How should a cluster randomized trial be analyzed?

In cluster randomized trials, individuals from the same cluster tend to have more similar outcomes than individuals from different clusters. This correlation must be taken into account in the analysis of every cluster trial to avoid incorrect inferences. In this paper, we describe the principles guiding the analysis of cluster trials including how to correctly account for intra-cluster correlations as well as how to analyze more advanced designs such as stepped-wedge and cluster cross-over trials. We then describe how to handle specific issues such as small sample sizes and missing data.

Longitudinal pathways between maternal depression, parenting behaviors, and early childhood development: a mediation analysis.

Maternal depression is a global public health concern with far-reaching impacts on child development, yet our understanding of mechanisms remains incomplete. This study examined whether parenting mediates the association between maternal depression and child outcomes. Participants included 841 rural Pakistani mother-child dyads (50% female). Maternal depression was measured at 12 months postpartum, parenting behaviors (warmth, stimulation, and harsh parenting) were measured at 24 months, and child outcomes (mental health, socioemotional development, and cognitive skills) were measured at 36 months. Maternal depression predicted increased harsh parenting, child mental health difficulties, and child socioemotional concerns; however, there was little evidence for parenting as a mediator between maternal depression and child outcomes. Sex-stratified results are discussed, and findings are situated in context.

A cluster-randomized trial of client and provider-directed financial interventions to align incentives with appropriate case management in retail medicine outlets: Results of the TESTsmART Trial in western Kenya.

ACTs are responsible for a substantial proportion of the global reduction in malaria mortality over the last ten years, made possible by publicly-funded subsidies making these drugs accessible and affordable in the private sector. However, inexpensive ACTs available in retail outlets have contributed substantially to overconsumption. We test an innovative, scalable strategy to target ACT-subsidies to clients with a confirmatory diagnosis. We supported malaria testing(mRDTs) in 39 medicine outlets in western Kenya, randomized to three study arms; control arm offering subsidized mRDT testing (0.4USD), client-directed intervention where all clients who received a positive RDT at the outlet were eligible for a free (fully-subsidized) ACT, and a combined client and provider directed intervention where clients with a positive RDT were eligible for free ACT and outlets received 0.1USD for every RDT performed. Our primary outcome was the proportion of ACT dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients tested at the outlet and adherence to diagnostic test results. 43% of clients chose to test at the outlet. Test results informed treatment decisions, resulting in targeting of ACTs to confirmed malaria cases- 25.3% of test-negative clients purchased an ACT compared to 75% of untested clients. Client-directed and client+provider-directed interventions did not offer further improvements, compared to the control arm, in testing rates(RD = 0.09, 95%CI:-0.08,0.26) or dispensing of ACTs to test-positive clients(RD = 0.01,95% CI:-0.14, 0.16). Clients were often unaware of the price they paid for the ACT leading to uncertainty in whether the ACT subsidy was passed on to the client. This uncertainty undermines our ability to definitively conclude that client-directed subsidies are not effective for improving testing and appropriate treatment. We conclude that mRDTs could reduce ACT overconsumption in the private retail sector, but incentive structures are difficult to scale and their value to private providers is uncertain. Trial registration: ClinicalTrials.gov NCT04428307.

Autism Caregiver Coaching in Africa (ACACIA): Protocol for a type 1-hybrid effectiveness-implementation trial.

