Composite Outcome Measure Research Articles

OGC SO10 - Modification of the Complications Parameter for ‘Textbook Outcome’ in Oesophageal Cancer Surgery

Abstract Background Surgical resection is cornerstone of curative treatment for most patients with oesophageal cancer. ‘Textbook outcome’ (TBO), a composite outcome measure, was proposed to benchmark quality of care for patients undergoing oesophagogastric cancer surgery. One required parameter for TBO is the absence of ‘severe’ complications (defined as Clavien-Dindo (CD) grade ≥2). In recent years there has been debate regarding whether a CD grade 2 complication should be considered a significant deviation from the desired post-operative course. This study aimed to assess whether revised a TBO parameter of CD≥3 is associated with improved overall survival in patients undergoing oesophagectomy for cancer. Method Data were collected for consecutive patients who underwent oesophagectomy for cancer at a single tertiary centre in the United Kingdom, between January 2018 and February 2020. Patients were identified from a prospectively maintained regional database with additional datapoints sought from electronic patient records. These included baseline clinicopathological characteristics, treatment details and the previously defined postoperative outcomes required for assessment of TBO. The primary outcome of interest was overall survival. Results Ninety-one patients (68.1% male, median 67 years (IQR: 59-72)) underwent oesophagectomy. Most had clinical stage III (61.5%) or IVA disease (28.6%) and underwent neoadjuvant chemotherapy (82.4%). When classified using the CD≥2 parameter, 15.4% achieved TBO compared with 41.8% when using CD≥3. Improved overall survival was observed in patients with a TBO using CD≥3 complication parameter (p=0.033). Survival was comparable between TBO and non-TBO group with the CD≥2 cut-off (p=0.550). TBO using CD≥3 remained associated with better survival, following adjustment for confounding variables, (HR:0.50 (95%CI:0.26-0.97), p=0.042)) while TBO using CD≥2 was not (HR:0.81 (95%CI:0.33-2.00, p=0.648)). Conclusion This study demonstrates that an association between TBO and overall survival in our patient population was only evident when the parameter requiring no ‘severe complication’ was re-defined as CD≥3. Consideration of TBO for specialist units may be useful for benchmarking quality and for prognostication.

Abstract 4134460: Application of Principal Component Analysis to Heterogenous Fontan Registry Data to Identify Independent Contributing Factors to Decline

Introduction: Single ventricle heart disease is a severe and life-threatening illness, and improvements in clinical outcomes of those with Fontan circulation have not yet yielded acceptable survival over the past two decades. Patients are at risk of developing a diverse variety of Fontan-associated comorbidities that may ultimately require heart transplant. Goal: Our study goal was to determine if principal component analysis (PCA), which determines unique directions of data variance, applied to data collected from a pediatric Fontan cohort can predict functional decline (N=140). Methods: Heterogeneous data broadly consisting of measures of cardiac and vascular function, exercise (VO 2max ), lymphatic biomarkers, and blood biomarkers were collected over 9 years at a single site as part of a prospectively applied clinical care pathway; in that time, 16 events occurred that are considered here in a composite adverse outcome measure. After standardization and PCA, principal components (PCs) representing >5% of total variance were thematically labeled based on their constituents and tested for association with the composite outcome. Results: Our main findings suggest that the 6 th PC (PC6), representing 7.1% percent of the total variance in the set, is greatly influenced by albumin, alkaline phosphatase, total protein, BUN and BNP max and is a superior measure of proportional hazard compared to EF; it displayed the greatest accuracy for classifying Fontan patients as determined by AUC. In bivariate hazard analysis, we found that models combining systolic function (EF or PC5) and blood biomarkers (PC6) were most predictive, with the former having the greatest AIC, and the latter having the highest c-statistic. Conclusion: Our findings support the hypothesis that a broad, prospectively collected, multiorgan system model analyzed by way of unsupervised machine learning methods will improve prognosis of adverse outcomes in a Fontan cohort.

Ideal outcome post-pancreatoduodenectomy: a comprehensive healthcare system analysis.

