Different cohort, disparate results: Selection bias is a key factor in autopsy cohorts.

INTRODUCTION: Research-oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter-cohort differences. METHODS: The National Alzheimer's Coordinating Center (NACC) provided data on N = 7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit. RESULTS: Cohorts with more participants who were cognitively normal at recruitment contained more individuals who were older, female, had lower frequencies of apolipoprotein E ε4, Lewy body disease, and frontotemporal dementia, but higher rates of cerebrovascular disease. Alzheimer's disease (AD) pathology was little different between groups. DISCUSSION: The percentage of participants recruited while cognitively normal predicted differences in findings in autopsy research cohorts. Most differences were in non-AD pathologies. HIGHLIGHTS: Systematic differences exist between autopsy cohorts that serve dementia research. We propose a metric to use for gauging a research-oriented autopsy cohort. It is essential to consider the characteristics of autopsy cohorts.

The Effect of Disclosure of PrEP Use on Adherence Among African Young Women in an Open-Label PrEP Study: Findings from HPTN 082.

To develop effective PrEP adherence interventions, it is important to understand the interplay between disclosure of pre-exposure prophalxis (PrEP) use, social support, and PrEP adherence. We leveraged the HPTN 082 study conducted among 451 adolescent girls and young women (AGYW) (ages 16 to 25 years, 2016 to 2019) in South Africa and Zimbabwe. Among the 349 who had month three disclosure and PrEP adherence data, 60% (n = 206) felt supported by adults, and 89% (n = 309) disclosed PrEP use to at least one person. PrEP disclosure was not associated with increased adherence, measured by intracellular tenofovir-diphosphate concentrations in dried blood spots. Women who reported having supportive adults, and disclosed to their parents, had higher adherence at 6 months with an increase of 177 fmol/punch (95% CI 12 to 343, t = 2.11, p = 0.04). PrEP interventions that help AGYW identify supportive relationships and effectively communicate the benefits of PrEP may improve PrEP adherence.Clinicaltrials.gov ID number: NCT02732730.

Trust in the provider and accurate self-reported PrEP adherence among adolescent girls and young women in South Africa and Zimbabwe: HPTN 082 study.

BACKGROUND: Trust is an important cornerstone of patient-provider communication. Accurate reporting of pre-exposure prophylaxis (PrEP) adherence is vital for providers to determine who needs adherence support, especially adolescent girls and young women (AGYW) disproportionately affected by newly diagnosed HIV. METHODS: This is a secondary analysis of the HPTN 082 open-label PrEP demonstration trial. From 2016-2018, 451 AGYW aged 16-25 years were enrolled in South Africa (Cape Town and Johannesburg) and Zimbabwe (Harare). PrEP was initiated by 427, and 354 (83%) had month three patient-reported adherence responses and intracellular tenofovir diphosphate (TFV-DP) measurements. The patient-reported adherence response to 'In the past month, how often did you take the tablet?' was dichotomized as 'high' if the response was every day or most days, and 'low' if some days or not many days or never. The biomarker marker evidence of adherence in dried blood spots was defined as 'high' if TFV-DP ≥ 700, and 'low' if < 350 fmol/punch. We used multinomial logistic regression to examine if trust in the PrEP provider was associated with concordance between patient-reported adherence and intracellular tenofovir-diphosphate (TFV-DP). RESULTS: AGYW who reported trust in their providers were almost four-fold (aOR 3.72, 95% CI 1.20-11.51) more likely to have concordant adherence (high self-reported adherence and high TFV-DP concentrations) compared to discordant non-adherence (high self-reported adherence and low TFV-DP concentrations). CONCLUSION: Education and training of providers to build trusting relationships with AGYW may lead to more accurate reporting of PrEP adherence. With accurate reporting, adequate support can be provided to bolster adherence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02732730.