BACKGROUND: While early autism intervention can significantly improve outcomes, gaps in implementation exist globally. These gaps are clearest in Africa, where forty percent of the world's children will live by 2050. Task-sharing early intervention to non-specialists is a key implementation strategy, given the lack of specialists in Africa. Naturalistic Developmental Behavioral Interventions (NDBI) are a class of early autism intervention that can be delivered by caregivers. As a foundational step to address the early autism intervention gap, we adapted a non-specialist delivered caregiver coaching NDBI for the South African context, and pre-piloted this cascaded task-sharing approach in an existing system of care. OBJECTIVES: First, we will test the effectiveness of the caregiver coaching NDBI compared to usual care. Second, we will describe coaching implementation factors within the Western Cape Department of Education in South Africa. METHODS: This is a type 1 effectiveness-implementation hybrid design; assessor-blinded, group randomized controlled trial. Participants include 150 autistic children (18-72 months) and their caregivers who live in Cape Town, South Africa, and those involved in intervention implementation. Early Childhood Development practitioners, employed by the Department of Education, will deliver 12, one hour, coaching sessions to the intervention group. The control group will receive usual care. Distal co-primary outcomes include the Communication Domain Standard Score (Vineland Adaptive Behavior Scales, Third Edition) and the Language and Communication Developmental Quotient (Griffiths Scales of Child Development, Third Edition). Proximal secondary outcome include caregiver strategies measured by the sum of five items from the Joint Engagement Rating Inventory. We will describe key implementation determinants. RESULTS: Participant enrolment started in April 2023. Estimated primary completion date is March 2027. CONCLUSION: The ACACIA trial will determine whether a cascaded task-sharing intervention delivered in an educational setting leads to meaningful improvements in communication abilities of autistic children, and identify implementation barriers and facilitators. TRIAL REGISTRATION: NCT05551728 in Clinical Trial Registry (https://clinicaltrials.gov).

Dietary intervention in gestational diabetes: a qualitative study of the acceptability and feasibility of a novel whole-diet intervention in healthcare professionals.

Gestational diabetes is treated with medical nutrition therapy, delivered by healthcare professionals; however, the optimal diet for affected women is unknown. Randomised controlled trials, such as the DiGest (Dietary Intervention in Gestational Diabetes) trial, will address this knowledge gap, but the acceptability of whole-diet interventions in pregnancy is unclear. Whole-diet approaches reduce bias but require high levels of participant commitment and long intervention periods to generate meaningful clinical outcomes. We aimed to assess healthcare professionals' views on the acceptability of the DiGest dietbox intervention for women with gestational diabetes and to identify any barriers to adherence which could be addressed to support good recruitment and retention to the DiGest trial. Female healthcare professionals (n 16) were randomly allocated to receive a DiGest dietbox containing 1200 or 2000 kcal/d including at least one weeks' food. A semi-structured interview was conducted to explore participants' experience of the intervention. Interviews were audio-recorded, transcribed verbatim and analysed thematically using NVivo software. Based on the findings of qualitative interviews, modifications were made to the dietboxes. Participants found the dietboxes convenient and enjoyed the variety and taste of the meals. Factors which facilitated adherence included participants having a good understanding of study aims and sufficient organisational skills to facilitate weekly meal planning in advance. Barriers to adherence included peer pressure during social occasions and feelings of deprivation or hunger (affecting both standard and reduced calorie groups). Healthcare professionals considered random allocation to a whole-diet replacement intervention to be acceptable and feasible in a clinical environment and offered benefits to participants including convenience.

Designing individually randomized group treatment trials with repeated outcome measurements using generalized estimating equations.

Individually randomized group treatment (IRGT) trials, in which the clustering of outcome is induced by group-based treatment delivery, are increasingly popular in public health research. IRGT trials frequently incorporate longitudinal measurements, of which the proper sample size calculations should account for correlation structures reflecting both the treatment-induced clustering and repeated outcome measurements. Given the relatively sparse literature on designing longitudinal IRGT trials, we propose sample size procedures for continuous and binary outcomes based on the generalized estimating equations approach, employing the block exchangeable correlation structures with different correlation parameters for the treatment arm and for the control arm, and surveying five marginal mean models with different assumptions of time effect: no-time constant treatment effect, linear-time constant treatment effect, categorical-time constant treatment effect, linear time by treatment interaction, and categorical time by treatment interaction. Closed-form sample size formulas are derived for continuous outcomes, which depends on the eigenvalues of the correlation matrices; detailed numerical sample size procedures are proposed for binary outcomes. Through simulations, we demonstrate that the empirical power agrees well with the predicted power, for as few as eight groups formed in the treatment arm, when data are analyzed using the matrix-adjusted estimating equations for the correlation parameters with a bias-corrected sandwich variance estimator.

The Use and Perceptions of the Defense and Veterans Pain Rating Scale by Nursing Personnel.