Indicators, such as mortality and complications, are commonly used to measure the quality of care. However, a more comprehensive assessment of surgical quality is captured using composite outcome measures such as Textbook Outcome (TO), Optimal Pancreatic Surgery, and a newer 'Ideal Outcome' (IO) measure. We reviewed our institutional experience to assess the impact of demographics, comorbidities, and operative variables on IO after pancreatoduodenectomy (PD). A retrospective study was conducted on PD patients at Northwell Health between 2009 and 2023. IO was determined by the absence of six adverse outcomes, including in-hospital mortality, Clavien-Dindo ≥ III complications, clinically-relevant postoperative pancreatic fistula, reoperation, hospital stay > 75th percentile, and readmission within 30 days. Logistic regression analyzed the effects of various factors on achieving IO. Of the 578 patients who underwent PD, 248 (42.91%) achieved the IO. On multivariable analysis, factors associated with increased odds of achieving IO included neoadjuvant chemotherapy (OR 1.30, 95% CI 1.05-1.62) and the presence of neuroendocrine tumors (OR 3.37, 95% CI 1.35-8.41). Percutaneous transhepatic biliary drainage (PTBD) (OR 0.34, 95% CI 0.14-0.80) and older age (≥ 70 years) (OR 0.48, 95% CI 0.32-0.74) were associated with decreased odds of achieving IO. Patients with IO had significantly improved survival on Kaplan-Meier log-rank test (p = 0.001) as well as adjusted Cox analysis (HR 0.62 95% CI: 0.39-0.97). IO may offer a comprehensive metric for assessing PD outcomes, highlighting the impact of age, chemotherapy, biliary drainage, and tumor types. These findings suggest targeted interventions and quality improvements could enhance PD outcomes by addressing modifiable factors and refining clinical strategies.

226. PHILOSOPHICAL CONSIDERATIONS IN SURGICAL INNOVATION

Abstract Background Innovation in surgery has been viewed as synonymous with progress. This is not always the case as many new innovative processes, devices and techniques do not yield same results in "real world" as they do in the experimental stage. The purpose of this presentation is to discuss the role of philosophical experiment in the process of appraisal of surgical innovation. Methods A thought experiment was conducted analysing past surgical innovations. Introduction of electrosurgery, laparoscopic cholecystectomy, surgical safety checklist and laparoscopic aortic aneurysm repair were tested. All consequences (known and hypothetical) of these innovations were considered in attempt to establish a more holistic metric of success. Results Significant limitations exist in the current assessment methods of innovation "success" which is commonly defined based on the results of a study of chosen pre-set metrics (main outcome). The utility of key metric used to assess innovation (e.g. lengths of hospital stay or visual pain scores) is limited by the choice of these outcomes. This reduces the changes of detecting rate, but possibly, much more significant unintended effects both advantageous and harmful (e.g. discovery of insulin vs thalidomide). The magnitude of detectable change is dictated by practicality of powering controlled studies and exposes results to the sensitivity bias. Unanticipated effects of the innovation are frequently not discovered until it is adopted on a large scale. Various outcomes of innovation are non-commensurable and further complicate the definition of "success". A novel innovation outcome assessment process is proposed: net global utility, a composite outcome measure which considers all potential effects of innovation (clinical, social, economic, ethical and other). Net global utility is a subjective measure that allows observer to compare non-commensurable values by not using them in isolation. One of the main advantages of net global utility is that it only requires knowledge of available metrics and principles of logical argument, providing an easy assessment tool to boost local oversight of introduction of innovation and policy-making. It includes calculation of risk (probability x consequence) which allows to account for improbable but highly consequential outcomes. Net global utility is compared to the best available alternative and derives internal face validity from this. Net global utility encompasses potential incidental future benefits as well as assessment of innovation against the test of justice. Conclusion Defining success in surgical innovation can be challenging. The use of thought experiment and logical argument is described to introduce a novel metric "net global utility" allowing for composite assessment of innovation success. Various previous surgical innovations used to demonstrate the application of the net global utility.

Exploratory analysis of the potential disconnect between objective inflammatory response and clinical response following certolizumab pegol treatment in patients with active axial spondyloarthritis

IntroductionThis post hoc analysis evaluated the relationship between objective measures of inflammation and clinical outcomes following 12 weeks of certolizumab pegol (CZP) treatment in patients with active axial spondyloarthritis (axSpA).MethodsWe...