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

INTRODUCTION: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts. METHODS: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives. RESULTS: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes. DISCUSSION: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

Cognitive trajectory in mild cognitive impairment due to primary age-related tauopathy.

Primary age-related tauopathy is increasingly recognized as a separate neuropathological entity different from Alzheimer's disease. Both share the neuropathological features of tau aggregates and neuronal loss in the temporal lobe, but primary age-related tauopathy lacks the requisite amyloid plaques central to Alzheimer's disease. While both have similar clinical presentations, individuals with symptomatic primary age-related tauopathy are commonly of more advanced ages with milder cognitive dysfunction. Direct comparison of the neuropsychological trajectories of primary age-related tauopathy and Alzheimer's disease has not been thoroughly evaluated and thus, our objective was to determine how cognitive decline differs longitudinally between these two conditions after the onset of clinical symptoms. Data were obtained from the National Alzheimer's Coordinating Center on participants with mild cognitive impairment at baseline and either no neuritic plaques (i.e. primary age-related tauopathy) or moderate to frequent neuritic plaques (i.e. Alzheimer neuropathological change) at subsequent autopsy. For patients with Alzheimer's disease and primary age-related tauopathy, we compared rates of decline in the sum of boxes score from the CDR® Dementia Staging Instrument and in five cognitive domains (episodic memory, attention/working memory, executive function, language/semantic memory, and global composite) using z-scores for neuropsychological tests that were calculated based on scores for participants with normal cognition. The differences in rates of change were tested using linear mixed-effects models accounting for clinical centre clustering and repeated measures by individual. Models were adjusted for sex, age, education, baseline test score, Braak stage, apolipoprotein ε4 (APOE ε4) carrier status, family history of cognitive impairment, and history of stroke, hypertension, or diabetes. We identified 578 participants with a global CDR of 0.5 (i.e. mild cognitive impairment) at baseline, 126 with primary age-related tauopathy and 452 with Alzheimer's disease. Examining the difference in rates of change in CDR sum of boxes and in all domain scores, participants with Alzheimer's disease had a significantly steeper decline after becoming clinically symptomatic than those with primary age-related tauopathy. This remained true after adjusting for covariates. The results of this analysis corroborate previous studies showing that primary age-related tauopathy has slower cognitive decline than Alzheimer's disease across multiple neuropsychological domains, thus adding to the understanding of the neuropsychological burden in primary age-related tauopathy. The study provides further evidence to support the hypothesis that primary age-related tauopathy has distinct neuropathological and clinical features compared to Alzheimer's disease.

Estimating the hazard rate difference from case-cohort studies.

The case-cohort design, among many two-phase sampling designs, substantially reduces the cost of an epidemiological study by selecting more informative participants within the full cohort for expensive variable measurements. Despite their benefits, additive hazards models, which estimate hazard differences, have rarely been used for the analysis of case-cohort studies due to the lack of software and application examples. In this paper, we describe a newly developed estimation method that fits the additive hazards models to general two-phase sampling studies along with the R package addhazard that implements it. It allows for missing covariates among cases, cohort stratification, robust variances, and the incorporation of auxiliary information from the full cohort to enhance inference precision. We demonstrate the use of this tool to estimate the association of the risk of coronary heart disease (CHD) with biomarkers high-sensitivity C-reactive protein (hs-CRP) and Lipoprotein-associated phospholipase A2 (Lp-PLA2) by analyzing the Atherosclerosis Risk in Communities Study, which adopted a two-phase sampling design for studying these two biomarkers. We show that the use of auxiliary variables from the full cohort based on calibration techniques improves the precision of the hazard difference being estimated. We observe a synergistic effect of the two biomarkers among participants with lower LDL cholesterol (LDL-C): the CHD hazard rate attributable to the combined action of high hs-CRP and high Lp-PLA2 exceeded the sum of the CHD hazard rate attributable to each one independently by 11.58 (95% CI 2.16-21.01) cases per 1000 person-years. With higher LDL-C, we observe the CHD hazard rate attributable to the combined action of high hs-CRP and medium Lp-PLA2 was less than the sum of their individual effects by 13.42 (95% CI 2.44-24.40) cases per 1000 person-years. This demonstration serves the dual purposes of illustrating analysis techniques and providing insights about the utility of hs-CRP and Lp-PLA2 for identifying the high-risk population of CHD that the traditional risk factors such as the LDL-C may miss. Epidemiologists are encouraged to use this new tool to analyze other case-cohort studies and incorporate auxiliary variables embedded in the full cohort in their analysis.