BACKGROUND: In 2010, the Office of the US Army Surgeon General recommended the Veterans Administration (VA) assess pain using the Defense and Veterans Pain Rating Scale (DVPRS). One item in the DVPRS is for measuring pain intensity. This item contains a combination of five response metrics: categories, faces, colors, numbers, and functional descriptors. A few studies have supported patients' and health care providers' preferences for the DVPRS and its psychometric properties. However, they also left uncertainties about its usability and validity. AIMS: To advance our understanding of the DVPRS, this study examined the use and perceptions of the DVPRS' pain intensity item by nursing personnel during multi-modal care. DESIGN: A cross-sectional survey design was used. SETTING: VA Community Living Center. PARTICIPANTS: Nursing personnel. METHODS: Nursing personnel answered closed- and open-ended survey questions during a single session. RESULTS: Nursing personnel reported sufficient training before implementing the measure and that patients primarily used the numeric metric. When patients used a non-numeric metric, the nursing personnel responded in variable ways. In addition, the nursing personnel interpreted the functional descriptors differently. The nursing personnel also noted the need to supplement the pain intensity item with patients' pain duration and pain location. CONCLUSIONS: Results from this study inform the nursing community about the DVPRS' pain intensity item, which combines multiple response metrics. The results support the need for nursing units to generate and standardize procedures for using the item to measure multi-site pain and for interpreting and documenting patients' non-numeric responses. The effects of such procedures on the measure's usability and psychometric properties warrants additional investigation.

The Patient Experience After Spontaneous Coronary Artery Dissection.

OBJECTIVE: There is considerable burden of anxiety, depression, and post-traumatic stress disorder in patients with spontaneous coronary artery dissection (SCAD), yet research is limited on the experience and impact of SCAD from the patient perspective. This literature review sought to describe the current state of the literature on the patient experience of SCAD and consequences for patients following a SCAD event from the patient perspective. To better understand how people's experiences of SCAD affect their wellbeing, quality of life, lifestyles, and identity, and what would be useful from the patient perspective, an integrative review was performed. METHODS: An integrative literature review was conducted to understand the experience of SCAD and the post-event implications. Five databases were searched. Search terms included 'spontaneous coronary artery dissection', 'SCAD', 'patient', 'experience', 'perspective', and 'opinion'. English-language, peer-reviewed primary research in people with a diagnosis of SCAD that reflected the patient experience was included. Data indicating the SCAD experience including distress prevalence were extracted into an Excel spreadsheet, and narrative synthesis of included studies followed. FINDINGS: From 325 identified studies, five were included for review, yielding a combined sample of 447 participants. Patients with SCAD reported a lack of information about SCAD and the recovery process, and use of the internet for obtaining information. Patients with SCAD reported challenges in recovery including anxiety associated with fear of recurrence and uncertainty, and a need for greater support. A wide range of negative emotions was reported during and after the SCAD event. Participants reported participating in support groups, with mixed reviews of their appropriateness and effectiveness.

Towards Novel Nutritional Strategies in Gestational Diabetes: Eating Behaviour and Obesity in Women with Gestational Diabetes Compared with Non-Pregnant Adults.

BACKGROUND: Gestational diabetes is associated with increased risk of obesity, type 2 diabetes and cardiovascular disease. Effective nutritional strategies are needed to reduce BMI and improve long-term maternal cardiometabolic health, but the relative contribution of maternal eating behaviour, a potential barrier to dietary change, has not been explored. We compared eating behaviour in women with gestational diabetes with that of men and non-pregnant women with comparable risk factors, and tested associations between eating behaviour traits and BMI in women with gestational diabetes. We hypothesized that eating behaviour would be unfavourable in gestational diabetes and would be associated with BMI. METHODS: Participants (n = 417) including 53 men, 164 non-pregnant women and 200 women with gestational diabetes (singleton pregnancy; 29 weeks' gestation) were recruited into three prospective studies assessing weight loss interventions, with similar entry criteria. The three-factor eating questionnaire (TFEQ-R18) assessed uncontrolled eating, emotional eating and cognitive restraint at study enrolment. Associations between BMI at study enrolment and TFEQ-R18 (% maximum score) were assessed using linear regression. RESULTS: Women with gestational diabetes had significantly lower uncontrolled eating scores vs. men (53% vs. 65%; p < 0.001) and non-pregnant women (53% vs. 66%; p < 0.001), lower emotional eating scores vs. non-pregnant women (60% vs. 71%; p < 0.001) and higher cognitive restraint (p < 0.001 vs. men and non-pregnant women). In women with gestational diabetes, emotional eating scores were positively associated with BMI at study enrolment (beta coefficient 7.8 (95% CI 3.9 to 11.7), p < 0.001). CONCLUSIONS: Women with gestational diabetes have favourable eating behaviour compared with other population groups. Because BMI at study enrolment was associated with emotional eating, nutritional strategies which reduce emotional eating may provide new opportunities to improve long-term maternal health after gestational diabetes.