Process indicators outshine outcome measures: assessing hospital quality of care in breast cancer treatment in China

Reporting the results of quality indicators can narrow the gap in the quality of care between hospitals. While most studies rely on outcome indicators, they may not accurately measure the quality of care. Process indicators are not only strongly associated with treatment outcomes, but are also more sensitive to whether patients are treated accurately, enabling timely intervention. Our study aims to investigate whether process indicators provide a more reasonable assessment of hospital quality of care compared to outcome indicators. Data were sourced from the Specific Disease Medical Service Quality Management and Control System in China. A total of 113,942 patients with breast cancer treated in 298 hospitals between January 2019 and April 2023 were included in this retrospective study. The rankability of 11 process indicators was calculated and used as a weight to create a new composite indicator. The composite indicators and outcome measures were compared using the O/E ratio categories. Finally, in order to determine the impact of different years on the results, a sensitivity analysis was conducted using bootstrap sampling. The rankability (ρ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\rho$$\\end{document}) values of the eleven process indicators showed significant differences, with the highest ρ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\rho$$\\end{document} value for preoperative cytological or histological examination before surgery (0.919). The ρ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\rho$$\\end{document} value for the outcome indicator was 0.011. The rankability-weighting method yielded a comprehensive score (ρ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\rho$$\\end{document} = 0.883). The comparison with categorical results of the outcome indicator has different performance classifications for 113 hospitals (37.92%) for composite scores and 140 (46.98%) for preoperative cytological or histological examinationbefore surgery. Process indicators are more suitable than outcome indicators for assessing the quality of breast cancer care in hospitals. Healthcare providers can use process indicators to identify specific areas for improvement, thereby driving continuous quality improvement efforts.

Evaluating two implant designs in patients undergoing primary total knee arthroplasty using a novel measure of early optimal recovery: a retrospective observational study.

Quality of care in total knee arthroplasty (TKA) between implants was assessed using a novel composite outcome measure, early optimal recovery (EOR), to indicate ideal clinical outcomes and minimal healthcare resource utilization. Patients that underwent primary TKA in the study group (ATTUNE® Knee System) or control group (LCS® COMPLETE Knee System) were included in this retrospective, single-center study. EOR was defined as no complications, no readmissions, no extra outpatient visits, ≤ 48h length of hospital stay (LOS), and restored range of motion and pain perception at 3-month follow-up. Multivariate logistic regression was used to compare EOR between the study and control groups. Results were adjusted for differences in baseline characteristics and are presented with 95% confidence intervals (CI). Data were collected from a specialized clinic for elective surgeries in the Netherlands, between January 2017 and December 2020. A total of 566 patients (62.4% female, mean age 67years) were included for analysis; 185 patients (32.7%) underwent TKA in the study group. Compared to the control group, patients in the study group had greater probability of achieving EOR (65.8% [95% CI: 55.1-75.2] vs. 38.9% [95% CI: 32.8-45.3]; p < 0.001), a LOS ≤ 48h (77.2% [95% CI: 67.7-84.5] vs. 61.4% [95% CI: 54.7-67.7]; p < 0.05), and ideal pain perception at 3-month follow-up (93.3% [95% CI: 85.7-97.0] vs. 78.2% [95% CI: 71.0-83.9]; p < 0.05). The study group was associated with a greater probability of achieving EOR versus the control group, suggesting improved quality of care.

The OPI•AID Zone Tool as a composite outcome for postoperative pain management quality-A protocol for an observational pilot study.