Risk of mild cognitive impairment among older adults in the United States by ethnoracial group.

OBJECTIVES: To compare the risk of mild cognitive impairment (MCI) among a wide range of ethnoracial groups in the US. DESIGN: Non-probabilistic longitudinal clinical research. SETTING: Participants enrolling into the National Alzheimer's Coordinating Center Unified Data Set recruited via multiple approaches including clinician referral, self-referral by patients or family members, or active recruitment through community organizations. PARTICIPANTS: Cognitively normal individuals 55 and older at the initial visit, who reported race and ethnicity information, with at least two visits between September 2005 and November 2018. MEASUREMENTS: Ethnoracial information was self-reported and grouped into non-Latino Whites, Asian Americans, Native Americans, African Americans (AAs), and individuals simultaneously identifying as AAs and another minority race (AA+), as well as Latinos of Caribbean, Mexican, and Central/South American origin. MCI was evaluated clinically following standard criteria. Four competing risk analysis models were used to calculate MCI risk adjusting for risk of death, including an unadjusted model, and models adjusting for non-modifiable and modifiable risk factors. RESULTS: After controlling for sex and age at initial visit, subhazard ratios of MCI were statistically higher than non-Latino Whites among Native Americans (1.73), Caribbean Latinos (1.80), and Central/South American Latinos (1.55). Subhazard ratios were higher among AA+ compared to non-Latino Whites only in the model controlling for all risk factors (1.40). CONCLUSION: Compared to non-Latino Whites, MCI risk was higher among Caribbean and South/Central American Latinos as well as Native Americans and AA+. The factors explaining the differential MCI risk among ethnoracial groups are not clear and warrant future research.

Local Health Departments' Capacity for Workplace Health Promotion Programs to Prevent Chronic Disease: Comparison of Rural, Micropolitan, and Urban Contexts.

OBJECTIVE: To examine local health department (LHD) contexts, capacity for, and interest in partnering with employers on workplace health promotion programs (WHPPs) for chronic disease prevention. DESIGN: Qualitative interviews with LHD directors. SETTING: LHDs from 21 counties in 10 states. PARTICIPANTS: Twenty-one LHD directors. MAIN OUTCOME MEASURESS: Experiences and perceptions of existing partnerships, decision making, funding, data needs, and organizational capacity for WHPP partnerships with employers. RESULTS: We identified 3 themes: (1) LHDs see the value of partnering with employers but lack the capacity to do so effectively; (2) while LHDs base priorities on community need, funding ultimately drives decision making; and (3) rural, micropolitan, and urban LHDs differ in their readiness and capacity to work with employers. CONCLUSIONS: Understanding LHDs' partnership capacity and context is essential to the successful implementation of WHPP partnerships with employers. Expanding these partnerships may require additional financial investments, particularly among rural LHDs.

Factor Consistency of Neuropsychological Test Battery Versions in the NACC Uniform Data Set.

The proprietary neuropsychological tests (Form C1) of the National Alzheimer's Coordinating Center (NACC) Uniform Data Set were replaced with nonproprietary versions (Form C2) chosen to closely model their proprietary counterparts. Correlations between analogous test pairs as measured in previous work were good (0.68-0.78), but it is unclear whether the paired tests represent the same set of common factors of cognition or if important factors specific to C1 or C2 only exist. The authors performed multiple factor analysis to analyze correlated C1 and C2 data. They included participants who completed both neuropsychological batteries within 1 year with no change in cognitive status. They found that the C1 and C2 neuropsychological test pairs are strongly related and are represented by the same principal factors. These findings support the use of the C2 test results in conjunction with C1 in longitudinal analyses of NACC data.