When Shepherds Shed: Trajectories of Weight-Related Behaviors in a Holistic Health Intervention Tailored for US Christian Clergy.

Maintaining healthy behaviors is challenging. Based upon previous reports that in North Carolina (NC), USA, overweight/obese clergy lost weight during a two-year religiously tailored health intervention, we described trajectories of diet, physical activity, and sleep. We investigated whether behavior changes were associated with weight and use of health-promoting theological messages. Improvements were observed in sleep, calorie-dense food intake, and physical activity, with the latter two associated with weight loss. While theological messages were well-retained, their relationship with behaviors depended on the specific message, behavior, and timing. Findings offer insights into weight loss mechanisms, including the role of theological messages in religiously tailored health interventions.

Autism Caregiver Coaching in Africa (ACACIA): Protocol for a type 1-hybrid effectiveness-implementation trial.

Background: While early autism intervention can significantly improve outcomes, gaps in implementation exist globally. These gaps are clearest in Africa, where forty percent of the world's children will live by 2050. Task-sharing early intervention to non-specialists is a key implementation strategy, given the lack of specialists in Africa. Naturalistic Developmental Behavioral Interventions (NDBI) are a class of early autism intervention that can be delivered by caregivers. As a foundational step to address the early autism intervention gap, we adapted a non-specialist delivered caregiver coaching NDBI for the South African context, and pre-piloted this cascaded task-sharing approach in an existing system of care. Objectives: First, we will test the effectiveness of the caregiver coaching NDBI compared to usual care. Second, we will describe coaching implementation factors within the Western Cape Department of Education in South Africa. Methods: This is a type 1 effectiveness-implementation hybrid design; assessor-blinded, group randomized controlled trial. Participants include 150 autistic children (18-72 months) and their caregivers who live in Cape Town, South Africa, and those involved in intervention implementation. Early Childhood Development practitioners, employed by the Department of Education, will deliver 12, one hour, coaching sessions to the intervention group. The control group will receive usual care. Distal co-primary outcomes include the Communication Domain Standard Score (Vineland Adaptive Behavior Scales, Third Edition) and the Language and Communication Developmental Quotient (Griffiths Scales of Child Development, Third Edition). Proximal secondary outcome include caregiver strategies measured by the sum of five items from the Joint Engagement Rating Inventory. We will describe key implementation determinants. Results: Participant enrolment started in April 2023. Estimated primary completion date is March 2027. Conclusion: The ACACIA trial will determine whether a cascaded task-sharing intervention delivered in an educational setting leads to meaningful improvements in communication abilities of autistic children, and identify implementation barriers and facilitators.

Generalizing the information content for stepped wedge designs: A marginal modeling approach.

Stepped wedge trials are increasingly adopted because practical constraints necessitate staggered roll-out. While a complete design requires clusters to collect data in all periods, resource and patient-centered considerations may call for an incomplete stepped wedge design to minimize data collection burden. To study incomplete designs, we expand the metric of information content to discrete outcomes. We operate under a marginal model with general link and variance functions, and derive information content expressions when data elements (cells, sequences, periods) are omitted. We show that the centrosymmetric patterns of information content can hold for discrete outcomes with the variance-stabilizing link function. We perform numerical studies under the canonical link function, and find that while the patterns of information content for cells are approximately centrosymmetric for all examined underlying secular trends, the patterns of information content for sequences or periods are more sensitive to the secular trend, and may be far from centrosymmetric.

Hip Manipulation Under Anesthesia for Post-Hip Arthroscopy Pericapsular Scarring: Indications and Techniques.

