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The Finkelstein and Schoenfeld (FS) test is a popular generalized pairwise comparison approach to analyze prioritized composite endpoints (eg, components are assessed in order of clinical importance). Power and sample size estimation for the FS test, however, are generally done via simulation studies. This simulation approach can be extremely computationally burdensome, compounded by increasing number of composite endpoints and with increasing sample size. Here we propose an analytical solution to calculate power and sample size for commonly encountered two-component hierarchical composite endpoints. The power formulas are derived assuming underlying distributions in each of the component outcomes on the population level, which provide a computationally efficient and practical alternative to the standard simulation approach. Monte Carlo simulation results demonstrate that performance of the proposed power formulas are consistent with that of the simulation approach, and have generally desirable objective properties including robustness to mis-specified distributional assumptions. We demonstrate the application of the proposed formulas by calculating power and sample size for the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial.

We developed and validated a set of composite scores that combine quantitative magnetic resonance imaging (MRI)-based measurements of hyaline cartilage damage, bone marrow lesions (BMLs), and effusion-synovitis into composite scores.We selected 300 participants (n = 100 for development cohort; n = 200 for validation cohort) from the Osteoarthritis Initiative with complete clinical, radiographic, and MRI data at baseline and 24 months. We used semiautomated programs to quantify tibiofemoral and patellar cartilage damage, BML volume, and whole-knee effusion-synovitis volume. The candidate composite scores were formed by summing changes from baseline to 24 months based on prespecified methods. We evaluated the candidate composite scores for 1) the ability to differentiate groups with and without knee osteoarthritis progression (17 radiographic and patient-reported definitions), 2) sensitivity to change (standardized response means), and 3) relative performance relating to legacy outcome measures of knee osteoarthritis progression.Three of 13 developed composite scores qualified for testing in the validation cohort (ranked by sensitivity to change): whole-knee cumulative cartilage damage, unweighted total knee score, and BML plus effusion-synovitis volume. Change in cumulative cartilage damage associated with radiographic progression (Kellgren/Lawrence grade: odds ratio [OR] 1.84; joint space width progression: OR 2.11). Changes in the unweighted total knee score (OR 1.97) and BML plus effusion-synovitis score (OR 1.92) associated with Western Ontario and McMaster Universities Osteoarthritis Index knee pain progression.Two composite scores emerged, reflecting discrete domains of knee osteoarthritis progression. First, cumulative damage, which is measured by a whole-knee cartilage damage score, reflects the damage accrued over time. Second, dynamic disease activity, which is measured by a BML plus effusion-synovitis score, relates to changes in a patient's state of disease and symptoms.

Lifetime risk measures the cumulative risk for developing a disease over one's lifespan. Modeling the lifetime risk must account for left truncation, the competing risk of death, and inference at a fixed age. In addition, statistical methods to predict the lifetime risk should account for covariate-outcome associations that change with age. In this paper, we review and compare statistical methods to predict the lifetime risk. We first consider a generalized linear model for the lifetime risk using pseudo-observations of the Aalen-Johansen estimator at a fixed age, allowing for left truncation. We also consider modeling the subdistribution hazard with Fine-Gray and Royston-Parmar flexible parametric models in left truncated data with time-covariate interactions, and using these models to predict lifetime risk. In simulation studies, we found the pseudo-observation approach had the least bias, particularly in settings with crossing or converging cumulative incidence curves. We illustrate our method by modeling the lifetime risk of atrial fibrillation in the Framingham Heart Study. We provide technical guidance to replicate all analyses in R.

Diagnosis of pulmonary hypertension (PH) in systemic sclerosis (SSc) requires an invasive right heart catheterization (RHC), often based on an elevated estimated pulmonary artery systolic pressure on screening echocardiography. However, due to the poor specificity of echocardiography, a greater number of patients undergo RHC than necessary, exposing patients to potentially avoidable complication risks. The development of improved prediction models for PH in SSc may inform decision-making for RHC in these patients.We conducted a retrospective study of 130 patients with SSc; 66 (50.8%) were diagnosed with PH by RHC. We used data from pulmonary function testing, electrocardiography, echocardiography, and computed tomography to identify and compare the performance characteristics of three models predicting the presence of PH: 1) Random forest; 2) Classification and regression tree; and, 3) Logistic regression. For each model, we generated receiver operating curves and calculated sensitivity and specificity. We internally validated models using a train-test split of the data.The random forest model performed best with an area under the curve of 0.92 (95% CI: 0.83, 1.00), sensitivity of 0.95 (95% CI: 0.75, 1.00), and specificity of 0.80 (95% CI: 0.56, 0.94). The two most important variables in our random forest model were pulmonary artery diameter on chest computed tomography and diffusing capacity for carbon monoxide on pulmonary function testing.In patients with SSc, a random forest model can aid in the detection of PH with high sensitivity and specificity, and may allow for better patient selection for RHC, thereby minimizing patient risk. This article is protected by copyright. All rights reserved.

Editors’ note The Editors of the 5 journals of the American College of Rheumatology and European Alliance of Associations for Rheumatology have been reminded by this editorial that ACR and EULAR have jointly agreed on various classification criteria, definitions, recommendations, or points to consider, which do not always find reflection in manuscripts submitted to the journals. Consequently, in the future, the Editors will enforce the use of the products obtained in the course of joint ACR/EULAR or EULAR/ACR activities in all respective papers. For rheumatoid arthritis this would mean use of the ACR/EULAR or EULAR/ACR classification criteria, remission definitions, recommendations on what to report in clinical trials, and others, as pertinent. The same applies to other diseases. There are valid and important reasons that these activities have been undertaken by ACR and EULAR, and therefore, the conclusions of the various task forces, which have been endorsed by ACR and EULAR, should be respected by investigators and study administrators. This does not mean other methods could not be used in a study, but at the least, the reports should address the methods agreed on by the two organisations. Maintaining uniformity across major publications regarding rheumatoid arthritis remission or other definitions not only allows for more appropriate comparison across analyses, but also enhances readers' ability to interpret results. Author instructions across the five journals will more strongly reflect this requirement. Over the last 30 years, treatment for rheumatoid arthritis (RA) has improved dramatically. By the early 2000s, disease remission had become a realistic goal, although definitions of remission varied widely, making it difficult to compare treatment strategies and gauge how often remission occurred. In 2009, the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) created a joint committee whose charge was to recommend a definition of remission. Members …