Risk of dementia and mild cognitive impairment among older adults in same-sex relationships.

INTRODUCTION: Sexual minority discrimination might lead to a higher risk of mild cognitive impairment (MCI) and dementia. The aim of this study was to assess the risk of MCI and dementia between older adults in same-sex relationships (SSR) and opposite-sex relationships (OSR). METHODS: We analyzed longitudinal data from the National Alzheimer's Coordinating Center up to September 2017. Analyses included cognitively normal individuals 55+ at baseline who had a spouse, partner, or companion as study partner at any assessment. Associations were calculated using survival analysis adjusting for demographics and APOE-e4 carrier status. RESULTS: Hazard ratios of MCI and dementia did not differ statistically between SSR and OSR individuals in the total sample nor stratified by sex. CONCLUSION: The lack of association between SSR and MCI and dementia warrants future research into their potential resilience mechanisms and the inclusion of sexual minority status questions in research and surveillance studies. The potential recruitment bias caused by nonprobabilistic sampling of the cohort and the reporting and ascertainment bias caused by using SSR to infer sexual minority status may have influenced our findings.

Estimating the Effect of PrEP in Black Men Who Have Sex with Men: A Framework to Utilize Data from Multiple Non-Randomized Studies to Estimate Causal Effects.

Black men who have sex with men (MSM) are disproportionately burdened by the HIV epidemic in the US. The effectiveness of pre-exposure prophylaxis (PrEP) in preventing HIV infection has been demonstrated through randomized placebo-controlled clinical trials in several populations. Importantly, no such trial has been conducted exclusively among Black MSM in the US, and it would be unethical and infeasible to do so now. To estimate the causal effects of PrEP access, initiation, and adherence on HIV risk, we utilized causal inference methods to combine data from two non-randomized studies that exclusively enrolled Black MSM. The estimated relative risks of HIV were: (i) 0.52 (95% confidence interval: 0.21, 1.22) for individuals with versus without PrEP access, (ii) 0.48 (0.12, 0.89) for individuals who initiated PrEP but were not adherent versus those who did not initiate, and (iii) 0.23 (0.02, 0.80) for individuals who were adherent to PrEP versus those who did not initiate. Beyond addressing the knowledge gap around the effect of PrEP in Black MSM in the US, which may have ramifications for public health, we have provided a framework to combine data from multiple non-randomized studies to estimate causal effects, which has broad utility.

Machine learning models identify predictive features of patient mortality across dementia types.

BACKGROUND: Dementia care is challenging due to the divergent trajectories in disease progression and outcomes. Predictive models are needed to flag patients at risk of near-term mortality and identify factors contributing to mortality risk across different dementia types. METHODS: Here, we developed machine-learning models predicting dementia patient mortality at four different survival thresholds using a dataset of 45,275 unique participants and 163,782 visit records from the U.S. National Alzheimer's Coordinating Center (NACC). We built multi-factorial XGBoost models using a small set of mortality predictors and conducted stratified analyses with dementiatype-specific models. RESULTS: Our models achieved an area under the receiver operating characteristic curve (AUC-ROC) of over 0.82 utilizing nine parsimonious features for all 1-, 3-, 5-, and 10-year thresholds. The trained models mainly consisted of dementia-related predictors such as specific neuropsychological tests and were minimally affected by other age-related causes of death, e.g., stroke and cardiovascular conditions. Notably, stratified analyses revealed shared and distinct predictors of mortality across eight dementia types. Unsupervised clustering of mortality predictors grouped vascular dementia with depression and Lewy body dementia with frontotemporal lobar dementia. CONCLUSIONS: This study demonstrates the feasibility of flagging dementia patients at risk of mortality for personalized clinical management. Parsimonious machine-learning models can be used to predict dementia patient mortality with a limited set of clinical features, and dementiatype-specific models can be applied to heterogeneous dementia patient populations.