Hip arthroscopy has become an increasingly common procedure with expanding indications over the last several decades. With the increase in number of procedures performed a complication profile has emerged, although there is yet to be a formal classification system for complications. The most cited complications include lateral femoral cutaneous nerve neuropraxia, other sensory deficits, chondral or labral iatrogenic damage, superficial infection and deep vein thrombosis. One complication that has not yet been well documented in the literature is pericapsular scarring/adhesions resulting in decreased hip range of motion and function. If this complication is noted to persist after adequate impingement resection and a rigorous post-operative physical therapy regimen, the senior author has addressed this with a hip manipulation under anesthesia. Therefore, this techniques paper aims to describe pericapsular scarring as a post hip-arthroscopy condition which may cause pain and demonstrate our technique to address this diagnosis through hip manipulation under anesthesia.

Pregnancy glucagon-like peptide 1 predicts insulin but not glucose concentrations.

AIMS: Incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) cause increased insulin secretion in non-pregnant adults, but their role in pregnancy, where there are additional metabolically-active hormones from the placenta, is less clear. The aim of the present study was to assess if fasting and post-load incretin concentrations were predictive of pregnancy insulin and glucose concentrations. METHODS: Pregnant women (n = 394) with one or more risk factors for gestational diabetes were recruited at 28 weeks for a 75 g oral glucose tolerance test (OGTT). Glucose, insulin, GLP-1 and GIP were measured in the fasting state and 120 min after glucose ingestion. RESULTS: Fasting plasma GLP-1 concentrations were associated with plasma insulin (standardised ß' 0.393 (0.289-0.498), p = 1.3 × 10-12; n = 306), but not with glucose concentrations (p = 0.3). The association with insulin was still evident when adjusting for BMI (ß' 0.271 (0.180-0.362), p = 1.1 × 10-8; n = 297). Likewise, at 120 min the OGTT GLP-1 concentrations were associated with plasma insulin concentrations (ß' 0.216 (0.100-0.331), p = 2.7 × 10-4; n = 306) even after adjusting for BMI (ß' 0.178 (0.061-0.294), p = 2.9 × 10-3; n = 296), but not with glucose (p = 0.9). GIP concentrations were not associated with insulin or glucose concentrations at either time point (all p > 0.2). In pregnancy plasma GLP-1, but not GIP, concentrations appear to be predictive of circulating insulin concentrations, independently of associations with BMIs. CONCLUSIONS: These results suggest that the relationship between insulin and incretins is preserved in pregnancy, but that other factors, such as placental hormones or counter-regulatory hormones, may be more important determinants of glycaemia and gestational diabetes aetiology.

Protocol for a pilot randomized controlled trial of a telehealth-delivered counseling intervention to reduce suicidality and improve HIV care engagement in Tanzania.

OBJECTIVE: Suicidal ideation is strikingly common among people living with HIV (PLWH) worldwide, leading to higher burden of disease, poor HIV care engagement, and loss of life. In low- and middle-income countries such as Tanzania, mental health resources are scarce, requiring innovative strategies for treatment. We describe the protocol for a clinical trial of a three-session telehealth counseling intervention to reduce suicidality and improve HIV care engagement in Tanzania. METHODS: In a pilot randomized controlled trial, we will assess the feasibility, acceptability, and potential efficacy of a new telehealth intervention, termed "IDEAS for Hope". A total of 60 PLWH will be enrolled from two HIV clinics in the Kilimanjaro region and connected to telehealth counsellors based at a large regional hospital. Participants will be ≥18 years old and speak either Kiswahili or English. Patient screening will occur during routine HIV clinical care to identify PLWH experiencing suicidal ideation. Baseline surveys will be administered upon enrollment and participants will be randomized 1:1 to receive either IDEAS for Hope or the comparison condition, a brief safety planning session. All participants will receive an additional referral for psychiatric treatment. Follow-up assessment will occur at three months. IDEAS for Hope is informed by a Motivational Interviewing-enhanced safety planning intervention (MI-SafeCope) and our formative work in Tanzania. The model consists of Four Pillars: living healthy with HIV, managing HIV stigma, seeking social support, and meeting basic needs. Together, these mechanisms serve as a foundation for developing a sense of safety and hope for the future. Outcome measures will include intervention feasibility, acceptability, participant suicidality, and HIV care engagement. SIGNIFICANCE: Innovative, telehealth-based counseling represents a promising treatment for suicidality among PLWH in low-resource settings. Results from this pilot trial will inform intervention refinement and parameter estimates for a future clinical trial powered to evaluate effectiveness.