Although classified as group 1 pulmonary arterial hypertension (PAH), patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) experience poorer clinical response to PAH therapy and increased mortality compared to those with idiopathic PAH. Due to heterogeneity in phenotypes, identifying patients likely to respond to therapy is challenging. The goal of this study was to determine clinical factors associated with hemodynamic response, defined by a 20% reduction in pulmonary vascular resistance on repeat right heart catheterization.We applied a time-to-event model using a retrospective cohort of 39 patients with precapillary SSc-PH, defined by a mean pulmonary artery pressure of ≥ 25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg on right heart catheterization.Patients with PAWP ≤ 8 mmHg were nearly fourfold more likely to achieve a hemodynamic response compared to those with PAWP 8 mmHg (HR 3.88; 95% CI: 1.20, 12.57); each 1 mmHg increase in PAWP was associated with a decreased hazard for hemodynamic response (HR 0.84; 95% CI: 0.70, 1.00).In patients with precapillary SSc-PH, PAWP was associated with time to hemodynamic response, suggesting the importance of subclinical cardiac disease in determining hemodynamic response to oral vasodilator therapy.

In clinical trials, surrogate endpoints are useful when the endpoint of interest is difficult to measure or requires a long follow-up time. Current methodology for validating surrogate endpoints encounters challenges in the presence of collinearity between the treatment and surrogate endpoint, which is often present in clinical trials. The proposed methods adapt current methodology in the structural framework of path analysis to quantify the validity of a surrogate endpoint. The path analysis framework provides an improved interpretation of treatment effect. Through derivation and simulation we show the proposed path likelihood reduction factor (LRF P ), is less biased and more robust than current methodology in cases of collinearity between the treatment and surrogate endpoint, with notable improvement when surrogacy is weak or moderate. LRF P can be expanded to evaluate multiple correlated surrogate endpoints, which as shown through simulation, is also less biased and more robust than current methodology in the case of collinearity between the treatment and surrogate endpoint.

ObjectiveTo determine the relationship of patellofemoral osteoarthritis (PFOA) to changes in performance-based function over 7 years.MethodsThere were 2666 participants (62.2 ± 8.0 yrs, BMI 30.6 ± 5.9 kg/m2, 60% female) from the Multicenter Osteoarthritis Study with knee radiographs at baseline who completed repeated chair stands and a 20-meter walk test (20MWT) at baseline, 2.5, 5, and 7 years. Generalized linear models assessed the relation of radiographic PFOA and radiographic PFOA with frequent knee pain to longitudinal changes in performance-based function. Analyses were adjusted for age, sex, BMI, tibiofemoral OA, and injury/surgery.ResultsLinear models demonstrated a significant group-by-time interaction for the repeated chair stands (P = 0.04) and the 20MWT (P < 0.0001). Those with radiographic PFOA took 1.01 seconds longer on the repeated chair stands (P = 0.02) and 1.69 seconds longer on the 20MWT (P < 0.0001) at 7 years compared with baseline. When examining the relation of radiographic PFOA with frequent knee pain to performance-based function, there was a significant group-by-time interaction for repeated chair stands (P = 0.05) and the 20MWT (P < 0.0001). Those with radiographic PFOA with frequent knee pain increased their time on the repeated chair stands by 1.12 seconds (P = 0.04) and on the 20MWT by 1.91 seconds (P < 0.0001) over 7 years.ConclusionIndividuals with radiographic PFOA and those with radiographic PFOA with frequent knee pain have worsening of performance-based function over time. This knowledge may present opportunities to plan for early treatment strategies for PFOA to limit functional decline over time.

ObjectiveDespite increasing prevalence of end-stage renal disease (ESRD), little attention has been directed to how occupational exposures may contribute to risk. Our objective was to investigate the relationship between metalworking fluids (MWF) and ESRD in a cohort of 36 703 male autoworkers.MethodsWe accounted for competing risk of death, using the subdistribution hazard approach to estimate subhazard ratios (sHRs) and 95% CIs in models with cubic splines for cumulative exposure to MWF (straight, soluble or synthetic).ResultsBased on 501 ESRD cases and 13 434 deaths, we did not observe an association between MWF and ESRD overall. We observed modest associations between MWF and ESRD classification of glomerulonephritis and diabetic nephropathy. For glomerulonephritis, the 60th percentile of straight MWF was associated with an 18% increased subhazard (sHR=1.18, 95% CI: 0.99 to 1.41). For diabetic nephropathy, the subhazard increased 28% at the 60th percentile of soluble MWF (sHR=1.28, 95% CI: 1.00 to 1.64). Differences by race suggest that black males may have higher disease rates following MWF exposure.ConclusionsExposure to straight and soluble MWF may be related to ESRD classification, though this relationship should be further examined.

Summary Objective Inflammation worsens joint destruction in osteoarthritis (OA) and aggravates pain. Saturated and n-6 fatty acids (FAs) increase, whereas n-3 FAs reduce inflammation. We examined whether FA levels affected the development of OA. Design We studied participants from the Multicenter Osteoarthritis study (MOST) at risk of developing knee OA. After baseline, repeated knee x-rays and MRIs were obtained and knee symptoms queried through 60 month follow-up. Using baseline fasting samples, serum FAs were analyzed with standard assays. After excluding participants with baseline OA, we defined two sets of cases: those developing radiographic OA and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of MRI cartilage loss and synovitis and of knee pain using WOMAC and evaluated the number of hand joints affected by nodules. In regression models, we tested the association of each OA outcome with levels of saturated, n-3 and n-6 FAs adjusting for age, sex, BMI, education, race, baseline pain and depressive symptoms. Results We studied 260 cases with incident symptomatic and 259 with incident radiographic OA. Mean age was 61 years (61% women). We found no signficant nor suggestive associations of FA levels with incident OA (e.g., for incident symptomatic OA, OR per s.d. increase in n-3 FA 1.00 (0.85, 1.18) nor with any OA outcome in knee or hand. Conclusion Despite previously described effects on systemic inflammation, blood levels of FAs were not associated with risk of later knee OA or other OA outcomes.

