric visit, insurance plan type, and geographic region. RESULTS: There were 18,609 patients identified representing a total of 11,886 months of therapy with ATX; 40,949 months with LAS; 13,622 months with IAS; 38,141 months with SAS; 22,087 months with BUP; and 1,916 months with A2A. Combination therapy was present in 19.7% of continuing months (months after the first month of therapy) for ATX, 21.0% for LAS, 27.4% for IAS, 23.1% for SAS, 36.9% for BUP, and 53.0% for A2A.For patients receiving LAS, being age 25-44 or age 45 and older versus being 18-24 years old, seeing a psychiatrist, having comorbid depression, or having point-of-service coverage versus a Health Maintenance Organization (HMO) resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD.For patients receiving ATX, being age 25-44 or age 45 and older versus being 18-24 years old, seeing a psychiatrist, having a hyperactive component to ADHD, or having comorbid depression resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD. CONCLUSION: ATX and LAS are the most likely drugs to be used as monotherapy. Factors predicting combination use were similar for months in which ATX was used and for months in which LAS was used except that a hyperactive component to ADHD predicted increased combination use for ATX but not for LAS.

Estimating the distribution of a novel clinical biomarker (FGF-23) in the US population using findings from a regional research registry.

Evidence of involvement of novel biomarkers in disease pathogenesis from research cohorts often precedes an understanding of their distributions in broader populations. This study aimed to estimate the distribution of fibroblast growth factor 23 (FGF-23), an endocrine hormone that helps to regulate serum phosphate levels, in the overall US population and in important subgroups. We used a predictive model generated using data from the Framingham Health Study to estimate FGF-23 values for adults in the US National Health and Nutrition Examination Survey and the size of patient subgroups with levels of FGF-23 above selected thresholds. To assess the face validity of our FGF-23 estimates, we examined the relationship between estimated FGF-23 and cardiovascular and all-cause mortality within NHANES using Kaplan-Meier estimates and Cox proportional-hazards regression models and compared it to that observed in Framingham. Estimated FGF-23 values from NHANES were lower (median [interquartile range] 47.4 [35.8, 64.0] vs. 67.0 [54.0, 85.0] RU/mL) than the observed FGF-23 values from the Framingham cohort. Age- and sex-adjusted 10-year all-cause mortality was significantly higher (hazard ratio 2.43 [95% confidence interval: 1.42, 4.16]) for subjects with estimated FGF-23 levels in the highest versus lowest quartile. Estimating the distribution of biomarker values in the general population by applying predictive equations from smaller research cohorts is feasible and can inform drug research decision making.

Application of a decision support tool for anticoagulation in patients with non-valvular atrial fibrillation.

BACKGROUND: Atrial fibrillation affects more than two million Americans and results in a fivefold increased rate of embolic strokes. The efficacy of adjusted dose warfarin is well documented, yet many patients are not receiving treatment consistent with guidelines. The use of a patient-specific computerized decision support tool may aid in closing the knowledge gap regarding the best treatment for a patient. METHODS: This retrospective, observational cohort analysis of 6,123 Ohio Medicaid patients used a patient-specific computerized decision support tool that automated the complex risk-benefit analysis for anticoagulation. Adverse outcomes included acute stroke, major gastrointestinal bleeding, and intracranial hemorrhage. Cox proportional hazards models were developed to compare the group of patients who received warfarin treatment with those who did not receive warfarin treatment, stratified by the decision support tool's recommendation. RESULTS: Our decision support tool recommended warfarin for 3,008 patients (49%); however, only 9.9% received warfarin. In patients for whom anticoagulation was recommended by the decision support tool, there was a trend towards a decreased hazard for stroke with actual warfarin treatment (hazard ratio 0.90) without significant increase in gastrointestinal hemorrhage (0.87). In contrast, in patients for whom the tool recommended no anticoagulation, receipt of warfarin was associated with statistically significant increased hazard of gastrointestinal bleeding (1.54, p = 0.03). CONCLUSIONS: We have shown that our atrial fibrillation decision support tool is a useful predictor of those at risk of major bleeding for whom anticoagulation may not necessarily be beneficial. It may aid in weighing the benefits versus risks of anticoagulation treatment.

Characteristics of patients initiating raloxifene compared to those initiating bisphosphonates.

BACKGROUND: Both raloxifene and bisphosphonates are indicated for the prevention and treatment of postmenopausal osteoporosis, however these medications have different efficacy and safety profiles. It is plausible that physicians would prescribe these agents to optimize the benefit/risk profile for individual patients. The objective of this study was to compare demographic and clinical characteristics of patients initiating raloxifene with those of patients initiating bisphosphonates for the prevention and treatment of osteoporosis. METHODS: This study was conducted using a retrospective cohort design. Female beneficiaries (45 years and older) with at least one claim for raloxifene or a bisphosphonate in 2003 through 2005 and continuous enrollment in the previous 12 months and subsequent 6 months were identified using a collection of large national commercial, Medicare supplemental, and Medicaid administrative claims databases (MarketScan). Patients were divided into two cohorts, a combined commercial/Medicare cohort and a Medicaid cohort. Within each cohort, characteristics (demographic, clinical, and resource utilization) of patients initiating raloxifene were compared to those of patients initiating bisphosphonate therapy. Group comparisons were made using chi-square tests for proportions of categorical measures and Wilcoxon rank-sum tests for continuous variables. Logistic regression was used to simultaneously examine factors independently associated with initiation of raloxifene versus a bisphosphonate. RESULTS: Within both the commercial/Medicare and Medicaid cohorts, raloxifene patients were younger, had fewer comorbid conditions, and fewer pre-existing fractures than bisphosphonate patients. Raloxifene patients in both cohorts were less likely to have had a bone mineral density (BMD) screening in the previous year than were bisphosphonate patients, and were also more likely to have used estrogen or estrogen/progestin therapy in the previous 12 months. These differences remained statistically significant in the multivariate model. CONCLUSION: In this sample of patients enrolled in commercial, Medicare, and Medicaid plans, patients who initiated raloxifene treatment differed from those initiating bisphosphonates. Raloxifene patients were younger, had better overall health status and appeared to be less likely to have risk factors for new osteoporotic fractures than bisphosphonate patients. Differences in the clinical profiles of these agents may impact prescribing decisions. Investigators using observational data to make comparisons of treatment outcomes associated with these medications should take these important differences in patient characteristics into consideration.