Composite measures of pain, anxiety, and depressive (PAD) symptoms: Construct and predictive validity.

OBJECTIVE: Pain, anxiety, and depression (PAD) are common, co-occurring symptoms that adversely affect one another and may respond to common treatments. PAD composite measures would be useful for tracking treatment response in patients with PAD symptoms. The goal of this study is to compare 3 different PAD composite scales in terms of construct validity, responsiveness, and utility in predicting global improvement. METHOD: The sample consisted of 294 primary care patients enrolled in a telecare trial for treating pain, anxiety, and depression. Assessments at baseline and 3 months included the Brief Pain Inventory, PHQ-9 depression scale, GAD-7 anxiety scale, PROMIS measures, Medical Outcomes Study Short-Form items, disability measures, and patient-reported global improvement. Construct validity of the PAD composite measures, their responsiveness, and their ability to predict global improvement was analyzed using Pearson correlations, standardized response means, and receiver operating characteristics analysis. RESULTS: PAD composite measures correlated strongly with one another, and moderately with measures of function, vitality, and disability. Each PAD composite measure demonstrated similar responsiveness in detecting improvement at 3 months as assessed by standardized response means (SRMs) and area under the curve (AUC analyses).The SRMs for partial and substantial global improvement corresponded to moderate (Cohen's d of 0.58 to 0.69) and large (0.81 to 0.93) effect sizes, respectively. CONCLUSIONS: Three different PAD composite measures demonstrate good construct validity as well as responsiveness in detecting global improvement of pain, anxiety and depression at 3 months.

Comparison of nonlinear curves and surfaces.

Estimation of nonlinear curves and surfaces has long been the focus of semiparametric and nonparametric regression analysis. What has been less studied is the comparison of nonlinear functions. In lower-dimensional situations, inference typically involves comparisons of curves and surfaces. The existing comparative procedures are subject to various limitations, and few computational tools have been made available for off-the-shelf use. To address these limitations, two modified testing procedures for nonlinear curve and surface comparisons are proposed. The proposed computational tools are implemented in an R package, with a syntax similar to that of the commonly used model fitting packages. An R Shiny application is provided with an interactive interface for analysts who do not use R. The new tests are consistent against fixed alternative hypotheses. Theoretical details are presented in an appendix. Operating characteristics of the proposed tests are assessed against the existing methods. Applications of the methods are illustrated through real data examples.

Telecare management of pain and mood symptoms: Adherence, utility, and patient satisfaction.

INTRODUCTION: Pain, depression, and anxiety are prominent symptoms that frequently co-occur, causing significant debilitation and frequent primary care visits. This paper examines the acceptability of telecare and self-management modules in managing these conditions in a randomized trial. METHODS: The Comprehensive Management of Mood and Physical Symptoms (CAMMPS) trial compared an automated symptom management (ASM) plus self-management intervention with a comprehensive symptom management (CSM) intervention that added telecare facilitation of enhanced services. Data from the CAMMPS trial were analysed to compare the acceptability of these two interventions as indicated by utilization and patient satisfaction surveys. RESULTS: The mean number of automated reports completed was similar between the CSM and ASM groups (14.5 vs 14.0). Responses designated with clinically relevant "red alerts" (i.e. patient reports warranting an expedited nurse contact) were more frequent in the CSM group (10.2 vs 8.3). The CSM and ASM groups completed a similar number of the nine self-management modules (6.3 vs 5.8). The mean helpfulness score across all modules was higher in the CSM group than in the ASM group (1.8 vs 1.5; p = .003). The most common feedback suggestion from the ASM group was to have more personal interaction, while participants from both groups commonly suggested technical improvements or requests for more flexible timing of calls. DISCUSSION: Participants generally found both interventions satisfactory, with a trend in satisfaction data suggesting that patients tended to find the CSM intervention more helpful.

Comparative Responsiveness and Minimally Important Difference of Common Anxiety Measures.