BACKGROUND AND PURPOSE Walking activity in persons with Parkinson disease (PD) is important for preventing functional decline. The contribution of walking activity to home and community mobility in PD is poorly understood. METHODS Cross-sectional baseline data (N = 69) were analyzed from a randomized controlled PD trial. The Life-Space Assessment (LSA) quantified the extent, frequency, and independence across 5 expanding levels of home and community mobility, producing individual subscores and a total score. Two additional summed scores were used to represent mobility within (Levels 1-3) and beyond (Levels 4-5) neighborhood limits. An accelerometer measured walking activity for 7 days. Regression and correlation analyses evaluated relationships between daily steps and mobility scores. Mann-Whitney U tests secondarily compared differences in mobility scores between the active and sedentary groups. RESULTS Walking activity contributed significantly to the summed Level 1-3 score (β = 0.001, P = 0.004) but not to the summed Level 4-5 (β = 0.001, P = 0.33) or total (β = 0.002, P = 0.07) scores. Walking activity was significantly related to Level 1 (ρ = 0.336, P = 0.005), Level 2 (ρ = 0.307, P = 0.010), and Level 3 (ρ = 0.314, P = 0.009) subscores. Only the summed Level 1-3 score (P = 0.030) was significantly different between the active and sedentary groups. DISCUSSION AND CONCLUSIONS Persons with PD who demonstrated greater mobility beyond the neighborhood were not necessarily more active; walking activity contributed more so to home and neighborhood mobility. Compared with LSA total score, the Level 1-3 summed score may be a more useful participation-level measure for assessing the impact of changes in walking activity.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A349).

Objectives Nicaraguan sugarcane workers, particularly cane cutters, have an elevated prevalence of chronic kidney disease of unknown origin, also referred to as Mesoamerican nephropathy (MeN). The pathogenesis of MeN may include recurrent heat stress, crystalluria, and muscle injury with subsequent kidney injury. Yet, studies examining the frequency of such events in long-term, longitudinal studies are limited. Methods Using employment and medical data for male workers at a Nicaraguan sugarcane company, we classified months of active work as either work as a cane cutter or other sugarcane job and determined occurrence of dysuria, heat events and muscle events. Work months and events occurred January 1997 to June 2010. Associations between cane cutting and each outcome were analyzed using logistic regression based on generalized estimating equations for repeated events, controlling for age. Results Among 242 workers with 7257 active work months, 19.5% of person-months were as a cane cutter. There were 160, 21, and 16 episodes of dysuria, heat events, and muscle events, respectively. Compared with work months in other jobs, cane cutting was associated with an elevated odds of dysuria [odds ratio 2.40 (95% confidence interval 1.56–3.68)]. The number of heat and muscle events by cane cutter and other job were limited. Conclusions Working as a cane cutter compared with other jobs in the sugarcane industry was associated with increased dysuria, supporting the hypothesis that cane cutters are at increased risk of events suspected of inducing or presaging clinically evident kidney injury.

Objective Hypomagnesemia increases the risk of chondrocalcinosis and calcium pyrophosphate disease. We examined whether the use of drugs that can cause hypomagnesemia, diuretics and proton pump inhibitors (PPIs), increases the risk of chondrocalcinosis. Methods Participants in the Multicenter Osteoarthritis (MOST) Study obtained weight‐bearing knee radiographs, and their medication use was recorded at baseline and 30‐, 60‐, 84‐, and 144‐month examinations. We read radiographs serially for chondrocalcinosis and characterized incident chondrocalcinosis when it first appeared. We classified diuretic use as thiazide, loop, and other. To test drug effects on incident chondrocalcinosis at each interval (eg, 30‐60 months), we excluded persons with chondrocalcinosis at the interval’s beginning. For each drug, we evaluated exposure at the beginning and end of the interval. We conducted knee‐based analyses using Bayesian mixed‐effects discrete time survival models adjusted for age, sex, body mass index, radiographic osteoarthritis, race, and clinic site. Results Of 5272 knees, 196 developed chondrocalcinosis. Thiazide use (21.7% of examinations) and PPI use (13.7%) were common. Neither loop nor other diuretic use was associated with incident chondrocalcinosis. Thiazide use at the beginning and end of the interval of incidence conferred a high risk (hazard ratio [HR] = 2.18; 95% confidence interval [CI] 1.23‐3.89), but use at the beginning of the interval was not associated with risk (HR = 1.04). PPI use at the interval’s beginning increased risk of chondrocalcinosis (HR = 2.29; 95% CI 1.37‐3.79). Conclusion Thiazide diuretics, but not other diuretics, and PPI use probably increase the risk of chondrocalcinosis. These findings may have important clinical implications.

To assess whether vascular activity seen onPatients with LVV were recruited into a prospective cohort. All patients underwent magnetic resonance angiography or computed tomography angiography and FDG-PET imaging. Follow-up imaging using the same imaging modalities was obtained ≥6 months later per a standardized imaging protocol. Arterial damage, defined as stenosis, occlusion, or aneurysm, and corresponding FDG uptake were evaluated in 17 arterial territories. On follow-up, development of new lesions was recorded, and existing lesions were characterized as improved, worsened, or unchanged.A total of 1,091 arterial territories from 70 patients with LVV (38 patients with Takayasu arteritis, 32 patients with giant cell arteritis) were evaluated. Over a median 1.6 years of follow-up, new lesions developed only in 8 arterial territories in 5 patients with Takayasu arteritis. Arterial lesions improved in 16 territories and worsened in 6 territories. Most arterial territories that did not have vascular activity on FDG-PET scan at baseline had no angiographic change over the follow-up period (787 [99%] of 793). Few territories with baseline FDG-PET activity had angiographic change over time (24 [8%] of 298), but of the territories that developed angiographic change, 80% had FDG-PET activity at baseline. Within the same patient, an arterial territory with baseline FDG-PET activity had significantly increased risk for angiographic change compared to a paired arterial territory without FDG-PET activity (odds ratio 19.49 [95% confidence interval 2.44-156.02]; P 0.01). Concomitant edema and wall thickening further increased risk for angiographic change.Development of angiographic change was infrequent in this cohort of patients with LVV. A lack of baseline FDG-PET activity was strongly associated with stable angiographic disease. In cases of angiographic progression, change was preceded by the presence of FDG-PET activity.