Dementia has emerged as a major cause of death in societies with increasingly aging populations. However, predicting the exact timing of death in dementia cases is challenging, due to variations in the gradual process where cognitive decline interferes with the body's normal functions. In our study, we build machine-learning models to predict whether a patient diagnosed with dementia will survive or die within 1, 3, 5, or 10 years. We found that the prediction models can work well across patients from different parts of the US and across patients with different types of dementia. The key predictive factor was the information that is already used to diagnose and stage dementia, such as the results of memory tests. Interestingly, broader risk factors related to other causes of death, such as heart conditions, were less significant for predicting death in dementia patients. The ability of these models to identify dementia patients at a heightened risk of mortality could aid clinical practices, potentially allowing for earlier interventions and tailored treatment strategies to improve patient outcomes.

Predicting high-intensity resuscitation needs in injured patients in the post-hemostasis phase of care following intervention.

BACKGROUND: Best resuscitation practices in the posthemostasis phase of care are poorly defined; this phase of care is characterized by a range of physiologic derangements and multiple therapeutic modalities used to address them. Using a cohort of injured patients who required an immediate intervention in the operating room or angiography suite following arrival to the emergency department, we sought to define high-intensity resuscitation (HIR) in this posthemostasis phase of care; we hypothesized that those who would require HIR could be identified, using only data available at intensive care unit (ICU) admission. METHODS: Clinical data were extracted for consecutive injured patients (2016-2019) admitted to the ICU following an immediate procedure in the operating room or angiography suite. High-intensity resuscitation thresholds were defined as the top decile of blood product (≥3 units) and/or crystalloid (≥4 L) use in the initial 12 hours of ICU care and/or vasoactive medication use between ICU hours 2 and 12. The primary outcome, HIR, was a composite of any of these modalities. Predictive modeling of HIR was performed using logistic regression with predictor variables selected using Least Absolute Shrinkage and Selection Operator (LASSO) estimation. Model was trained using 70% of the cohort and tested on the remaining 30%; model predictive ability was evaluated using area under receiver operator curves. RESULTS: Six hundred five patients were included. Patients were 79% male, young (median age, 39 years), severely injured (median Injury Severity Score, 26), and an approximately 3:2 ratio of blunt to penetrating mechanisms of injury. A total of 215 (36%) required HIR. Predictors selected by LASSO included: shock index, lactate, base deficit, hematocrit, and INR. The area under receiver operator curve for the LASSO-derived HIR prediction model was 0.82. CONCLUSION: Intensive care unit admission data can identify subsequent HIR in the posthemostasis phase of care. Use of this model may facilitate triage, nursing ratio determination, and resource allocation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Effects of intervention stage completion in an integrated behavioral health and primary care randomized pragmatic intervention trial.

Purpose: A pragmatic, cluster-randomized controlled trial of a comprehensive practice-level, multi-staged practice transformation intervention aimed to increase behavioral health integration in primary care practices and improve patient outcomes. We examined association between the completion of intervention stages and patient outcomes across a heterogenous national sample of primary care practices. Methods: Forty-two primary care practices across the U.S. with co-located behavioral health and 2,426 patients with multiple chronic medical and behavioral health conditions completed surveys at baseline, midpoint and two year follow-up. Effects of the intervention on patient health and primary care integration outcomes were examined using multilevel mixed-effects models, while controlling for baseline outcome measurements. Results: No differences were found associated with the number of intervention stages completed in patient health outcomes were found for depression, anxiety, fatigue, sleep disturbance, pain, pain interference, social function, patient satisfaction with care or medication adherence. The completion of each intervention stage was associated with increases in Practice Integration Profile (PIP) domain scores and were confirmed with modeling using multiple imputation for: Workflow 3.5 (95% CI: 0.9-6.1), Integration Methods 4.6 (95% CI: 1.5-7.6), Patient Identification 2.9 (95% CI: 0.9-5.0), and Total Integration 2.7 (95% CI: 0.7-4.7). Conclusion: A practice-centric flexible practice transformation intervention improved integration of behavioral health in primary care across heterogenous primary care practices treating patients with multiple chronic conditions. Interventions that allow practices to flexibly improve care have potential to help complex patient populations. Future research is needed to determine how to best target patient health outcomes at a population level.

