Longitudinal Mixed-effects Models Research Articles

Abstract P4-10-04: Health-related quality of life (HRQoL) in hormone receptor-positive, HER2-negative, luminal B breast cancer patients treated with ribociclib plus letrozole or chemotherapy

Abstract Background: Neoadjuvant ribociclib plus letrozole (R+L), was evaluated in the phase II Coralleen study (NCT03248427) in comparison with poli-chemotherapy (CT) in women with hormone receptor-positive (HR+), HER2-negative, luminal B breast cancer. In the primary efficacy analysis, both groups showed a similar proportion of pts with PAM50 low-risk risk of recurrence at surgery (46.9% vs 46.1%) (Prat. Lancet Oncol. 2020). Now we present patients (pts)-reported HRQoL results. Methods: In the CORALLEEN study, 106 postmenopausal women with stage I-IIIA HR+/HER2-negative Luminal B breast cancer by PAM50 were randomized 1:1 to receive six 28-days cycles of R+L (n=52) or four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel (n=54). The primary efficacy endpoint was the proportion of patients with PAM50 Risk of Recurrence (ROR) low disease at surgery in each arm. Pts-reported HRQoL was evaluated at baseline (bl), day 1 of each subsequent cycle and before surgery, using i) the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) and ii) the breast cancer-specific EORTC QLQ-BR23 questionnaires. On-treatment comparison of mean change from bl in global health status (GHS), functioning and symptom scales was performed. Longitudinal linear mixed-effect models using a random intercept and random slope were fitted to estimated least squares (LS) mean change. The proportion of patients with clinically meaningful (10-point thereshold) deterioration was estimated in each group. Results: Completion and compliance rates of HRQoL questionaries at bl was 100% for R+L group and 98% for CT group, at week 12 completion rate was 92% and 87% and before surgery 80% in both groups. At bl, EORTC QLQ-C30 GHS scores were similar between R+L and CT groups (median 80.4 and 79.4, respectively). Before surgery, GHS scores presented a slight decrease in the R+L group while it considerably decreased in the CL group (mean change -5.2 vs. -23.6). The between-group difference in mean change from bl was 18.4 points (95% CI 9.8 - 26.9) showing a worsening in patients receiving CT. Overall, at the end of treatment 38% of patients in the R+L and 68% of patients in the CT group reported a clinically meaningful deterioration. R+L group presented better results in the mean change from bl in all functioning and symptom scales, specially in terms of fatigue and appetite loss (28.7 and 24 points difference between groups, respectively) (Table). Conclusions: R+L provided better outcomes in GHS HRQoL, functioning and symptoms in comparison with CT for the treatment of patient with high-risk breast cancer in the pre-operative setting. Together with the similar clinical efficacy and manageable safety profile, these results provide additional support for the development of clinical trials evaluating R+L in this patient population. Estimated mean change from baseline to before surgery (95% CI)Estimated mean change from baseline to before surgery (95% CI)Difference in the mean change in R+L vs. CTR+LCTGlobal health status 1-5.2 (-11.3 ; 0.9)-23.6 (-29.6 ; -17.6)18.4 (9.8 ; 26.9)Functional scales• Physical1-4.3 ( -9.5 ; 0.8)-20.3 (-25.5 ; -15.1)16 (8.7 ; 23.2)• Social1-6.3 (-13 ; 0.4)-19.7 (-26.1 ; -13.4)13.4 (4.2 ; 22.6)• Emotional1-0.7 (-7.4 ; 6.0)-6.8 (-13.3 ; -0.2)6.1 (-3.3 ; 15.4)• Role1-4.8 (-11.8 ; 2.2)-26.7 (-33.7 ; -19.7)21.9 (12 ; 31.8)• Body imagine2-3.2 (-8.9 ; 2.5)-12.9 (-18.5 ; -7.3)9.7 (1.7 ; 17.7)• Sexual enjoymnet2-5.3 (-20.4 ; 9.9)-36.1 (-54.4 ; -17.8)30.8 (7.2 ; 54.5)Symptom scales• Fatigue15.7 (0.7 ; 10.9)35.1 (26.6 ; 43.7)-28.7 (-38.2 ; -19.1)• Pain15.5 (-1.2 ; 12.1)15.5 (9 ; 22.1)-10.1 (-19.4 ; -0.8)• Insomnia14.8 (-2.7 ; 12.4)10.6 (3.2 ; 18.0)-5.8 (-16.2 ; 4.6)• Appetite loss12.5 (-5.8 ; 10.8)26.5 (18.2 ; 34.9)-24 (-35.8 ; -12.3)• Upset by hair loss28.8 (-10.4 ; 27.9)27.7 (8.3 ; 47.2)-18.9 (-45.6 ; 7.7)• Breast symptoms2-2.6 (-6.3 ; 1.2)0.7 (-3.0 ; 4.3)-3.3 (-8.5 ; 1.9)Positive values favour R+L except for symptom scale where negative values favour R+L. Changes from baseline were estimated using a repeated-measures mixed-effect model. CI, confidence interval. 1 EORTC QLQ-C30, 2EORTC QLQ-BR23 questionnaires. Citation Format: Guillermo Villacampa, Laia Paré, Cristina Hernando, Miriam Arumí, Montserrat Muñoz, Miguel Gil-Gil, Yann Izarzugaza, Neus Ferrer, Alvaro Montaño, Eva Ciruelos, Santiago González-Santiago, Claudette Falato, Patricia Villagrasa, Joaquín Gavilá, Aleix Prat, Tomás Pascual. Health-related quality of life (HRQoL) in hormone receptor-positive, HER2-negative, luminal B breast cancer patients treated with ribociclib plus letrozole or chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-04.