The Day-in-the-Life method for assessing infant caregiving in rural Pakistan.

Objective: This manuscript describes the Day-in-the-Life (DIL) method for assessing child caregiving activities, its implementation, and findings regarding family members' roles and associations with maternal depression symptoms. Background: Infant caregiving activities are most commonly performed by the mother, although there is increasing acknowledgement of others' contribution. Few methods exist to measure the diverse caregiving activities that mothers and others perform. Method: Method development occurred within the Bachpan Cohort Study in rural Pakistan (N = 1,154 maternal-child dyads) when the child was 3 months old. The DIL was designed as a semi-structured interview in which the mother describes her child's day from their perspective. Regression analyses were then used to explore the correlation between the DIL and depression symptoms, using the Patient Health Questionnaire-9 (PHQ-9) measure. Results: The DIL method was easy to administer and displayed excellent interrater agreement. The findings indicated that instrumental caregiving was mostly provided by the mother alone, others in the household tended to contribute more to infant social interactions, and there was more support from others when the mother was less able to provide care (e.g., when ill). Depression symptoms were higher among women who experienced less contribution from family members when the mother was less able to provide care. Conclusions: The DIL can be deployed to measure infant caregiving activities and associations with maternal mental health. Implications: This method is promising for researchers interested in disentangling the contribution of multiple family members toward child caregiving and its impacts on maternal and child health.

Outcomes of Protocol-Driven Venous Thromboembolic Chemo-Prophylaxis in Trauma Patients: A Trauma Quality Improvement Project Analysis.

INTRODUCTION: Low molecular weight heparin (LMWH) is the standard for venous thromboembolic (VTE) chemo-prophylaxis in trauma patients; however, inconsistencies in the use of LMWH exist. The objective of this study was to assess VTE outcomes in response to a chemo-prophylaxis protocol guided by patient physiology (eg, creatinine clearance) and comorbidities. METHODS: ACS TQIP Benchmark Reports at a level 1 trauma center using a patient physiology and comorbidity directed VTE chemo-prophylaxis protocol were analyzed for Spring 2019 to Fall 2021. Patient demographics, VTE rates and pharmacologic VTE prophylaxis type were collected for "All Patients" and "Elderly" (TQIP: age ≥ 55 years) cohorts. RESULTS: Data was analyzed for 1919183 "All Hospitals" (AH) and 5843 patients single institution (SI) using the physiologic and comorbidity guided VTE chemo-prophylaxis protocol. Elderly subgroup had 701965 (AH) and 2939 (SI) patients. Use of non-LMWH chemo-prophylaxis was significantly higher at SI: All patients = 62.6% SI vs 22.1% (P < .01); Elderly = 68.8% SI vs 28.1% AH (P < .01). VTE, DVT, and PE rates for All Patients and Elderly subgroup were significantly reduced at SI, except Elderly PE which was statistically equivalent. CONCLUSIONS: Protocol-driven VTE chemo-prophylaxis was associated with significantly lower LMWH use accompanied by significant reductions in All VTE, DVT, PE, and Elderly VTE and DVT with no difference in Elderly PE rates. These results may imply that adherence to a physiologic and comorbidity directed chemo-prophylaxis protocol, rather than LMWH, reduces VTE events in trauma patients. Further investigation to elucidate best practice is warranted.

Telemedicine Referral to Improve Access to Specialty Care for Preschool Children in Rural Alaska: A Cluster-Randomized Controlled Trial.