OBJECTIVE: Adults with radiographic knee OA (rKOA) are at increased risk of mortality and walking difficulty may modify this relation. Little is known about specific aspects of walking difficulty that increase mortality risk. We investigated the association of walking speed (objective measure of walking difficulty) with mortality and examined the threshold that best discriminated this risk in adults with rKOA. METHODS: Participants with rKOA from the Johnston County Osteoarthritis Project (JoCoOA, longitudinal population-based cohort), Osteoarthritis Initiative and Multicenter Osteoarthritis Study (OAI and MOST, cohorts of individuals with or at high risk of knee OA) were included. Baseline speed was measured via 2.4-meter (m) walk test (short-distance) in JoCoOA and 20-m walk test (standard-distance) in OAI and MOST. To examine the association of walking speed with mortality risk over nine years, hazard ratios (aHR) and 95% confidence intervals (CI) were calculated from Cox regression models adjusted for potential confounders., A Maximal Likelihood Ratio Chi-square Approach was utilized to identify an optimal threshold of walking speed predictive of mortality. RESULTS: Deaths after 9 years of follow-up occurred in 23.3% (290/1244) of JoCoOA and 5.9% (249/4215) of OAI+MOST. Walking 0.2 meters/second slower during short- and standard-distance walk tests was associated with 23% (aHR[95%CI]; 1.23[1.10, 1.39]) and 25% (1.25[1.09, 1.43]) higher mortality risk, respectively. Walking

Objective To determine whether the Boston Overcoming Osteoarthritis through Strength Training Telephone-Linked Communication (BOOST-TLC) program, a novel telephone-based, motivational, strength-training exercise-adherence counseling intervention, improved adherence to a strength-training exercise program over 2 years. Methods Participants were recruited for this 2-year, single-blind, parallel-arm randomized controlled trial from knee osteoarthritis patient registries, community newspapers, and online websites in Massachusetts. Eligibility criteria included age 50 years or older, painful knee osteoarthritis, and ability to use a telephone. Exclusion criteria included medical conditions precluding exercise, inflammatory arthritis, current regular strength training, planned knee replacement surgery, dementia, inability to follow exercise instructions, and inability to use the TLC system. After participating in a group exercise class, participants were randomized to receiving motivational telephone calls through the BOOST-TLC program for 24 months or the control. Both control and intervention participants received a monthly automated phone message reminder to continue the program. Exercise adherence was ascertained by a single self-report item scored 0-10, where 10 represented complete adherence. Outcomes were evaluated at 6, 12, 18, and 24 months. Results A total of 104 subjects were randomized, and 89 subjects (44 control, 45 TLC) completed the 24-month follow-up. There was no significant difference in adherence at 24 months between groups (mean for control group 4.01 [95% confidence interval (95% CI) 3.03, 4.99], mean for TLC subjects 3.63 [95% CI 2.70, 4.56]; P = 0.57). Conclusion In those with knee osteoarthritis who had participated in an exercise program, frequent motivational telephone reminders did not increase adherence to strength-training exercise.

Objective Osteoarthritis (OA) and pain are both made more severe by low-grade inflammation. This study was undertaken to examine whether visceral fat, a major source of inflammatory cytokines and adipokines, is associated with an increased risk of knee OA or musculoskeletal pain. Methods Subjects in the Multicenter Osteoarthritis Study cohort, who were age 50-79 years and had or were at high risk of knee OA, underwent whole-body dual x-ray absorptiometry (DXA) at baseline. At baseline, 30 months, and 60 months radiographs and magnetic resonance images (MRIs) of the knees were obtained, and patients were asked to score the severity of their knee pain and to identify sites of joint pain using a body homunculus. Baseline DXA scans were used to measure total body fat and visceral and subcutaneous fat in the torso. The association of fat depot size with structural outcomes (incident radiographic OA and cartilage loss and synovitis on MRI) and with pain outcomes (worsening knee pain, number of painful joints, and widespread pain) was assessed. Regression analyses were adjusted for age, sex, race, education level, smoking status, physical activity, body mass index (BMI), and depressive symptoms. Results Of the 2,961 participants at baseline, 60.7% were women. The mean age was 62.5 years and mean BMI was 30.5 kg/m2 . After adjustment for covariates, no fat measures were associated with any structural outcomes. However, total and visceral, but not subcutaneous, fat were positively associated with worsening knee pain (P = 0.0005 for total fat and P = 0.007 for visceral fat) and widespread pain (P = 0.001 for total fat and P = 0.02 for visceral fat), and the amount of visceral fat was associated with the number of painful joints (P = 0.07). Conclusion Our findings indicate that visceral fat is associated with an increased risk of musculoskeletal and widespread pain.

ObjectivesAlthough treatment development in osteoarthritis (OA) focuses on chondroprotection, it is unclear how much preventing cartilage loss reduces joint pain. It is also unclear how nociceptive tissues may be involved.MethodsUsing data from the Osteoarthritis Initiative, we quantified the relation between cartilage loss and worsening knee pain after adjusting for bone marrow lesions (BMLs) and synovitis, and examined how much these factors mediated this association. 600 knee MRIs were scored at baseline, 12 months and 24 months for quantitative and semiquantitative measures of OA structural features. We focused on change in medial cartilage thickness using an amount similar to that seen in recent trials. Linear models calculated mean change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score with cartilage loss, adjusted for baseline BMLs, synovitis and covariates. Mediation analysis tested whether change in synovitis or BMLs mediated the cartilage loss–pain association. We carried out a subanalysis for knees with non-zero baseline WOMAC pain scores and another for non-valgus knees.ResultsCartilage thickness loss was significantly associated with a small degree of worsening in pain over 24 months. For example, a loss of 0.1 mm of cartilage thickness over 2 years was associated with a 0.32 increase in WOMAC pain (scale 0–20). The association of cartilage thickness loss with pain was mediated by synovitis change but not by BML change. Subanalysis results were similar.ConclusionsCartilage thickness loss is associated with only a small amount of worsening knee pain, an association mediated in part by worsening synovitis. Demonstrating that chondroprotection reduces knee pain will be extremely challenging and is perhaps unachievable.