Cognitive Aging with Dementia, Mild Cognitive Impairment, or No Impairment: A Comparison of Same- and Mixed-Sex Couples.

BACKGROUND: Lesbian and gay older adults have health disparities that are risk factors for Alzheimer's disease, yet little is known about the neurocognitive aging of sexual minority groups. OBJECTIVE: To explore cross-sectional and longitudinal dementia outcomes for adults in same-sex relationships (SSR) and those in mixed-sex relationships (MSR). METHODS: This prospective observational study utilized data from the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS) collected from contributing Alzheimer's Disease Research Centers. Participants were adults aged 55+ years at baseline with at least two visits in NACC UDS (from September 2005 to March 2021) who had a spouse, partner, or companion as a co-participant. Outcome measures included CDR® Dementia Staging Instrument, NACC UDS neuropsychological testing, and the Functional Activities Questionnaire. Multivariable linear mixed-effects models accounted for center clustering and repeated measures by individual. RESULTS: Both MSR and SSR groups experienced cognitive decline regardless of baseline diagnosis. In general, MSR and SSR groups did not differ statistically on cross-sectional or longitudinal estimates of functioning, dementia severity, or neuropsychological testing, with two primary exceptions. People in SSR with mild cognitive impairment showed less functional impairment at baseline (FAQ M = 2.61, SD = 3.18 vs. M = 3.97, SD = 4.53, respectively; p < 0.01). The SSR group with dementia had less steep decline in attention/working memory (ß estimates = -0.10 versus -0.18; p < 0.01). CONCLUSION: Participants in SSR did not show cognitive health disparities consistent with a minority stress model. Additional research into protective factors is warranted.

Development of a tool to assess HIV prevention readiness of adolescent girls and young women in HPTN 082 study.

BACKGROUND: African adolescent girls and young women (AGYW) represent a large proportion of new HIV infections, a priority population for pre-exposure prophylaxis (PrEP), but adherence remains a challenge. A reliable, valid readiness tool would help identify AGYW motivated to take PrEP who need adherence support. METHODS: In the HPTN 082 open-label PrEP study (2016-2019), South African and Zimbabwean women ages 16-25 were administered an HIV prevention readiness measure (HPRM). The 25 items in the HPRM included medication beliefs, connection with care, disclosure of PrEP use, social support, and housing stability using a 5-point Likert scale. Exploratory factor analysis (EFA) using polychoric correlations, scale reliability, and predictive validity were performed on data from 315 participants who responded to all items. We assessed the predictive value of HPRM scores with PrEP adherence, defined as tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots, as a continuous measure and dichotomized as high PrEP adherence (≥700 fmol/punch). RESULTS: EFA yielded 23 items with three subscales: self-efficacy (16 items), PrEP disclosure (4 items), and social support (3 items). Cronbach's α ranged from 0.71 to 0.92 for the overall scale and the subscales. The average overall scale and the subscales were predictive of 3-month PrEP adherence for TFV-DP concentrations: for each unit increase of the HPRM score, TFV-DP concentration increased by 103 fmol/punch (95% CI: 16, 189, p = 0.02); the highest HPRM score equated with 608 fmol/punch on average. For the self-efficacy subscale, TFV-DP increased by 90 fmol/punch (95% CI: 7, 172, p = 0.03); PrEP disclosure, 68 fmol/punch (95% CI: 19, 117 p = 0.01); and social support, 58fmol/punch (95% CI: 2, 113, p = 0.04). Higher PrEP disclosure suggests high adherence (OR 1.36, 95% CI: 1.00, 1.86, p = 0.05) and predicted persistent high adherence at both months three and six (OR: 1.50, 95% CI: 1.03, 2.21, p = 0.04). CONCLUSIONS: The HPRM scale overall and the subscales individually demonstrated good internal consistency among African young women. PrEP disclosure subscale exhibiting significant association with persistent high PrEP adherence is an important finding for PrEP adherence support programs. Future work will assess replicability and expand self-efficacy and social-support subscales after item revision. TRIAL REGISTRATION: ClinicalTrials.gov NCT02732730.