BACKGROUND: Anxiety is one of the most prevalent mental disorders and accounts for substantial disability as well as increased health care costs. This study examines the minimally important difference (MID) and responsiveness of 6 commonly used anxiety scales. METHODS: The sample comprised 294 patients from 6 primary care clinics in a single VA medical center who were enrolled in a telecare trial for treatment of chronic musculoskeletal pain and comorbid depression and/or anxiety. The measures assessed were the Patient Reported Outcomes Measurement Information System (PROMIS) 4-item, 6-item, and 8-item anxiety scales; the Generalized Anxiety Disorder 7-item scale (GAD-7); the Symptom Checklist anxiety subscale (SCL); the Posttraumatic Stress Disorder Checklist (PCL); the Short Form (SF)-36 Mental Health subscale; and the SF-12 Mental Component Summary (MCS). Validity was assessed with correlations of these measures with one another and with measures of quality of life and disability. MID was estimated by triangulating several methods. Responsiveness was evaluated by comparing: (a) the standardized response means for patients who reported their mood as being better, the same, or worse at 3 months; (b) the area under the curve for patients who had improved (better) versus those who had not (same/worse). RESULTS: Convergent and construct validity was supported by strong correlations of the anxiety measures with one another and moderate correlations with quality of life and disability measures, respectively. All measures differentiated patients who reported global improvement at 3 months from those who were unchanged, but were less able to distinguish worsening from no change. The area under the curves showed comparable responsiveness of the scales. The estimated MID was 4 for the PROMIS scales; 3 for the GAD-7; 6 for the PCL; 9 for the SF-36 mental health subscale; 5 for the MCS score, and 0.3 for the SCL anxiety scale. CONCLUSIONS: Six commonly used anxiety scales demonstrate similar responsiveness, and estimated MIDs can be used to gauge anxiety change in clinical research and practice.

Assessing depression improvement with the remission evaluation and mood inventory tool (REMIT).

OBJECTIVE: The Remission Evaluation and Mood Inventory Tool (REMIT) was developed as a brief complementary measure to provide a more robust assessment of depression improvement than tracking DSM-V symptom improvement alone. This study provides further validation of the REMIT tool and examines its utility in predicting depression improvement. METHODS: The sample comprised 294 primary care patients enrolled in a telecare trial of pain plus depression and/or anxiety. Assessments collected included: REMIT, PHQ-9 and measures assessing anxiety, pain, sleep, fatigue, somatization, health-related quality of life and disability. Data was analyzed to assess the REMIT's validity, its minimally important difference (MID), and its utility in predicting 6-month depression improvement. RESULTS: Convergent and construct validity of REMIT was supported by moderate correlations with mental health measures and weaker correlation with physical health measures. MID of approximately 2 points for REMIT was estimated by two metrics: 0.5 standard deviation and 1 standard error of measurement. Both baseline and 3-month change in REMIT scores predicted depression improvement at 6 months. Indeed, REMIT was as good or better predictor than the PHQ-9. CONCLUSION: The REMIT measure is a brief 5-item tool that augments core DSM-V symptom-oriented metrics in assessing and predicting recovery from major depression.

Automated Self-management (ASM) vs. ASM-Enhanced Collaborative Care for Chronic Pain and Mood Symptoms: the CAMMPS Randomized Clinical Trial.