Network Financial Transfers and Psychological Distress Among Unmarried Mothers

Almost 50% of single-mother households live below 200% of the poverty line. In addition to material needs, mothers living in poverty have higher levels of psychological distress. Although some forms of network support (e.g., perceived support, welcomed support) promote well-being, how do financial transfers relate to unmarried mothers’ levels of distress? Drawing from support mobilization, social inequity, and reciprocity theories, this study used The Fragile Families and Child Wellbeing Study (FFCWS) ( n = 3,117 mothers and 10,676 observations) and longitudinal mixed-effects models to examine financial transfer behavior stability and its relationship to maternal psychological distress. Results indicate that, net of extensive controls, mothers commonly participated in giving or receiving money despite their disadvantaged, volatile circumstances, and engagement, regardless of direction, related to more symptoms of distress. This connection is problematic given the weakening public cash safety net and U.S. economic uncertainty.

Impact of Small Vessel Disease Progression on Long-term Cognitive and Functional Changes After Stroke.

Background and ObjectivesThe severity of white matter hyperintensities (WMH) at presentation with stroke is associated with poststroke dementia and dependency. However, WMH can decrease or increase after stroke; prediction of cognitive decline is imprecise; and there are few data assessing longitudinal interrelationships among changing WMH, cognition, and function after stroke, despite the clinical importance.MethodsWe recruited patients within 3 months of a minor ischemic stroke, defined as NIH Stroke Scale (NIHSS) score <8 and not expected to result in a modified Rankin Scale (mRS) score >2. Participants repeated MRI at 1 year and cognitive and mRS assessments at 1 and 3 years. We ran longitudinal mixed-effects models assessing change in Addenbrooke’s Cognitive Examination–Revised (ACE-R) and mRS scores. For mRS score, we assessed longitudinal WMH volumes (cube root; percentage intracranial volume [ICV]), adjusting for age, NIHSS score, ACE-R, stroke subtype, and time to assessment. For ACE-R score, we additionally adjusted for ICV, mRS, premorbid IQ, and vascular risk factors. We then used a multivariate model to jointly assess changing cognition/mRS score, adjusted for prognostic variables, using all available data.ResultsWe recruited 264 patients; mean age was 66.9 (SD 11.8) years; 41.7% were female; and median mRS score was 1 (interquartile range 1–2). One year after stroke, normalized WMH volumes were associated more strongly with 1-year ACE-R score (β = −0.259, 95% CI −0.407 to −0.111 more WMH per 1-point ACE-R decrease, p = 0.001) compared to subacute WMH volumes and ACE-R score (β = 0.105, 95% CI −0.265 to 0.054, p = 0.195). Three-year mRS score was associated with 3-year ACE-R score (β = −0.272, 95% CI −0.429 to −0.115, p = 0.001). Combined change in baseline-1-year jointly assessed ACE-R/mRS scores was associated with fluctuating WMH volumes (F = 9.3, p = 0.03).DiscussionAfter stroke, fluctuating WMH mean that 1-year, but not baseline, WMH volumes are associated strongly with contemporaneous cognitive scores. Covarying longitudinal decline in cognition and independence after stroke, central to dementia diagnosis, is associated with increasing WMH volumes.

Efficacy and safety exposure-response analyses of entrectinib in patients with advanced or metastatic solid tumors.