OBJECTIVES: Preschool programs provide essential preventive services, such as hearing screening, but in rural regions, limited access to specialists and loss to follow-up compound rural health disparities. We conducted a parallel-arm cluster-randomized controlled trial to evaluate telemedicine specialty referral for preschool hearing screening. The goal of this trial was to improve timely identification and treatment of early childhood infection-related hearing loss, a preventable condition with lifelong implications. We hypothesized that telemedicine specialty referral would improve time to follow-up and the number of children receiving follow-up compared with the standard primary care referral. DESIGN: We conducted a cluster-randomized controlled trial in K-12 schools in 15 communities over two academic years. Community randomization occurred within four strata using location and school size. In the second academic year (2018-2019), an ancillary trial was performed in the 14 communities that had preschools to compare telemedicine specialty referral (intervention) to standard primary care referral (comparison) for preschool hearing screening. Randomization of communities from the main trial was used for this ancillary trial. All children enrolled in preschool were eligible. Masking was not possible because of timing in the second year of the main trial, but referral assignment was not openly disclosed. Study team members and school staff were masked throughout data collection, and statisticians were blinded to allocation during analysis. Preschool screening occurred once, and children who were referred for possible hearing loss or ear disease were monitored for follow-up for 9 months from the screening date. The primary outcome was time to ear/hearing-related follow-up from the date of screening. The secondary outcome was any ear/hearing follow-up from screening to 9 months. Analyses were conducted using an intention-to-treat approach. RESULTS: A total of 153 children were screened between September 2018 and March 2019. Of the 14 communities, 8 were assigned to the telemedicine specialty referral pathway (90 children), and 6 to the standard primary care referral pathway (63 children). Seventy-one children (46.4%) were referred for follow-up: 39 (43.3%) in the telemedicine specialty referral communities and 32 (50.8%) in the standard primary care referral communities. Of children referred, 30 (76.9%) children in telemedicine specialty referral communities and 16 (50.0%) children in standard primary care referral communities received follow-up within 9 months (Risk Ratio = 1.57; 95% confidence interval [CI], 1.22 to 2.01). Among children who received follow-up, median time to follow-up was 28 days (interquartile range [IQR]: 15 to 71) in telemedicine specialty referral communities compared with 85 days (IQR: 26 to 129) in standard primary care referral communities. Mean time to follow-up for all referred children was 4.5 (event time ratio = 4.5; 95% CI, 1.8 to 11.4; p = 0.045) times faster in telemedicine specialty referral communities compared with standard primary care referral communities in the 9-month follow-up time frame. CONCLUSIONS: Telemedicine specialty referral significantly improved follow-up and reduced time to follow-up after preschool hearing screening in rural Alaska. Telemedicine referrals could extend to other preventive school-based services to improve access to specialty care for rural preschool children.

ORTH.Ord: An R package for analyzing correlated ordinal outcomes using alternating logistic regressions with orthogonalized residuals.

BACKGROUND AND OBJECTIVES: Marginal models with generalized estimating equations (GEE) are usually recommended for analyzing correlated ordinal outcomes which are commonly seen in a longitudinal study or clustered randomized trial (CRT). Within-cluster association is often of interest in longitudinal studies or CRTs, and can be estimated with paired estimating equations. However, the estimators for within-cluster association parameters and variances may be subject to finite-sample biases when the number of clusters is small. The objective of this article is to introduce a newly developed R package ORTH.Ord for analyzing correlated ordinal outcomes using GEE models with finite-sample bias corrections. METHODS: The R package ORTH.Ord implements a modified version of alternating logistic regressions with estimation based on orthogonalized residuals (ORTH), which use paired estimating equations to jointly estimate parameters in marginal mean and association models. The within-cluster association between ordinal responses is modeled by global pairwise odds ratios (POR). The R package also provides a finite-sample bias correction to POR parameter estimates based on matrix multiplicative adjusted orthogonalized residuals (MMORTH) for correcting estimating equations, and bias-corrected sandwich estimators with different options for covariance estimation. RESULTS: A simulation study shows that MMORTH provides less biased global POR estimates and coverage of their 95% confidence intervals closer to the nominal level than uncorrected ORTH. An analysis of patient-reported outcomes from an orthognathic surgery clinical trial illustrates features of ORTH.Ord. CONCLUSIONS: This article provides an overview of the ORTH method with bias-correction on both estimating equations and sandwich estimators for analyzing correlated ordinal data, describes the features of the ORTH.Ord R package, evaluates the performance of the package using a simulation study, and finally illustrates its application in an analysis of a clinical trial.