BACKGROUND: Chronic musculoskeletal pain is often accompanied by depression or anxiety wherein co-occurring pain and mood symptoms can be more difficult to treat than either alone. However, few clinical trials have examined interventions that simultaneously target both pain and mood conditions. OBJECTIVE: To determine the comparative effectiveness of automated self-management (ASM) vs. ASM-enhanced collaborative care. DESIGN: Randomized clinical trial conducted in six primary care clinics in a VA medical center. PARTICIPANTS: Two hundred ninety-four patients with chronic musculoskeletal pain of at least moderate intensity and clinically significant depressive and/or anxiety symptoms. INTERVENTION: ASM consisted of automated monitoring and 9 web-based self-management modules. Comprehensive symptom management (CSM) combined ASM with collaborative care management by a nurse-physician team. Both interventions were delivered for 12 months. MAIN MEASURES: Primary outcome was a composite pain-anxiety-depression (PAD) z-score consisting of the mean of the BPI, PHQ-9, and GAD-7 z-scores: 0.2, 0.5, and 0.8 represent potentially small, moderate, and large clinical differences. Secondary outcomes included global improvement, health-related quality of life, treatment satisfaction, and health services use. KEY RESULTS: Both CSM and ASM groups had moderate PAD score improvement at 12 months (z = - 0.65 and - 0.52, respectively). Compared to the ASM group, the CSM group had a - 0.23 (95% CI, - 0.38 to - 0.08; overall P = .003) greater decline in composite PAD z-score over 12 months. CSM patients were also more likely to report global improvement and less likely to report worsening at 6 (P = .004) and 12 months (P = .013). CONCLUSIONS: Two intervention models relying heavily on telecare delivery but differing in resource intensity both produced moderate improvements in pain and mood symptoms. However, the model combining collaborative care led by a nurse-physician team with web-based self-management was superior to self-management alone. TRIAL REGISTRATION: ClinicalTrials.gov : NCT0175730.

Comparative validity and responsiveness of PHQ-ADS and other composite anxiety-depression measures.

BACKGROUND: Composite measures that assess the overall burden of anxiety and depressive symptoms have been infrequently evaluated in the same study. The objective of this study was to compare the validity and responsiveness of the Patient Health Questionnaire Anxiety-Depression Scale (PHQ-ADS) and other composite anxiety-depression measures. METHODS: The sample comprised 256 primary care patients enrolled in a telecare trial of chronic musculoskeletal pain and comorbid depression and/or anxiety. Measures included the PHQ-ADS; the 8-item and 4-item depression and anxiety scales from the PROMIS profiles; the PHQ-anxiety-depression scale (PHQ-4); the SF-36 Mental Health scale; and the SF-12 Mental Component Summary scale. Correlations among these measures and health-related quality of life measures were examined. Responsiveness was evaluated by standardized response means, area under the curve (AUC) analyses, and treatment effect sizes in the trial. RESULTS: Convergent and construct validity was supported by strong correlations of the composite depression-anxiety measures with one another and moderate correlations with health-related quality of life measures, respectively. All composite measures differentiated patients who were better at 3 months, whereas the PHQ-ADS and PHQ-4 also distinguished the subgroup that had worsened. AUCs for composite measures were generally similar, whereas treatment effect sizes were largest for the PHQ-ADS. LIMITATIONS: The study sample was predominantly male veterans enrolled from primary care who had chronic musculoskeletal pain and moderate levels of depression and anxiety. CONCLUSIONS: Composite depression and anxiety scales are valid and responsive measures that may be useful as outcomes in research and clinical practice.

Sample enrichment for clinical trials to show delay of onset in huntington disease.

BACKGROUND: Disease-modifying clinical trials in persons without symptoms are often limited in methods to assess the impact associated with experimental therapeutics. This study suggests sample enrichment approaches to facilitate preventive trials to delay disease onset in individuals with the dominant gene for Huntington disease. METHODS: Using published onset prediction indexes, we conducted the receiver operating curve analysis for diagnosis within a 3-year clinical trial time frame. We determined optimal cut points on the indexes for participant recruitment and then conducted sample size and power calculations to detect varying effect sizes for treatment efficacy in reducing 3-year rates of disease onset (or diagnosis). RESULTS: Area under the curve for 3 onset prediction indexes all demonstrated excellent value in sample enrichment methodology, with the best-performing index being the multivariate risk score (MRS). CONCLUSIONS: This study showed that conducting an intervention trial in premanifest and prodromal individuals with the gene expansion for Huntington disease is highly feasible using sample enrichment recruitment methods. Ongoing natural history studies are highly likely to indicate additional markers of disease prior to diagnosis. Statistical modeling of identified markers can facilitate participant enrichment to increase the likelihood of detecting a difference between treatment arms in a cost-effective and efficient manner. Such variations may expedite translation of emerging therapies to persons in an earlier phase of the disease. TRIAL REGISTRATION: PREDICT-HD is registered with www.clinicaltrials.gov, number NCT00051324. © 2019 International Parkinson and Movement Disorder Society.