Entrectinib is an anti-cancer agent that inhibits TRKA/B/C, ROS1, and ALK. Secondary pharmacokinetic (PK) exposure parameters for entrectinib derived from a previously described population PK model were used to characterize exposure-response relationships in patients treated with entrectinib. Data were pooled from Phase 1 and 2 studies of entrectinib (600-800mg/day in adults, 250-750mg/m2/day in children) in 293 patients with NTRK-, ROS1-, or ALK-positive, locally advanced or metastatic tumors. Efficacy was evaluated by the changes in sum of target lesion diameters and best overall response defined by RECIST1.1. A longitudinal nonlinear mixed-effect model described the relationship between entrectinib exposure and tumor size data in patients with ROS1-positive non-small-cell lung cancer (NSCLC) or NTRK fusion-positive solid tumors. The relationship between exposure and treatment-emergent (TEAEs) or serious (SAEs) adverse events was assessed by logistic regression in all patients for whom secondary PK parameter estimates were derived. Among the 89 patients with evaluable efficacy data included in the exposure-efficacy analysis, 73% (65/89) achieved a complete or partial response. Entrectinib exposure distribution was similar in responders and non-responders. Model-described tumor shrinkage rates were 8-12 times greater than growth rates in both ROS-1-positive NSCLC patients and NTRK fusion-positive solid tumor patients, with no relationship between exposure and these rates. The probability of experiencing a Grade ≥ 3 TEAE or SAE increased with exposure, primarily at doses > 600mg/day. These analyses supported that entrectinib at 600mg/day provides an acceptable benefit-risk ratio in adults with NTRK-, ROS1-, or ALK-positive tumors, considered as rare disease.

Opioid Taper is Associated with Improved Experimental Pain Tolerance in Patients with Chronic Pain: An Observational Study.

IntroductionThe degree to which opioid-induced hyperalgesia contributes to the pain experience of patients with chronic pain remains relatively undescribed. The objective of this pilot study was to determine if experimental pain responses improve in patients with chronic pain as they undergo a planned opioid taper.MethodsThis was a prospective observational study. Seven patients with chronic neuropathic pain on at least 120 mg morphine equivalents/day were enrolled. The participants were followed over the course of an individualized opioid taper to a lower dose. Measures of experimental pain sensitivity, including indicators of central pain modulation, were collected on a biweekly basis; in addition, measures of function and quality of life were collected monthly. The effect of opioid taper on pain responses and functional outcomes over time were examined using longitudinal mixed-effects regression modeling and general linear regression modeling with regularization as a function of baseline dose, end dose, and taper rate.ResultsIn this small sample of patients undergoing highly individualized and variable opioid taper, the opioid taper was significantly associated with improved pain responses to the cold-pressor test, with the pain threshold on average increasing by 1.14 s every 6 weeks (p = 0.0084, 95% confidence interval [CI] for 6-week change 0.3039–2.0178) and pain tolerance on average increasing by 2.87 s every 6 weeks (p = 0.0026, 95% CI for 6-week change 1.02–4.7277). Taper-related changes in central pain modulation were not observed, although conditioned modulation trended toward improvement by the completion of opioid taper. Similarly, no declines in function and quality of life were observed with the opioid taper, suggesting stability despite decreased opioid dose.ConclusionsOpioid taper was associated with improvements in experimental pain responses without a decline in function and quality of life, suggestive of diminished opioid-induced hyperalgesia in this clinical sample.Trial RegistrationClinicalTrials.gov identifier, NCT03912298.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40122-021-00348-8.

The impact of COVID-19 on the safety, housing stability, and mental health of unstably housed domestic violence survivors.

Using data from an ongoing longitudinal study, we examined the impact of the COVID‐19 stay‐at‐home orders on a racially diverse population of unstably housed domestic violence (DV) survivors over time. Specifically, we examined survivors' safety, housing stability, and mental health before, during, and after the onset of COVID‐19, and how demographic, social, and familial factors attenuated or exacerbated the effect of the stay‐at‐home orders. Approximately 300 participants were initially interviewed after they sought services from a DV agency, and then again, every 6 months over 2 years. COVID‐19 stay‐at‐home orders occurred midway through the completion of this multi‐year study. Longitudinal mixed effects models were estimated to examine the impact of COVID‐19 on the safety, housing stability, and mental health of survivors over time. We also examined models with several time‐varying (e.g., employment, income, social support, and number of children) and time‐invariant (baseline outcome scores, racial/ethnic identity, education, and disability status) control variables. Results revealed that safety, housing stability and mental health were improving for study participants before the onset of the COVID‐19 pandemic but plateaued after the stay‐at‐home orders were issued. Experiences of abuse, housing instability, and mental health symptomatology did not worsen as a result of the COVID‐19 stay‐at‐home orders. Notably, social support and housing services emerged as important predictors of outcomes, such that participants who received housing‐related services and greater social support reported less abuse, less housing instability, and lower mental health distress. COVID‐19 temporarily disrupted the positive trajectory unstably housed DV survivors were experiencing in regard to safety, housing stability and mental health. These findings provide critical insight into the importance of service access during and after global catastrophes. Additional resources and support may be helpful in assisting survivors to return to their pre‐pandemic recovery and growth trajectories.