Improving Power and Accuracy in Randomized Controlled Trials of Pain Treatments by Accounting for Concurrent Analgesic Use.

The 0 to 10 numeric rating scale of pain intensity is a standard outcome in randomized controlled trials (RCTs) of pain treatments. For individuals taking analgesics, there may be a disparity between "observed" pain intensity (pain intensity with concurrent analgesic use) and pain intensity without concurrent analgesic use (what the numeric rating scale would be had analgesics not been taken). Using a contemporary causal inference framework, we compare analytic methods that can potentially account for concurrent analgesic use, first in statistical simulations, and second in analyses of real (non-simulated) data from an RCT of lumbar epidural steroid injections. The default analytic method was ignoring analgesic use, which is the most common approach in pain RCTs. Compared to ignoring analgesic use and other analytic methods, simulations showed that a quantitative pain and analgesia composite outcome based on adding 1.5 points to pain intensity for those who were taking an analgesic (the QPAC1.5) optimized power and minimized bias. Analyses of real RCT data supported the results of the simulations, showing greater power with analysis of the QPAC1.5 as compared to ignoring analgesic use and most other methods examined. We propose alternative methods that should be considered in the analysis of pain RCTs. PERSPECTIVE: This article presents the conceptual framework behind a new quantitative pain and analgesia composite outcome, the QPAC1.5, and the results of statistical simulations and analyses of trial data supporting improvements in power and bias using the QPAC1.5. Methods of this type should be considered in the analysis of pain RCTs.

Receipt of Smoking Cessation Medications Among People With and Without Human Immunodeficiency Virus in the Veterans Aging Cohort Study (2003-2018).

Background: Nicotine replacement therapy, bupropion, and varenicline are smoking cessation medications (SCMs) shown to be similarly effective in people with and without human immunodeficiency virus (PWH and PWoH, respectively), although rates of receipt of these medications are unknown. Methods: We identified patients in the Veterans Aging Cohort Study with electronic health record-documented current smoking using clinical reminder data for tobacco use (2003-2018). We measured receipt of SCMs using Veterans Affairs pharmacy data for outpatient prescriptions filled 0-365 days after current smoking documentation. We used log-linear, Poisson-modified regression models to evaluate the relative risk (RR) for receiving SCM by human immunodeficiency virus (HIV) status, the annual rate of receipt, and rate difference among PWH relative to PWoH. Results: The sample included 92 632 patients (29 086 PWH), reflecting 381 637 documentations of current smoking. From 2003 to 2018, the proportion receiving SCMs increased from 15% to 34% for PWH and from 17% to 32% among PWoH. There was no statistical difference in likelihood of receiving SCM by HIV status (RR, 1.010; 95% confidence interval [CI], .994-1.026). Annual rates of receiving SCM increased for PWH by 4.3% per year (RR, 1.043; 95% CI, 1.040-1.047) and for PWoH by 3.7% per year (RR, 1.037; 95% CI, 1.036-1.038; rate difference +0.6% [RR, 1.006; 95% CI, 1.004-1.009]). Conclusions: In a national sample of current smokers, receipt of SCM doubled over the 16-year period, and differences by HIV status were modest. However, fewer than 35% of current smokers receive SCM annually. Efforts to improve SCM receipt should continue for both groups given the known dangers of smoking.