Clinical Characteristics and Outcomes of Mild to Moderate Alcoholic Hepatitis.

INTRODUCTION & AIM: Much is known about alcoholic hepatitis (AH) that is severe enough to require hospitalization. The characteristics of individuals with alcoholic hepatitis presenting with mild to moderate severity are not well understood. In this study we investigated the risk factors, characteristics, and outcomes of mild to moderate AH. METHODS: Two hundred and fifty five Individuals with AH enrolled into a multicenter, prospective, observational study between 12/2014 and 4/2018 were included. Participants were seen at enrollment, 6 months, and 12 months. Mild to moderate AH (M-AH) was defined as MELD ≤ 20 at presentation whereas severe AH as MELD ≥ 21. RESULTS: One hundred individuals had M-AH whereas 155 had severe AH. Individuals with M-AH were older (49 vs 44 years, p=0.01), had lower BMI (27 vs 31 kg/m2, p=0.0007) and more likely to be male (68% vs 55%, p=0.046) compared to severe AH group. A higher proportion in M-AH group consumed coffee in the last 5 years compared to the severe AH (29% vs 18%, p=0.03), and fewer had PNPLA3 risk allele G (p=0.019) compared to the severe AH group. Average drinks per drinking day (12.9 vs 10.7, p=0.13) and total number of drinks in last 30 day period (331 vs 280, p=0.14) were not different between two groups. Compared to severe AH, patients with M-AH had significantly lower mortality at 30 days (2% vs. 13.6%), 90 days (3% vs. 22.6%), and 12 months (10.4% vs. 31.4%) (p <0.001 for all). CONCLUSIONS: Individuals with mild to moderate AH were older, less obese, drank coffee more often and carried more favorable PNPLA3 genotype compared to severe AH, despite similar alcohol consumption. Mild to moderate AH had substantial mortality with one in ten dying by 12 months. (Word Count 286).

Posttraumatic Stress Disorder in Patients with Heavy Alcohol Consumption and Alcoholic Hepatitis.

BACKGROUND: Lifetime prevalence of posttraumatic stress disorder (PTSD) in the general population is reported to be 6.8%. Individuals with alcohol dependence and substance abuse have high prevalence of PTSD. However, the prevalence of PTSD in heavy drinkers with alcoholic hepatitis (AH) is not known.The study's aim was to determine the prevalence of PTSD in heavy drinkers with and without AH. METHODS: We screened for PTSD using the Primary Care-PTSD questionnaire among heavy drinkers with (n = 115) and without (n = 64) AH participating in a multicenter observational study in which participants were followed up to 12 months following their enrollment. RESULTS: The prevalence of PTSD in heavy drinkers with AH was 34% and was not different from heavy drinking controls without liver disease (34%). In the entire group screened for PTSD, the presence of PTSD was associated with higher alcohol consumption as reported by average drinks per last 30 days and average grams of alcohol consumed per day (p = 0.047 for both tests), but not associated with relapse of heavy drinking or mortality. Similarly, patients with AH and PTSD did not have higher relapse rate or higher mortality compared to patients with AH but no PTSD. CONCLUSIONS: Compared to previously reported prevalence in general population, heavy drinking individuals with or without AH have significantly higher prevalence of PTSD. However, PTSD was not associated with higher relapse rate or higher mortality in this population.

What predicts medication therapy management completion rates? The role of community pharmacy staff characteristics and beliefs about medication therapy management.