Impact of Intra- and Subretinal Fluid on Vision Based on Volume Quantification in the HARBOR Trial

To investigate the functional associations of intraretinal fluid (IRF) and subretinal fluid (SRF) volumes at baseline and after the loading dose as well as fluid change after the first injection with best-corrected visual acuity (BCVA) in patients with neovascular age-related macular degeneration (nAMD) who received an anti-VEGF treatment over 24 months. Post hoc analysis of a phase III, randomized, multicenter trial in which ranibizumab was administered monthly or in a pro re nata regimen (HARBOR). Study eyes of 1094 treatment-naïve patients with nAMD. IRF and SRF volumes were segmented automatically on monthly spectral domain OCT images. Fluid volumes and changes thereof were included as covariates into longitudinal mixed-effects models, which modeled BCVA trajectories. BCVA estimates corresponding to baseline, follow-up, and persistent IRF/SRF volumes after the loading dose; BCVA estimates of change in fluid volumes after the first injection; and marginal and conditional R2. Analysis of 22 494 volumetric scans revealed that foveal IRF consistently shows a negative correlation with BCVA at baseline and subsequent visits (-3.23 and-4.32 letters/100 nL, respectively). After the first injection, BCVA increased by+2.13 letters/100 nL decrease in foveal IRF. Persistent IRF was associated with lower baseline BCVA and less improvement. Foveal SRF correlated with better BCVA at baseline and subsequent visits (+6.52 and+1.42 letters/100 nL, respectively). After the first injection, SRF decrease was associated with significant vision gain (+5.88 letters/100 nL). Foveal fluid correlated more with BCVA than parafoveal IRF/SRF. Although IRF consistently correlates with decreased function and recovery throughout therapy, SRF is associated with a more pronounced functional improvement. Moreover, SRF resolution provides increased benefit. Fluid-function correlation represents an essential base for the development of personalized treatment regimens, optimizing functional outcomes, and reducing treatment burden.

A stochastic mixed effects model to assess treatment effects and fluctuations in home‐measured peak expiratory flow and the association with exacerbation risk in asthma

Home‐based measures of lung function, inflammation, symptoms, and medication use are frequently collected in respiratory clinical trials. However, new statistical approaches are needed to make better use of the information contained in these data‐rich variables. In this work, we use data from two phase III asthma clinical trials demonstrating the benefit of benralizumab treatment to develop a novel longitudinal mixed effects model of peak expiratory flow (PEF), a lung function measure easily captured at home using a hand‐held device. The model is based on an extension of the mixed effects modeling framework to incorporate stochastic differential equations and allows for quantification of several statistical properties of a patient's PEF data: the longitudinal trend, long‐term fluctuations, and day‐to‐day variability. These properties are compared between treatment groups and related to a patient's exacerbation risk using a repeated time‐to‐event model. The mixed effects model adequately described the observed data from the two clinical trials, and model parameters were accurately estimated. Benralizumab treatment was shown to improve a patient's average PEF level and reduce long‐term fluctuations. Both of these effects were shown to be associated with a lower exacerbation risk. The day‐to‐day variability was neither significantly affected by treatment nor associated with exacerbation risk. Our work shows the potential of a stochastic model‐based analysis of home‐based lung function measures to support better estimation and understanding of treatment effects and disease stability. The proposed analysis can serve as a complement to descriptive statistics of home‐based measures in the reporting of respiratory clinical trials.

Longitudinal blood pressure patterns of women with hypertensive disorders of pregnancy: preconception through postpartum

Objective To investigate the longitudinal blood pressure (BP) pattern of women with hypertensive disorders of pregnancy (HDP) preconception through the postpartum day (PPD) 42. Study Design A retrospective study of women (≥15 years old) diagnosed with an HDP antenatally or postpartum, who were enrolled prospectively in a postpartum remote BP monitoring program between 3/2017 and 5/2020. BPs were collected from 47-time points: preconception, each trimester, delivery day, and 42 days postpartum. Analysis was conducted utilizing a mixed-effects longitudinal model. Main outcome measures Primary outcome was the longitudinal BP patterns. Secondary outcomes were the timing of BP stabilization (BPs < 140/90 mmHg for ≥48 h) and resolution (stabilized without antihypertensive medication use). Results Our final analysis included 897 of the 964 eligible women. The peak systolic and diastolic BPs were on PPDs 3, 4, 5, and 5, 6, 7, respectively. Systolic BP fell below the preconception level after PPD15; diastolic BP reached its plateau after PPD17 and remained above the preconception level till PPD42 (p < .001). Postpartum BP peaked with the highest percentage of BP spikes on PPDs 4–7. The median survival times to BP stabilization and resolution were PPDs 11 (95% CI: 10–12) and 23 (95% CI: 21–25), respectively. By PPD42, 91.0% and 74.1% of women achieved BP stabilization and resolution, respectively. Conclusion This study data could be used to develop evidence-based recommendations for women with an HDP. Diastolic BPs remaining significantly higher than the preconception level indicates the long-term risk of cardiovascular disease. In our cohort, 26% of women had unresolved hypertension by PPD42, which reinforces the necessity to ensure long-term follow-up.