Background Parkinson disease (PD) is a debilitating and chronic neurodegenerative disease resulting in ambulation difficulties. Natural walking activity often declines early in disease progression despite the relative stability of motor impairments. In this study, we propose a paradigm shift with a “connected behavioral approach” that targets real-world walking using cognitive-behavioral training and mobile health (mHealth) technology. Methods/design The Walking and mHealth to Increase Participation in Parkinson Disease (WHIP-PD) study is a twelve-month, dual site, two-arm, randomized controlled trial recruiting 148 participants with early to mid-stage PD. Participants will be randomly assigned to connected behavioral or active control conditions. Both conditions will include a customized program of goal-oriented walking, walking-enhancing strengthening exercises, and eight in-person visits with a physical therapist. Participants in the connected behavioral condition also will (1) receive cognitive-behavioral training to promote self-efficacy for routine walking behavior and (2) use a mHealth software application to manage their program and communicate remotely with their physical therapist. Active control participants will receive no cognitive-behavioral training and manage their program on paper. Evaluations will occur at baseline, three-, six-, and twelve-months and include walking assessments, self-efficacy questionnaires, and seven days of activity monitoring. Primary outcomes will include the change between baseline and twelve months in overall amount of walking activity (mean number of steps per day) and amount of moderate intensity walking activity (mean number of minutes per day in which > 100 steps were accumulated). Secondary outcomes will include change in walking capacity as measured by the six-minute walk test and ten-meter walk test. We also will examine if self-efficacy mediates change in amount of walking activity and if change in amount of walking activity mediates change in walking capacity. Discussion We expect this study to show the connected behavioral approach will be more effective than the active control condition in increasing the amount and intensity of real-world walking activity and improving walking capacity. Determining effective physical activity interventions for persons with PD is important for preserving mobility and essential for maintaining quality of life. Clinical trials registration NCT03517371, May 7, 2018. Trial registration ClinicalTrials.gov: NCT03517371. Date of registration: May 7, 2018. Protocol version: Original.

BACKGROUND: Few prognostic prediction models for total knee replacement are available, and the role of radiographic findings in predicting its use remains unclear. We aimed to develop and validate predictive models for total knee replacement and to assess whether adding radiographic findings improves predictive performance. METHODS: We identified participants with recent knee pain (in the past 3 months) in the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI). The baseline visits of MOST were initiated in 2003 and of OAI were initiated in 2004. We developed two predictive models for the risk of total knee replacement within 60 months of follow-up by fitting Cox proportional hazard models among participants in MOST. The first model included sociodemographic and anthropometric factors, medical history, and clinical measures (referred to as the clinical model). The second model added radiographic findings into the predictive model (the radiographic model). We evaluated each model’s discrimination and calibration performance and assessed the incremental value of radiographic findings using both category-free net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We tuned the models and externally validated them among participants in OAI. FINDINGS: We included 2658 participants from MOST (mean age 62·4 years [SD 8·1], 1646 [61·9%] women) in the training dataset and 4060 participants from OAI (mean age 60·9 years [9·1], 2379 [58·6%] women) in the validation dataset. 290 (10·9%) participants in the training dataset and 174 (4·3%) in the validation dataset had total knee replacement. The retained predictive variables included in the clinical model were age, sex, race, history of knee arthroscopy, frequent knee pain, current use of analgesics, current use of glucosamine, body-mass index, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, and the most predictive factors were age, race, and WOMAC pain score. The retained predictive variables in the radiographic model were age, sex, race, frequent knee pain, current use of analgesics, WOMAC pain score, and Kellgren–Lawrence grade, and the most predictive factors were Kellgren–Lawrence grade, race, and age. The C-statistic was 0·79 (95% CI 0·76–0·81) for the clinical model and 0·87 (0·85–0·99) for the radiographic model in the training dataset. The calibration slope was 0·95 (95% CI 0·86–1·05) and 0·96 (0·87–1·04), respectively. Adding radiograph findings significantly improved predictive performance with an NRI of 0·43 (95% CI 0·38–0·50) and IDI of 0·14 (95% CI: 0·10–0·18). Both models, with tuned coefficients, showed a good predictive performance among participants in the validation dataset. INTERPRETATION: The risk of total knee replacement can be predicted based on common risk factors with good discrimination and calibration. Additionally, adding radiographic findings of knee osteoarthritis into the model substantially improves its predictive performance. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, and Beijing Municipal Science & Technology Commission.

Patients with systemic sclerosis complicated by both pulmonary hypertension (SSc-PH) and interstitial lung disease (SSc-PH-ILD) have poor prognosis compared to those with SSc-PH or SSc-ILD alone. Little is known of how ILD severity affects outcomes in those with SSc-PH, or how PH severity affects outcomes in those with SSc-ILD. Herein, we aimed to delineate clinical features of patients with SSc-PH and SSc-ILD and determine to what degree PH and ILD severity contribute to mortality in patients with SSc. We conducted parallel retrospective studies in cohorts of patients with SSc-PH and SSc-ILD. We categorized ILD severity by pulmonary function testing and PH severity by cardiopulmonary hemodynamics. Our primary outcome was all-cause mortality from time of PH or ILD diagnosis for the SSc-PH and SSc-ILD cohorts, respectively. We calculated adjusted risks of time to all-cause mortality using Cox proportional hazards models. In patients with SSc-PH, severe ILD (HR: 3.54; 95% CI: 1.05, 11.99) was associated with increased hazards for all-cause mortality. By contrast, mild and moderate ILD were not associated with increased mortality risk. In patients with SSc-ILD, both moderate (HR: 2.65; 95% CI: 1.12, 6.31) and severe PH (HR: 6.60; 95% CI: 2.98, 14.61) were associated with increased hazards for all-cause mortality, while mild PH was not. Through our parallel study design, the risk of all-cause mortality increases as severity of concomitant ILD or PH worsens. Therapies that target slowing disease progression earlier in the disease course may be beneficial.

Objective To determine whether intra-articular corticosteroid injections are associated with increased knee osteoarthritis progression compared to hyaluronic acid injections which has been reported to delay OA progression and knee replacement. Methods We identified participants from two large cohort studies, the Osteoarthritis Initiative and the Multicenter Osteoarthritis Study. Study visits were performed at regular intervals and included questionnaires about intraarticular corticosteroid or hyaluronic acid injection use in the previous 6 months, incident total knee replacement and knee radiographs, which were obtained and interpreted in similar fashion. Outcomes were radiographic progression based on Kellgren and Lawrence grade and joint space narrowing for both cohorts; medial joint space width for Osteoarthritis Initiative participants; and incident total knee replacement. We compared pre- and post-injection x-rays to generate rate ratios of progression comparing corticosteroid injection with hyaluronic acid users. A Cox proportional hazards model was used to estimate rate of total knee replacement for both groups. Results We studied 791 participants (980 knees) with knee osteoarthritis, of whom 629 reported CSI use and 162 HAI use. Rate ratios of progression were similar between corticosteroid and hyaluronic acid injection users for Joint Space Narrowing (1.00 [95% CI 0.83-1.21]), Kellgren and Lawrence grade (1.03 [95% CI: 0.83 - 1.29]) and medial joint space width (1.03 [95% CI 0.72 - 1.48]). Hazard of total knee replacement was slightly lower for intraarticular corticosteroid compared to hyaluronic acid users (HR 0.75, 95% CI 0.51 - 1.09). Conclusions Intraarticular corticosteroid injections are not associated with increased risk of progression compared to hyaluronic acid.