Comparative effectiveness of two versions of a caring contacts intervention in healthcare providers, staff, and patients for reducing loneliness and mental distress: A randomized controlled trial.

BACKGROUND: Caring Contacts can effectively reduce suicide ideation, attempts, and death. In published clinical trials, Caring Contacts were sent by someone who knew the recipient. At scale, Caring Contacts programs rarely introduce the recipient and sender. It is not known whether receiving Caring Contacts from someone unknown is as effective as messages from someone the recipient has met. METHODS: Pragmatic randomized controlled trial comparing Caring Contacts with (CC+) versus without an introductory phone call (CC). Recruitment occurred January-July 2021, with outcomes assessed at 6 months. Participants were primary care patients or healthcare providers/staff reporting adverse mental health outcomes on a qualifying survey. Participants were sent 11 standardized caring text messages over 6 months; when participants replied, they received personalized unscripted responses. CC+ calls were semi-structured. The primary outcome was loneliness (NIH Toolkit). RESULTS: Participants included 331 patients (mean [SD] age: 45.5 [16.4], 78.9 % female) and 335 healthcare providers/staff (mean [SD] age: 40.9 [11.8], 86.6 % female). There were no significant differences in loneliness at 6 months by treatment arm in either stratum. In patients, mean (SD) loneliness was 61.9 (10.7) in CC, and 60.8 (10.3) in CC+, adjusted mean difference of -1.0 (95 % CI: -3.0, 1.0); p-value = 0.31. In providers/staff, mean (SD) loneliness was 61.2 (11) in CC, and 61.3 (11.1) in CC+, adjusted mean difference of 0.2 (95 % CI: -1.8, 2.2); p-value = 0.83. LIMITATIONS: Study population was 93 % white which may limit generalizability. CONCLUSIONS: Including an initial phone call added operational complexity without significantly improving the effectiveness of a Caring Contacts program.

Comparative effectiveness of safety planning intervention with instrumental support calls (ISC) versus safety planning intervention with two-way text message caring contacts (CC) in adolescents and adults screening positive for suicide risk in emergency departments and primary care clinics: Protocol for a pragmatic randomized controlled trial.

BACKGROUND: Suicide is a leading cause of death in adolescents and adults in the US. Follow-up support delivered when patients return home after an emergency department (ED) or primary care encounter can significantly reduce suicidal ideation and attempts. Two follow-up models to augment usual care including the Safety Planning Intervention have high efficacy: Instrumental Support Calls (ISC) and Caring Contacts (CC) two-way text messages, but they have never been compared to assess which works best. This protocol for the Suicide Prevention Among Recipients of Care (SPARC) Trial aims to determine which model is most effective for adolescents and adults with suicide risk. METHODS: The SPARC Trial is a pragmatic randomized controlled trial comparing the effectiveness of ISC versus CC. The sample includes 720 adolescents (12-17 years) and 790 adults (18+ years) who screen positive for suicide risk during an ED or primary care encounter. All participants receive usual care and are randomized 1:1 to ISC or CC. The state suicide hotline delivers both follow-up interventions. The trial is single-masked, with participants unaware of the alternative treatment, and is stratified by adolescents/adults. The primary outcome is suicidal ideation and behavior, measured using the Columbia Suicide Severity Rating Scale (C-SSRS) screener at 6 months. Secondary outcomes include C-SSRS at 12 months, and loneliness, return to crisis care for suicidality, and utilization of outpatient mental health services at 6 and 12 months. DISCUSSION: Directly comparing ISC and CC will determine which follow-up intervention is most effective for suicide prevention in adolescents and adults.