828. Short- and Long-Term Metabolic Changes in Virologically Suppressed Patients Switching from TDF to TAF Containing Antiretroviral Therapy

BackgroundSwitching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) containing antiretroviral therapy (ART) may negatively influence weight, cholesterol, and atherosclerotic cardiovascular disease (ASCVD) risk. The timing, duration, and extent of these changes and their definitive associations with TAF remain unclear. MethodsThis retrospective observational study evaluated weight, body mass index (BMI), cholesterol, and ASCVD risk score changes in virologically suppressed patients living with HIV infection (PLWH) who switched from TDF to TAF without switching any other ART regimen components. Adult patients on TDF and no HIV viral load values > 200 copies/mL for ≥ 2 years prior to and following a TAF switch were included. Body weight, BMI, cholesterol and other variables were collected for the 2 years before and after the switch. The Wilcoxon signed-rank test compared median values for each measurement pre and post switch in a univariate analysis. Longitudinal linear mixed effects models evaluated changes for each outcome measure at 1 and 2 years after the switch. Models were built with random effects for patients and included covariates such as time on TAF, age, sex, race, time with HIV, diabetes, smoking status, and concomitant medications associated with weight gain or loss. ResultsA total of 86 patients met study criteria (table 1). In the univariate analysis, there were significant increases in weight, BMI, total cholesterol, LDL, HDL, triglycerides, and ASCVD risk scores 2 years after switching to TAF (each p ≤ 0.05, table 2). However, after controlling for covariates, only the increases in total and LDL cholesterol were associated with switching to TAF and significantly different from expected changes predicted in the linear model. In terms of weight gain with TAF, patients gained an average of 4.3 pounds in year 1 and 3.8 pounds in year 2 after the switch. Neither of these increases were statistically different from the expected changes in weight predicted in the linear model (3.1 pounds/year, 95% CI: 1.6-4.6). ConclusionDespite observing significant increases in weight, BMI, cholesterol and ASCVD risk scores after switching to TAF, only the changes in cholesterol were significantly associated with TAF and different from changes expected in PLWH over time.Disclosures Jason J. Schafer, PharmD, MPH, Gilead (Research Grant or Support)Merck (Advisor or Review Panel member, Research Grant or Support)ViiV (Advisor or Review Panel member)

Estimation in multivariate linear mixed models for longitudinal data with multiple outputs: Application to PBCseq data analysis

In many biomedical studies or clinical trials, we have data with more than one response variable on the same subject repeatedly measured over time. In analyzing such data, we adopt a multivariate linear mixed-effects longitudinal model. On the other hand, in longitudinal data, we often find features that do not impact modeling the response variable and are eliminated from the study. In this paper, we consider the problem of simultaneous variable selection and estimation in a multivariate t linear mixed-effects model (MtLMM) for analyzing longitudinally measured multioutcome data. This work's motivation comes from a cohort study of patients with primary biliary cirrhosis. The interest is eliminating insignificant variables using the smoothly clipped and absolute deviation penalty function in the MtLMM. The proposed penalized model offers robustness and flexibility to accommodate fat tails. An expectation conditional maximization algorithm is employed for the computation of maximum likelihood estimates of parameters. The calculation of standard errors is affected by an information-based method. The methodology is illustrated by analyzing Mayo Clinic Primary Biliary Cirrhosis sequential (PBCseq) data and a simulation study. We found drugs and sex can be eliminated from the PBCseq analysis, and over time the diseaseprogresses.

Detraining Slows and Maintenance Training Over 6 Years Halts Parkinsonian Symptoms-Progression.

Introduction: There are scant data to demonstrate that the long-term non-pharmaceutical interventions can slow the progression of motor and non-motor symptoms and lower drug dose in Parkinson's disease (PD).Methods: After randomization, the Exercise-only (E, n = 19) group completed an initial 3-week-long, 15-session supervised, high-intensity sensorimotor agility exercise program designed to improve the postural stability. The Exercise + Maintenance (E + M, n = 22) group completed the 3-week program and continued the same program three times per week for 6 years. The no exercise and no maintenance control (C, n = 26) group continued habitual living. In each patient, 11 outcomes were measured before and after the 3-week initial exercise program and then, at 3, 6, 12, 18, 24, 36, 48, 60, and 72 months.Results: The longitudinal linear mixed effects modeling of each variable was fitted with maximum likelihood estimation and adjusted for baseline and covariates. The exercise program strongly improved the primary outcome, Motor Experiences of Daily Living, by ~7 points and all secondary outcomes [body mass index (BMI), disease and no disease-specific quality of life, depression, mobility, and standing balance]. In E group, the detraining effects lasted up to 12 months. E+M group further improved the initial exercise-induced gains up to 3 months and the gains were sustained until year 6. In C group, the symptoms worsened steadily. By year 6, levodopa (L-dopa) equivalents increased in all the groups but least in E + M group.Conclusion: A short-term, high-intensity sensorimotor agility exercise program improved the PD symptoms up to a year during detraining but the subsequent 6-year maintenance program was needed to further increase or sustain the initial improvements in the symptoms, quality of life, and drug dose.