Editor's note The Editors of the 5 journals of the American College of Rheumatology and European Alliance of Associations for Rheumatology have been reminded by this editorial that ACR and EULAR have jointly agreed on various classification criteria, definitions, recommendations, or points to consider, which do not always find reflection in manuscripts submitted to the journals. Consequently, in the future, the Editors will enforce the use of the products obtained in the course of joint ACR/EULAR or EULAR/ACR activities in all respective papers. For rheumatoid arthritis this would mean use of the ACR/EULAR or EULAR/ACR classification criteria, remission definitions, recommendations on what to report in clinical trials, and others, as pertinent. The same applies to other diseases. There are valid and important reasons that these activities have been undertaken by ACR and EULAR, and therefore, the conclusions of the various task forces, which have been endorsed by ACR and EULAR, should be respected by investigators and study administrators. This does not mean other methods could not be used in a study, but at the least, the reports should address the methods agreed upon by the 2 organizations. Maintaining uniformity across major publications regarding rheumatoid arthritis remission or other definitions not only allows for more appropriate comparison across analyses, but also enhances readers' ability to interpret results. Author instructions across the 5 journals will more strongly reflect this requirement. Over the last 30 years, treatment for RA has improved dramatically. By the early 2000s, disease remission had become a realistic goal, although definitions of remission varied widely, making it difficult to compare treatment strategies and gauge how often remission occurred. In 2009, the ACR and the EULAR created a joint committee whose charge was to recommend a definition of remission. Members of the committee suggested a large number of candidate definitions and using …

OBJECTIVE To evaluate the association of fatty infiltration of the quadriceps and vastus medialis (VM) with an increase in knee cartilage, meniscus, or bone marrow lesions, using magnetic resonance imaging (MRI) in knee osteoarthritis (OA) over 3 years. METHODS Participants (n = 69) with and without radiographic knee OA underwent MRI at baseline and 3 years later. Chemical shift-based water/fat MRI was used to quantify the intramuscular fat fraction and the lean anatomical cross-sectional area (ACSA) for the VM and entire quadriceps muscles. MRI images of the knee were analyzed using the semiquantitative modified whole-organ MRI score (mWORMS) grading to assess change in lesions in the articular cartilage, meniscus, and bone marrow. Logistic regression was used to assess whether baseline quadriceps and VM fat fraction and lean ACSA were associated with an increase in mWORMS scores. Odds ratios (ORs) were adjusted for age, sex, and body mass index. RESULTS Overall, of the 69 subjects, 43 (62%) had an increase in cartilage lesions (26 of 43), meniscus lesions (19 of 43), or bone marrow lesions (22 of 43) scores. The quadriceps (OR 2.13 [95% confidence interval (95% CI) 1.09-4.15]) and VM (OR 2.05 [95% CI 1.25-3.36]) fat fraction were both associated with an increase in cartilage, meniscus, or bone marrow lesion scores over 3 years. The association of quadriceps or VM lean ACSA with the outcomes was not significant. CONCLUSION These longitudinal findings using quantitative MRI methods for assessment of muscle adiposity highlight the role of quadriceps adiposity, specifically in the VM, in knee OA progression. However, studies in larger cohorts are needed to confirm these findings.

Key Points Question Is bariatric surgical weight loss intervention for obesity associated with microvascular and macrovascular outcomes, and are they differentially associated with sex, race, and metabolic status? Findings In 307 individuals with obesity who were followed up after bariatric surgery, the procedure was associated with significant weight loss and improvement in both macrovascular and microvascular function across subgroups of sex, race, and traditional metabolic syndrome. Biomarker assessment using high-sensitivity C-reactive protein plasma levels of greater than 2 mg/dL identified individuals with seemingly metabolically healthy obesity and low-grade inflammation who also derived microvascular benefit from weight loss surgery. Meaning These findings suggest that the beneficial effects of weight loss surgery extend broadly across sex, race, and certain metabolically healthy subgroups., This cohort study identifies variables associated with vascular remodeling after bariatric surgery and examines how sex, race, and metabolic status are associated with microvascular and macrovascular outcomes., Importance Bariatric surgical weight loss is associated with reduced cardiovascular mortality; however, the mechanisms underlying this association are incompletely understood. Objectives To identify variables associated with vascular remodeling after bariatric surgery and to examine how sex, race, and metabolic status are associated with microvascular and macrovascular outcomes. Design, Setting, and Participants This population-based longitudinal cohort included 307 individuals who underwent bariatric surgery. Participants were enrolled in the bariatric weight loss program at Boston Medical Center, a large, multi-ethnic urban hospital, with presurgical and postsurgical assessments. Data were collected from December 11, 2001 to August 27, 2019. Data were analyzed in September 2019. Exposure Bariatric surgery. Main Outcomes and Measures Flow-mediated dilation (FMD) and reactive hyperemia (RH) (as measures of macrovascular and microvascular function, respectively) and clinical variables were measured preoperatively at baseline and at least once postoperatively within 12 months of the bariatric intervention. Results A total of 307 participants with obesity (mean [SD] age, 42 [12] years; 246 [80%] women; 199 [65%] White; mean [SD] body mass index, 46 [8]) were enrolled in this study. Bariatric surgery was associated with significant weight loss and improved macrovascular and microvascular function across subgroups of sex, race, and traditional metabolic syndrome (mean [SD] pre- vs postsurgery weight: 126 [25] kg vs 104 [25] kg; P

Editor's note The Editors of the 5 journals of the American College of Rheumatology and European Alliance of Associations for Rheumatology have been reminded by this editorial that ACR and EULAR have jointly agreed on various classification criteria, definitions, recommendations, or points to consider, which do not always find reflection in manuscripts submitted to the journals. Consequently, in the future, the Editors will enforce the use of the products obtained in the course of joint ACR/EULAR or EULAR/ACR activities in all respective papers. For rheumatoid arthritis this would mean use of the ACR/EULAR or EULAR/ACR classification criteria, remission definitions, recommendations on what to report in clinical trials, and others, as pertinent. The same applies to other diseases. There are valid and important reasons that these activities have been undertaken by ACR and EULAR, and therefore, the conclusions of the various task forces, which have been endorsed by ACR and EULAR, should be respected by investigators and study administrators. This does not mean other methods could not be used in a study, but at the least, the reports should address the methods agreed upon by the 2 organizations. Maintaining uniformity across major publications regarding rheumatoid arthritis remission or other definitions not only allows for more appropriate comparison across analyses, but also enhances readers' ability to interpret results. Author instructions across the 5 journals will more strongly reflect this requirement. Over the last 30 years, treatment for RA has improved dramatically. By the early 2000s, disease remission had become a realistic goal, although definitions of remission varied widely, making it difficult to compare treatment strategies and gauge how often remission occurred. In 2009, the ACR and the EULAR created a joint committee whose charge was to recommend a definition of remission. Members of the committee suggested a large number of candidate definitions and using …