OBJECTIVES: To model the association between pharmacy technicians' attitudes and planned behaviors toward participating in medication therapy management (MTM) and MTM completion rates. Secondary objectives included 1) to compare pharmacy technician and pharmacist attitudes and planned behaviors toward participating in MTM and 2) to identify respondent and pharmacy demographic factors associated with MTM completion rates. DESIGN: A 27-item survey, adapted from a previously published survey tool based on the Theory of Planned Behavior (TPB), was used to collect respondent perceptions of MTM. Study procedures were approved by the institutional review board. SETTING AND PARTICIPANTS: Pharmacy technicians and pharmacists representing 116 Midwestern community pharmacy locations within a national supermarket chain were eligible to complete a telephone survey during February to May 2017. MAIN OUTCOME MEASURES: MTM completion rates were recorded during the 6-month time frame before survey administration. Unique, nonmeaningful survey codes were used to link responses from respondents to their store's MTM completion rates. Multivariate linear regression analysis was used to model the association between survey responses, pharmacy and staff demographics, and MTM completion rates. RESULTS: Of the 116 eligible pharmacy technicians and 114 pharmacists, 77 pharmacy technicians and 99 pharmacists completed the survey yielding response rates of 66.4% and 86.8%, respectively. Pharmacy technicians held significantly more positive perceptions about MTM delivery, particularly regarding adequate time and support. However, pharmacy technicians reported having the necessary knowledge and skills significantly less frequently compared with pharmacists. TPB variables for pharmacy technicians were not significant predictors of MTM completion rates. However, pharmacist attitudes, pharmacy technician education, and number of technician hours worked per week were positively associated with MTM completion rates. CONCLUSION: Pharmacists' attitudes, pharmacy technician level of education, and number of technician hours worked per week were associated with MTM completion rates.

Interaction between the patatin-like phospholipase domain-containing protein 3 genotype and coffee drinking and the risk for acute alcoholic hepatitis.

Only a subset of subjects with excessive alcohol consumption develops alcoholic liver disease (ALD). One of the major risk factors for ALD is the genetic variant of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene. Coffee is one of the most commonly consumed beverages, and coffee consumption has been associated with lower levels of serum alanine aminotransferase. The aim of this study was to investigate the role of coffee drinking and PNPLA3 rs738409 and their association with alcoholic hepatitis (AH) in a well-characterized cohort of subjects from the Translational Research and Evolving Alcoholic Hepatitis Treatment consortium. AH subjects and heavy drinking controls without a history of liver disease who were enrolled between May 2013 and May 2016 were included (n = 339), and the details of alcohol and coffee consumption were assessed. The PNPLA3 variant was determined among participants of European ancestry (n = 183). Relationships between baseline data and AH status were determined, and multivariable logistic regression modeling was performed. During the study period, 189 cases with AH and 150 heavy drinking controls were prospectively enrolled. The prevalence of regular coffee consumption was significantly lower in patients with AH compared to controls (20% versus 43%; P < 0.0001). The overall minor allele frequency of the PNPLA3 variant was higher in AH cases. Multivariable logistic regression revealed that coffee consumption and PNPLA3 were significantly associated with AH status at baseline after adjusting for relevant patient characteristics. Conclusion: We found a higher prevalence of AH among heavy drinkers with PNPLA3 G/G and G/C genotypes regardless of coffee consumption status and a higher prevalence of AH among heavy drinkers who were not regular coffee drinkers. These findings remained after considering relevant baseline patient characteristics. Further studies are needed to confirm our observation. (Hepatology Communications 2018;2:29-34).

Comprehensive vs. Assisted Management of Mood and Pain Symptoms (CAMMPS) trial: Study design and sample characteristics.