Using self-report RDoC measures to identify transdiagnostic translational targets for perinatal affective disorders.

Perinatal depression affects 6.5-12.9% of women, with high rates in women of color and comorbid perinatal anxiety in up to 50% of cases. The Research Domain Criteria (RDoC) provides a translational framework for identifying transdiagnostic psychiatric symptoms, but its application in perinatal affective disorders (PNAD) is yet limited. Here, we identified RDoC-based transdiagnostic features of PNAD in 140 primarily low-income Black and Hispanic women at 272 total longitudinal visits across the perinatal period. Women completed RDoC self-report measures of potential threat and reward valuation-Behavioral Inhibition System/Behavioral Activation System scale (BIS/BAS) and Intolerance of Uncertainty Scale (IUS)-and measures of depression (Patient Health Questionnaire-9; PHQ-9) and anxiety (Generalized Anxiety Disorder-7; GAD-7). Longitudinal mixed effects models assessed associations of between-person ("trait-like") and within-person ("state-like") measures of potential threat (BIS/IUS) and reward valuation (BAS-Drive) with depression and anxiety symptoms. Higher "trait-like" BIS (standardized b = 2.33, p < .001) and IUS (b = 2.97, p < .001) scores, higher "state-like" BIS (b = .71, p < .001), and lower "state-like" BAS-Drive (b = - .58, p = .04) scores were associated with worse depressive symptoms. Higher "trait-like" BIS (b = 2.22, p < .001) and IUS (b = 2.73, p < .001) and higher "state-like" BIS scores (b = .92, p < .001) were associated with worse anxiety symptoms. Potential threat may be a prominent, transdiagnostic feature of perinatal anxiety and depression, whereas reward valuation may be a non-transdiagnostic, weaker feature of perinatal depression. Potential threat is important as both a "trait-like" feature that is sustained across the perinatal period and a "state-like" feature that varies within a woman across pregnancy. Grounded in RDoC, this work reveals neurobiological targets for translational research into PNAD.

Naturalistic smartphone keyboard typing reflects processing speed and executive function.

ObjectiveThe increase in smartphone usage has enabled the possibility of more accessible ways to conduct neuropsychological evaluations. The objective of this study was to determine the feasibility of using smartphone typing dynamics with mood scores to supplement cognitive assessment through trail making tests.MethodsUsing a custom‐built keyboard, naturalistic keypress dynamics were unobtrusively recorded in individuals with bipolar disorder (n = 11) and nonbipolar controls (n = 8) on an Android smartphone. Keypresses were matched to digital trail making tests part B (dTMT‐B) administered daily in two periods and weekly mood assessments. Following comparison of dTMT‐Bs to the pencil‐and‐paper equivalent, longitudinal mixed‐effects models were used to analyze daily dTMT‐B performance as a function of typing and mood.ResultsComparison of the first dTMT‐B to paper TMT‐B showed adequate reliability (intraclass correlations = 0.74). In our model, we observed that participants who typed slower took longer to complete dTMT‐B (b = 0.189, p < .001). This trend was also seen in individual fluctuations in typing speed and dTMT‐B performance (b = 0.032, p = .004). Moreover, participants who were more depressed completed the dTMT‐B slower than less depressed participants (b = 0.189, p < .001). A practice effect was observed for the dTMT‐Bs.ConclusionTyping speed in combination with depression scores has the potential to infer aspects of cognition (visual attention, processing speed, and task switching) in people's natural environment to complement formal in‐person neuropsychological assessments that commonly include the trail making test.