OBJECTIVE: Systemic sclerosis-related pulmonary hypertension (SSc-PH) is a common complication of SSc associated with accelerated mortality. We hypothesized that cardiac axis deviation may indicate abnormalities in cardiac function allowing for prognostication of disease severity and mortality. METHODS: This was a retrospective study where electrocardiograms (ECGs) were reviewed for cardiac axis deviation and their association with echocardiography and cardiopulmonary hemodynamics on right heart catheterization. The primary outcome observed was all-cause mortality from the time of PH diagnosis. RESULTS: ECGs were reviewed from 169 patients with SSc-PH. Right axis deviation (RAD) and left axis deviation (LAD) occurred in 28.4% and 30.8% of patients with SSc-PH, respectively. Compared to those without, patients with RAD exhibited predominantly right-sided cardiac disease on echocardiography and increased PH severity by cardiopulmonary hemodynamics including a greater mean pulmonary artery pressure (42.0 ± 12.5 mm Hg vs. 29.8 ± 7.0 mm Hg) and pulmonary vascular resistance (645.6 ± 443.2 dyns/cm(5) vs. 286.3 ± 167.7 dyn·s/cm(5)). LAD was associated with predominantly left-sided cardiac disease on echocardiography but was not associated with PH severity on cardiopulmonary hemodynamics. Both RAD (HR: 10.36; 95% CI: 4.90 - 21.93; p < 0.001) and LAD (HR: 2.94; 95% CI: 1.53 – 5.68; p = 0.001) were associated with an increased hazard for all-cause mortality. CONCLUSION: RAD and LAD reflect structural cardiac abnormalities and are associated with poor prognosis in patients with SSc-PH. These findings support the importance of electrocardiography, an inexpensive, widely available non-invasive test, in risk stratification.

BACKGROUND: Back pain is the most common cause of disability worldwide. While disability generally is associated with greater mortality, the association between back pain and mortality is unclear. Our objective was to examine whether back pain is associated with increased mortality risk and whether this association varies by age, sex, and back pain severity. METHODS: A systematic search of published literature was conducted using PubMed, Web of Science, and Embase databases from inception through March 2019. We included English-language prospective cohort studies evaluating the association of back pain with all-cause mortality with follow-up periods >5 years. Three reviewers independently screened studies, abstracted data, and appraised risk of bias using the Quality in Prognosis Studies (QUIPS) tool. A random-effects meta-analysis estimated combined odds ratios (OR) and 95% confidence intervals (CI), using the most adjusted model from each study. Potential effect modification by a priori hypothesized factors (age, sex, and back pain severity) was evaluated with meta-regression and stratified estimates. RESULTS: We identified eleven studies with 81,337 participants. Follow-up periods ranged from 5 to 23 years. The presence of any back pain, compared to none, was not associated with an increase in mortality (OR, 1.06; 95% CI, 0.97 to 1.16). However, back pain was associated with mortality in studies of women (OR, 1.22; 95% CI, 1.02 to 1.46) and among adults with more severe back pain (OR, 1.26; 95% CI, 1.14 to 1.40). CONCLUSION: Back pain was associated with a modest increase in all-cause mortality among women and those with more severe back pain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06732-6.

Background Statistical methods for modeling longitudinal and time-to-event data has received much attention in medical research and is becoming increasingly useful. In clinical studies, such as cancer and AIDS, longitudinal biomarkers are used to monitor disease progression and to predict survival. These longitudinal measures are often missing at failure times and may be prone to measurement errors. More importantly, time-dependent survival models that include the raw longitudinal measurements may lead to biased results. In previous studies these two types of data are frequently analyzed separately where a mixed effects model is used for the longitudinal data and a survival model is applied to the event outcome. Methods In this paper we compare joint maximum likelihood methods, a two-step approach and a time dependent covariate method that link longitudinal data to survival data with emphasis on using longitudinal measures to predict survival. We apply a Bayesian semi-parametric joint method and maximum likelihood joint method that maximizes the joint likelihood of the time-to-event and longitudinal measures. We also implement the Two-Step approach, which estimates random effects separately, and a classic Time Dependent Covariate Model. We use simulation studies to assess bias, accuracy, and coverage probabilities for the estimates of the link parameter that connects the longitudinal measures to survival times. Results Simulation results demonstrate that the Two-Step approach performed best at estimating the link parameter when variability in the longitudinal measure is low but is somewhat biased downwards when the variability is high. Bayesian semi-parametric and maximum likelihood joint methods yield higher link parameter estimates with low and high variability in the longitudinal measure. The Time Dependent Covariate method resulted in consistent underestimation of the link parameter. We illustrate these methods using data from the Framingham Heart Study in which lipid measurements and Myocardial Infarction data were collected over a period of 26 years. Conclusions Traditional methods for modeling longitudinal and survival data, such as the time dependent covariate method, that use the observed longitudinal data, tend to provide downwardly biased estimates. The two-step approach and joint models provide better estimates, although a comparison of these methods may depend on the underlying residual variance.