BACKGROUND: Pain is the most common presenting somatic symptom in medical outpatients, and depression and anxiety are the two most common mental disorders. They frequently co-occur, are under-treated, and result in substantial disability and reduced health-related quality of life. OBJECTIVES: The Comprehensive vs. Assisted Management of Mood and Pain Symptoms (CAMMPS) study is a randomized comparative effectiveness trial designed to test the relative effectiveness of a lower-resource vs. a higher-resource technology-assisted intervention for the management of patients suffering from pain plus anxiety and/or depression. METHODS/DESIGN: CAMMPS has enrolled 294 primary care patients with chronic pain plus comorbid anxiety and/or depression and randomized them to either: 1) Assisted Symptom Management (ASM) consisting of automated symptom monitoring by interactive voice recording or Internet and prompted pain and mood self-management; or 2) Comprehensive Symptom Management (CSM) which combines ASM with optimized medication management delivered by a nurse-physician specialist team and facilitated mental health care. Outcomes are assessed at baseline, 1, 3, 6, and 12months. The primary outcome is a composite pain-anxiety-depression (PAD) severity score. Secondary outcomes include individual pain, anxiety, and depression scores, health-related quality of life, disability, healthcare utilization, and treatment satisfaction. DISCUSSION: CAMMPS provides an integrated approach to PAD symptoms rather than fragmented care of single symptoms; coordinated symptom management in partnership with primary care clinicians and psychologists embedded in primary care; efficient use of health information technology; attention to physical and psychological symptom comorbidity; and the coupling of self-management with optimized medication management and facilitated mental health care. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01757301.

Challenges in Patient Enrollment and Retention in Clinical Studies for Alcoholic Hepatitis: Experience of the TREAT Consortium.

The TREAT Consortium has carried out clinical studies on alcoholic hepatitis (AH) for over 4 years. We encountered problems with participant recruitment, retention, and eligibility for specific protocols. To improve our ability to carry out such trials, we reviewed recruitment screening logs, end of study logs, and surveyed study coordinators to learn the reasons for missing patients, why patients declined enrollment, and the number of patients eligible for treatment trials. Associations of the recruited subjects' demographics with their adherence to follow-up appointments were examined. Three hundred eight-seven patients (AH and heavy drinking controls) were enrolled in the observational study, and 55 AH patients were recruited into treatment trials. About half of patients identified with AH could not be recruited; no specific reason could be determined for about two-thirds of these. Among the patients who gave a reason for not participating, the most common reasons were feeling too sick to participate, desire to concentrate on abstinence, and lack of interest in research. Approximately a quarter of the AH patients met eligibility criteria for treatment trials for moderate or severe AH and we were able to recruit half to two-thirds of those eligible. Approximately 35% of participants in the observational study returned for both 6- and 12-month follow-up visits. We did not identify biopsychosocial or demographic correlates of retention in the study. This analysis revealed that attempts at recruitment into trials for AH miss some subjects because of structural issues surrounding their hospital admission, and encounter a high rate of patient refusal to participate. Nonetheless, more than half of the patients who met the eligibility criteria for moderate or severe AH were entered into clinical trials. Retention rates for the observational study are relatively low. These findings need to be accounted for in clinical trial design and power analysis.

Comparing the Patient Health Questionnaire - 15 and the Somatic Symptom Scale - 8 as measures of somatic symptom burden.

PURPOSE: The Patient Health Questionnaire - 15 (PHQ-15) and the Somatic Symptom Scale - 8 (SSS-8) are self-report measures which assess somatic symptom burden. The present study investigates whether the two measures are comparable in terms of their psychometric properties and estimates of symptom burden. METHOD: Item characteristics, reliability, symptom severity and construct validity with regard to other relevant psychological, health-related quality of life and disability measures were compared for the PHQ-15m and the SSS-8 in 294 primary care patients who participated in a randomized comparative effectiveness trial targeting pain and mood symptoms. RESULTS: The reliabilities of the PHQ-15m and the SSS-8 were α=0.66 and α=0.72, respectively. Both measures were highly correlated (r=0.79). All item characteristics were comparable and both instruments showed the same pattern of correlations with instruments measuring depression, anxiety, pain, quality of life and impairment (r=0.25 to 0.53). A 1-point score increase (worsening of somatic symptoms) on either instrument resulted in a 3.7% to 3.9% increase in the number of disability days reported for the last four weeks. Using the same severity thresholds (5: low, 10: medium, 15: high), both measures identified nearly identical subgroups of patients with regard to health-related quality of life and disability. CONCLUSION: The PHQ-15m and the SSS-8 are comparable measures in terms of reliability and validity and severity classifications. These findings are in line with previous results and support the use of the SSS-8 as a valuable and short alternative to the original PHQ-15 in settings with limited assessment time.