Neuroactive steroids and depression in early pregnancy

Progesterone (P4) can be metabolized to two general classes of neuroactive steroids (NAS) -those like allopregnanolone (ALLO) and pregnanolone (PA) which are positive allosteric modulators of the Gamma Aminobutyric Acid type A (GABAA) receptor and those like isoallopregnanolone (ISOALLO) and epipregnanolone (EPI) which are negative allosteric modulators of the GABAA receptor. While exogenous administration of ALLO is effective in treating postpartum depression, knowledge gaps remain in the dynamic interplay of NAS across the perinatal period. In particular little is known about ALLO and PA in relation to depression earlier in pregnancy, and the role of ISOALLO and EPI in relation to depression at any point in the perinatal period. In a prospective, nested case/control study in low-income women of color, we compared the metabolism of P4 to four NAS (i.e., ratios ALLO:P4, PA:P4, ISOALLO:P4, EPI:P4) in pregnant women with depression at either or both of the first and second trimesters (cases) and women without depression at either time point (controls). Fifty women (36% depressed, 56% Black, 28% Latina) completed depression screening using a computerized adaptive test of mental health (CAT-MH™) and provided blood serum samples in both trimesters. In longitudinal mixed effects models of both trimesters, PND cases showed higher ratios of ALLO:P4 (p = .002) and PA:P4 (p = .03) compared to controls. In regression models of only first trimester data, there was no significant difference in NAS ratios between cases and controls (p > .05). Conversely, in models of the second trimester, ratios of PA:P4 (p = .002) and ISOALLO:P4 (p = .01) were significantly higher in cases compared to controls, and ratios of ALLO:P4 (p = .08) and EPI:P4 (p = .1) also trended higher in cases. The most severe cases, those with depression at both trimesters, showed an increase in ALLO:P4 (p = .06) and EPI:P4 (p < .001) ratios from the first to the second trimester, whereas controls showed a decrease in these ratios. Secondary analyses confirmed higher levels of ALLO (p = .04) and PA (p = .07) overall in cases compared to controls, along with higher levels of PA (p = .005) and ISOALLO (p = .02) in the second trimester alone. This work suggests a dynamic relationship between NAS and PND; whereas low ALLO levels have been previously associated with postpartum depression, earlier in pregnancy a higher metabolism of P4 to ALLO (and higher ALLO levels) is associated with depression. Some women may show a hormone-sensitive depressive response to acute increases in NAS metabolism in early pregnancy.

Timing-specific associations between income-to-needs ratio and hippocampal and amygdala volumes in middle childhood: A preliminary study.

It is well known that financial disadvantage is associated with alterations in brain development in regions critical to socioemotional well-being such as the hippocampus and the amygdala. Yet little is known about whether family income at different points in development is differentially associated with these structures. Furthermore, little is known about which environmental factors statistically mediate associations between income and subcortical structure. Using a longitudinal birth cohort and linear mixed-effects models, we identified associations between income-to-needs ratio (INR) at 6 timepoints throughout childhood and hippocampal and amygdala volumes at age 7-9 years (n=41; 236 INR measurements; 41 brain measurements). Mediation analysis identified environmental sequelae of income that statistically accounted for INR-brain associations. Lower INR prior to age 4 was associated with smaller hippocampal volumes, whereas lower INR prior to age 2 was associated with smaller right amygdala volume. These associations were mediated by unmet basic needs (e.g., food, housing). These findings delineate the temporal specificity of associations between income and hippocampal and amygdala structures.

How Total Performance Scores of Medicare Value-Based Purchasing Program Hospitals Change Over Time.

The Medicare Value-Based Purchasing (VBP) program established performance-based financial incentives for hospitals. We hypothesized that total performance scores (TPS) would vary by hospital type. Value-Based Purchasing reports were collected from 2015 to 2017 and merged with the Centers for Medicare and Medicaid Services (CMS) Impact File data. A total of 3,005 hospitals were grouped into physician-owned surgical hospitals (POSH), accountable care organizations (ACO), Kaiser, Vizient, and General hospitals. Longitudinal linear mixed-effects models compared temporal differences of TPS and secondary composite outcome, process, patient satisfaction, safety, and cost efficiency measures between hospital types. Total performance scores decreased across all hospital types (p < .001). Physician-owned surgical hospitals had the highest TPS (59.9), followed by Kaiser (49.2), ACO (36.7), General (34.8), and Vizient (30.7) (p < .001). Hospital types differed significantly in size, geography, mean case-mix index, Medicare patient discharges, percent Medicare days to inpatient days, Disproportionate Share Hospital payments, and uncompensated care per claim. Scores improved in 84% of POSH and 14.6% of Kaiser hospitals using score reallocations. In comparison with General hospitals, the TPS was higher for POSH and Kaiser and lower for Vizient in part due to weighting reallocation and individual domain scores. Centers for Medicare and Medicaid Services scoring system changes have not addressed the methodological biases favoring certain hospital types.