Objective To examine the association of the volume and intensity of daily walking at baseline with the risk of knee replacement (KR) over 5 years in adults with advanced structural knee osteoarthritis. Design Prospective, longitudinal, and multicenter observational study. Setting Osteoarthritis Initiative study with follow-up from 2008-2015. Participants Community-dwelling adults with or at risk of knee osteoarthritis were recruited from 4 sites in the United States (N=516; mean age, 67.7±8.6y; body mass index, 29.3±4.7 kg/m2; 52% female). We included participants with advanced structural disease, without KR and had valid daily walking data (quantified using Actigraph GT1M), at baseline. Interventions Not applicable. Main outcomes KR. Walking volume was measured as steps/day and intensity as minutes/day spent not walking (0 steps/min) and walking at very light (1-49 steps/min), light (50-100 steps/min), or moderate (>100 steps/min) intensities. To examine the relationship of walking volume and intensity with the risk of KR, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for covariates. Results Of 516 adults with advanced structural disease, 88 received a KR over 5 years (17%). Walking an additional 1000 steps/d was not associated with the risk of KR (adjusted HR=0.95; 95% CI, 0.84-1.04). Statistically, replacing 10 min/d of very light and light walking with 10 min/d of moderate walking reduced the risk of KR incidence by 35% and 37%, respectively (adjusted HR=0.65, 95% CI, 0.45-0.94, for very light and adjusted HR=0.63; 95% CI, 0.40-1.00, for light). Conclusions Daily walking volume and intensity did not increase KR risk over 5 years and may be protective in some cases in adults with advanced structural knee osteoarthritis.

Background: There is a paucity of prognostic prediction models for KR. We aimed to develop and validate predictive models for knee replacement (KR). Methods: We identified participants with recent knee pain in the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI). We developed two predictive models for the risk of KR over 60 months by fitting Cox proportional hazard models among participants in the MOST. The first model included socio-demographic and anthropometric factors, medical history and clinical measures (i.e., clinical model). The second model added radiographic findings into predictive model (i.e., radiographic model). We evaluated each model’s discrimination and calibration performance and assessed the incremental value of radiographic findings using both category-free net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We externally validated both models among participants in the OAI. Findings: We included 2658 participants of the MOST (mean age=62·4 years, 61·9% women) and 4060 participants of the OAI (mean age=60·9 years, 58·6% women). The C statistic was 0·79 (95% CI: 0·76-0·81) for the clinical model and 0·87 (95% CI: 0·85-0·99) for the radiographic model. The calibration slope was 0·95 (95% CI: 0·86-1·05) and 0·96 (0·87-1·04), respectively. Adding radiograph findings significantly improved predictive performance with an NRI of 0·42 (95% CI: 0·34-0·48) and IDI of 0·13 (95% CI: 0·09-0·16). Both models showed a good predictive performance among participants in the OAI. Interpretation: Our study developed and externally validated two models that demonstrated good discrimination and calibration ability in predicting the risk of KR. Adding radiographic findings substantially improved the predictive ability. Funding: National Natural Science Foundation of China (81902247, 81672183) and Beijing Municipal Science & Technology Commission (D171100003217002, Z181100001618020). Declaration of Interest: None to declare. Ethical Approval: The institutional review board at each of the sites of the Multicenter Osteoarthritis Study and the Osteoarthritis Initiative approved the study, and informed consent was obtained from all participants.

Background: Statistical methods for modeling longitudinal and time-to-event data has received much attention in medical research and is becoming increasingly useful. In clinical studies, such as cancer and AIDS, longitudinal biomarkers are used to monitor disease progression and to predict survival. These longitudinal measures are often missing at failure times and may be prone to measurement errors. More importantly, time-dependent survival models that include the raw longitudinal measurements may lead to biased results. In previous studies these two types of data are frequently analyzed separately where a mixed effects model is used for the longitudinal data and a survival model is applied to the event outcome. Methods: In this paper we compare joint maximum likelihood methods, a two-step approach and a time dependent covariate method that link longitudinal data to survival data with emphasis on using longitudinal measures to predict survival. We apply a Bayesian semi-parametric joint method and maximum likelihood joint method that maximizes the joint likelihood of the time-to-event and longitudinal measures. We also implement the Two-Step approach, which estimates random effects separately, and a classic Time Dependent Covariate Model. We use simulation studies to assess bias, accuracy, and coverage probabilities for the estimates of the link parameter that connects the longitudinal measures to survival times. Results: Simulation results demonstrate that the Two-Step approach performed best at estimating the link parameter when variability in the longitudinal measure is low but is somewhat biased downwards when the variability is high. Bayesian semi-parametric and maximum likelihood joint methods yield higher link parameter estimates with low and high variability in the longitudinal measure. The Time Dependent Covariate method resulted in consistent underestimation of the link parameter. We illustrate these methods using data from the Framingham Heart Study in which lipid measurements and Myocardial Infarction data were collected over a period of 26 years.Conclusions: Traditional methods for modeling longitudinal and survival data, such as the time dependent covariate method, that use the observed longitudinal data, tend to provide downwardly biased estimates. The two-step approach and joint models provide better estimates, although a comparison of these methods may depend on the underlying residual variance.

Simulation studies provide an important statistical tool in evaluating survival methods, requiring an appropriate data-generating process to simulate data for an underlying statistical model. Many studies with time-to-event outcomes use the Cox proportional hazard model. While methods for simulating such data with time-invariant predictors have been described, methods for simulating data with time-varying covariates are sorely needed. Here, we describe an approach for generating data for the Cox proportional hazard model with time-varying covariates when event times follow an Exponential or Weibull distribution. For each distribution, we derive a closed-form expression to generate survival times and link the time-varying covariates with the hazard function. We consider a continuous time-varying covariate measured at regular intervals over time, as well as time-invariant covariates, in generating time-to-event data under a number of scenarios. Our results suggest this method can lead to simulation studies with reliable and robust estimation of the association parameter in Cox-Weibull and Cox-Exponential models.

BackgroundComorbid mental disorders in patients with tuberculosis (TB) may exacerbate TB treatment outcomes. We systematically reviewed current evidence on the association between mental disorders and TB outcomes.MethodsWe searched eight databases for studies published from 1990-2018 that compared TB treatment outcomes among patients with and without mental disorders. We excluded studies that did not systematically assess mental disorders and studies limited to substance use. We extracted study and patient characteristics and effect measures and performed a meta-analysis using random-effects models to calculate summary odds ratios (OR) with 95% confidence intervals (CI).FindingsOf 7,687 studies identified, ten were included in the systematic review and nine in the meta-analysis. Measurement of mental disorders and TB outcomes were heterogeneous across studies. The pooled association between mental disorders and any poor outcome, loss to follow-up, and non-adherence were OR 2.13 (95% CI: 0.85-5.37), 1.90 (0.33-10.91), and 1.60 (0.81-3.02), respectively. High statistical heterogeneity was present.InterpretationOur review suggests that mental disorders in TB patients increase the risk of poor TB outcomes, but pooled estimates were imprecise due to small number of eligible studies. Integration of psychological and TB services might improve TB outcomes and progress towards TB elimination.