Cognitive Control, Learning, and Clinical Motor Ratings Are Most Highly Associated with Basal Ganglia Brain Volumes in the Premanifest Huntington's Disease Phenotype.

OBJECTIVES: Huntington's disease (HD) is a debilitating genetic disorder characterized by motor, cognitive and psychiatric abnormalities associated with neuropathological decline. HD pathology is the result of an extended chain of CAG (cytosine, adenine, guanine) trinucleotide repetitions in the HTT gene. Clinical diagnosis of HD requires the presence of an otherwise unexplained extrapyramidal movement disorder in a participant at risk for HD. Over the past 15 years, evidence has shown that cognitive, psychiatric, and subtle motor dysfunction is evident decades before traditional motor diagnosis. This study examines the relationships among subcortical brain volumes and measures of emerging disease phenotype in prodromal HD, before clinical diagnosis. METHODS: The dataset includes 34 cognitive, motor, psychiatric, and functional variables and five subcortical brain volumes from 984 prodromal HD individuals enrolled in the PREDICT HD study. Using cluster analyses, seven distinct clusters encompassing cognitive, motor, psychiatric, and functional domains were identified. Individual cluster scores were then regressed against the subcortical brain volumetric measurements. RESULTS: Accounting for site and genetic burden (the interaction of age and CAG repeat length) smaller caudate and putamen volumes were related to clusters reflecting motor symptom severity, cognitive control, and verbal learning. CONCLUSIONS: Variable reduction of the HD phenotype using cluster analysis revealed biologically related domains of HD and are suitable for future research with this population. Our cognitive control cluster scores show sensitivity to changes in basal ganglia both within and outside the striatum that may not be captured by examining only motor scores. (JINS, 2017, 23, 159-170).

Longitudinal diffusion changes in prodromal and early HD: Evidence of white-matter tract deterioration.

INTRODUCTION: Huntington's disease (HD) is a genetic neurodegenerative disorder that primarily affects striatal neurons. Striatal volume loss is present years before clinical diagnosis; however, white matter degradation may also occur prior to diagnosis. Diffusion-weighted imaging (DWI) can measure microstructural changes associated with degeneration that precede macrostructural changes. DWI derived measures enhance understanding of degeneration in prodromal HD (pre-HD). METHODS: As part of the PREDICT-HD study, N = 191 pre-HD individuals and 70 healthy controls underwent two or more (baseline and 1-5 year follow-up) DWI, with n = 649 total sessions. Images were processed using cutting-edge DWI analysis methods for large multicenter studies. Diffusion tensor imaging (DTI) metrics were computed in selected tracts connecting the primary motor, primary somato-sensory, and premotor areas of the cortex with the subcortical caudate and putamen. Pre-HD participants were divided into three CAG-Age Product (CAP) score groups reflecting clinical diagnosis probability (low, medium, or high probabilities). Baseline and longitudinal group differences were examined using linear mixed models. RESULTS: Cross-sectional and longitudinal differences in DTI measures were present in all three CAP groups compared with controls. The high CAP group was most affected. CONCLUSIONS: This is the largest longitudinal DWI study of pre-HD to date. Findings showed DTI differences, consistent with white matter degeneration, were present up to a decade before predicted HD diagnosis. Our findings indicate a unique role for disrupted connectivity between the premotor area and the putamen, which may be closely tied to the onset of motor symptoms in HD. Hum Brain Mapp 38:1460-1477, 2017. © 2017 Wiley Periodicals, Inc.