Long-term exposure to ambient PM2.5 leads to increased risk of Type 2 diabetes in urban Delhi and Chennai, India

BACKGROUND AND AIM: India has high levels of ambient air pollution and a high burden of cardiometabolic disease. However, there is a lack of detailed exposure assessment and longitudinal studies on health impacts of ambient PM2.5. We studied the association between ambient PM2.5 with fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and incident Type 2 diabetes mellitus (T2DM) in the CARRS cohort (n=12066) in Delhi and Chennai, India, over 7 years of follow-up (median years of follow-up = 4.84 years). METHODS: Long-term exposure to PM2.5 was measured using daily predictions from a hybrid ensemble averaging based model. FPG and HbA1c were assessed at three time points, and T2DM was defined as FPG≥126mg/dl, or HbA1c≥6.5%, or self reported physician diagnosed diabetes, or being on medication for diabetes. Associations between PM2.5 and glycemic markers were assessed using longitudinal mixed effects models while incident T2DM was analyzed using Cox proportional hazard models. RESULTS:Median annual exposure at baseline was 41.14 μg/m3 (interquartile range, 38.70-43.35) and 92.08 μg/m3 (interquartile range, 87.60-95.74), in Chennai and Delhi respectively. For interquartile range(IQR) increase in annual exposures, we observed 2.54 mg/dL(95% CI:1.36-3.72) and 3.56 mg/dL(95% CI:1.16-5.96) increase in FPG at Chennai and Delhi respectively, after adjusting for covariates. The IQR differences in 2 years of exposure increased the risk of incident T2DM by 1.11(95% CI:1.03-1.19) times in Delhi and by 1.24(95% CI: 1.02-1.50) times in Chennai. Using a propensity score analysis, marginal hazard ratios for IQR change in 1 year, 1.5 years and 2 years of exposure were 4.1(95% CI:1.5-11.2), 5.6(95% CI:2.5-12.5) and 6.1(95% CI:2.5-14.8), indicating a dose-response rise in risk with continued long-term exposure. CONCLUSIONS:Our findings demonstrated the effect of a wide range of PM2.5 exposure on the risk of Type 2 diabetes, thus emphasizing the need to mitigate ambient air pollution for health benefits. KEYWORDS: Particulate matter, Long-term exposure, Obesity and metabolic disorders, Environmental epidemiology

The association between drought conditions and occupational psychosocial stress among Midwestern U.S. farmers: an occupational cohort study

BACKGROUND AND AIM: Drought represents a globally relevant natural disaster linked to adverse health. Evidence has shown agricultural communities to be particularly susceptible to drought conditions, but there is a limited understanding of how drought may impact occupational psychosocial stress in farmers. METHODS: We used repeated measures data collected in the Musculoskeletal Symptoms among Agricultural Workers Cohort study, including 498 Midwestern U.S. farmers surveyed with a Job Content Questionnaire (JCQ) at six-month intervals in 312 counties (2012-2015). A longitudinal mixed effects model was used to estimate the change in job strain ratio, a metric of occupational psychosocial stress, during drought conditions measured with a 12-month standardized precipitation index. We further evaluated associations between drought and psychological job demand and job decision latitude, the job strain components, and applied a stratified analysis to evaluate differences by participant sex, age, and geography. RESULTS:During the growing season, the job strain ratio increased by 0.031 (95% CI: 0.012, 0.05) during drought conditions, an amount equivalent to a one-half standard deviation change, compared to non-drought conditions. The association between drought and the job strain ratio was driven mostly by increases in the psychological job demand (2.09; 95% CI: 0.94, 3.24). No risk differences were observed by sex, age group, or geographic region. CONCLUSIONS:Our results suggest a previously unidentified association between drought and increased occupational psychosocial stress among farmers. With North American climate anticipated to become hotter and drier, these findings could provide important health effects data for federal drought early warning systems and mitigation plans. KEYWORDS: natural disasters, mental health outcomes, occupational epidemiology, climate

Disease Modelling of Cognitive Outcomes and Biomarkers in the European Prevention of Alzheimer's Dementia Longitudinal Cohort.

A key challenge for the secondary prevention of Alzheimer’s dementia is the need to identify individuals early on in the disease process through sensitive cognitive tests and biomarkers. The European Prevention of Alzheimer’s Dementia (EPAD) consortium recruited participants into a longitudinal cohort study with the aim of building a readiness cohort for a proof-of-concept clinical trial and also to generate a rich longitudinal data-set for disease modelling. Data have been collected on a wide range of measurements including cognitive outcomes, neuroimaging, cerebrospinal fluid biomarkers, genetics and other clinical and environmental risk factors, and are available for 1,828 eligible participants at baseline, 1,567 at 6 months, 1,188 at one-year follow-up, 383 at 2 years, and 89 participants at three-year follow-up visit. We novelly apply state-of-the-art longitudinal modelling and risk stratification approaches to these data in order to characterise disease progression and biological heterogeneity within the cohort. Specifically, we use longitudinal class-specific mixed effects models to characterise the different clinical disease trajectories and a semi-supervised Bayesian clustering approach to explore whether participants can be stratified into homogeneous subgroups that have different patterns of cognitive functioning evolution, while also having subgroup-specific profiles in terms of baseline biomarkers and longitudinal rate of change in biomarkers.