Analysis of longitudinal censored semicontinuous data with application to the study of executive dysfunction: The Towers Task.

Executive dysfunction is a deficiency in skills of planning and problem solving that characterizes many neuropsychiatric disorders. The Towers Task is a commonly used measure of planning and problem solving for assessing executive function. Towers Task data are usually zero-inflated and right-censored, and ignoring these features can result in biased inference for the disease characterization of executive dysfunction. In this manuscript, a mixed-effects model for longitudinal censored semicontinuous data is developed for analyzing longitudinal Towers Task data from the PREDICT-HD study. The model is contrasted with current practice, and implications for general use are discussed.

Acute Alcoholic Hepatitis: Natural History and Predictors of Mortality Using a Multicenter Prospective Study.

OBJECTIVE: To examine the natural history of acute alcoholic hepatitis (AH) and identify predictors of mortality for AH using data from a prospective multicenter observational study. PARTICIPANTS AND METHODS: We analyzed data from 164 patients with AH and 131 heavy-drinking controls with no liver disease. Participants underwent clinical/laboratory assessment at baseline and 6 and 12 months after enrollment. Multivariable analyses were conducted to identify variables associated with mortality and examine the association between coffee drinking and risk of AH. RESULTS: Thirty-six patients with AH died during follow-up, with estimated 30-day, 90-day, 180-day, and 1-year survival of 0.91 (95% CI, 0.87-0.96), 0.85 (95% CI, 0.80-0.91), 0.80 (95% CI, 0.74-0.87), and 0.75 (95% CI, 0.68-0.83), respectively. In the multivariable analysis, higher serum bilirubin level (hazard ratio [HR]=1.059; 95% CI, 1.022-1.089), lower hemoglobin level (HR=1.263; 95% CI, 1.012-1.575), and lower platelet count (HR=1.006; 95% CI, 1.001-1.012) were independently associated with mortality in AH. Compared with controls, fewer patients with AH regularly consumed coffee (20% vs 44%; P<.001), and this association between regular coffee drinking and lower risk of AH persisted after controlling for relevant covariates (odds ratio=0.26; 95% CI, 0.15-0.46). Time-dependent receiver operating characteristic curve analysis revealed that Model for End-Stage Liver Disease; Maddrey Discriminant Function; age, serum bilirubin, international normalized ratio, and serum creatinine; and Child-Pugh scores all provided similar discrimination performance at 30 days (area under the curve=0.73-0.77). CONCLUSION: Alcoholic hepatitis remains highly fatal, with 1-year mortality of 25%. Regular coffee consumption was associated with lower risk of AH in heavy drinkers.

Phenotype Characterization of HD Intermediate Alleles in PREDICT-HD.

BACKGROUND: Huntington disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion on chromosome 4. Pathology is associated with CAG repeat length. Prior studies examining people in the intermediate allele (IA) range found subtle differences in motor, cognitive, and behavioral domains compared to controls. OBJECTIVE: The purpose of this study was to examine baseline and longitudinal differences in motor, cognitive, behavioral, functional, and imaging outcomes between persons with CAG repeats in three ranges: normal (≤26), intermediate (27-35), and reduced penetrance (36-39). METHODS: We examined longitudinal data from 389 participants in three allele groups: 280 normal controls (NC), 21 intermediate allele [IA], and 88 reduced penetrance [RP]. We used linear mixed models to identify differences in baseline and longitudinal outcomes between groups. Three models were tested: 1) no baseline or longitudinal differences; 2) baseline differences but no longitudinal differences; and 3) baseline and longitudinal differences. RESULTS: Model 1 was the best fitting model for most outcome variables. Models 2 and 3 were best fitting for some of the variables. We found baseline and longitudinal trends of declining performance across increasing CAG repeat length groups, but no significant differences between the NC and IA groups. CONCLUSION: We did not find evidence to support differences in the IA group compared to the NC group. These findings are limited by a small IA sample size.