Managing postoperative pain while minimizing opioid-related adverse drug events (ORADEs) remains a significant challenge. The OPI•AID Zone Tool is proposed as a novel clinical decision support tool that - both graphically and in a scoring-system -represents the relationship between pain management and the occurrence of ORADEs, aiming to enhance patient outcomes in postoperative care. The OPI•AID Zone Tool places pain scoreon the x-axis and an ORADE score on the y-axis, and stratifies patients into five zones to reflect the composite impact of pain severity and ORADEs on the quality of postoperative patient care. The study will have two key aims: (1) to explore whether the OPI•AID Zone Tool can function as a composite outcome measure for postoperative pain and ORADEs, and (2) to evaluate the use of the OPI•AID Zone Tool in visual presentations and for evaluation of patients' postoperative pain management quality. This prospective observational cohort study will include 200 adults undergoing various surgical procedures in general anesthesia with a subsequent stay in the post-anesthesia care unit (PACU) at Bispebjerg Hospital, Denmark. Substudy 1 primary outcome: To assess whether a zone score in the OPI•AID Zone Tool is associated with patient-perceived health (EQ VAS), quality of recovery (QoR-PACU), and time to discharge readiness in PACU, and if the zone score has a stronger association than pain and ORADE score in themselves. Substudy 2 primary outcome: To assess how the use of intraoperative non-opioid analgesics impact where patients are placed in the OPI•AID Zone Tool's XY scatterplot right after surgery. To assess if patients who receive more comprehensive non-opioid analgesic basic regimens, generally fall into lower zones. The OPI•AID Zone Tool could potentially be a valuable clinical decision-making tool for optimizing postoperative care by simultaneously addressing pain management and the risk of ORADEs. By computing a composite measure of these two critical outcomes, the tool could guide more nuanced and patient-centered analgesic regimens, potentially improving patient satisfaction and operational efficiency in postoperative settings. The tool's applicability will be explored in this observational pilot and followed up in a planned series of studies (opiaid.dk).

Composite Outcome Measures for Psoriatic Arthritis: OMERACT and 3 and 4 Visual Analog Scale Progress in 2023.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Outcome Measures in Rheumatology (OMERACT) psoriatic arthritis (PsA) working group provided updates at the GRAPPA 2023 annual meeting on its work to evaluate composite outcome measures for PsA. An ongoing systematic literature review is in progress to evaluate psychometric measurement properties using the OMERACT filter 2.2 for a list of candidate composite outcome measures, which include minimal disease activity (MDA), Disease Activity for Psoriatic Arthritis (DAPSA), American College of Rheumatology (ACR) response criteria, Psoriatic Arthritis Disease Activity Score (PASDAS), Composite Psoriatic Disease Activity Index (CPDAI), 3 visual analog scale (3VAS), and 4VAS. The performance of the 3VAS and 4VAS in clinical practice and a synthesis of new data were presented, including estimates for minimal clinically important differences and thresholds of meaning, discrimination and construct validity, and longitudinal construct validity. Numeric rating scale (NRS) versions of the VAS have also been tested. Performance characteristics and psychometric properties are similar to the ASSESS study, a UK multicenter study, indicating that the VAS scales may be feasible tools for routine clinical care with a preference for the 4VAS because of superior face validity and clinical utility.

Application of Principal Component Analysis to Heterogenous Fontan Registry Data Identifies Independent Contributing Factors to Decline.

Single ventricle heart disease is a severe and life-threatening illness, and improvements in clinical outcomes of those with Fontan circulation have not yet yielded acceptable survival over the past two decades. Patients are at risk of developing a diverse variety of Fontan-associated comorbidities that ultimately requires heart transplant. Our observational cohort study goal was to determine if principal component analysis (PCA) applied to data collected from a substantial Fontan cohort can predict functional decline (N=140). Heterogeneous data broadly consisting of measures of cardiac and vascular function, exercise (VO2max), lymphatic biomarkers, and blood biomarkers were collected over 11 years at a single site; in that time, 16 events occurred that are considered here in a composite outcome measure. After standardization and PCA, principal components (PCs) representing >5% of total variance were thematically labeled based on their constituents and tested for association with the composite outcome. Our main findings suggest that the 6th PC (PC6), representing 7.1% percent of the total variance in the set, is greatly influenced by blood serum biomarkers and superior vena cava flow, is a superior measure of proportional hazard compared to EF, and displayed the greatest accuracy for classifying Fontan patients as determined by AUC. In bivariate hazard analysis, we found that models combining systolic function (EF or PC5) and lymphatic dysfunction (PC6) were most predictive, with the former having the greatest AIC, and the latter having the highest c-statistic. Our findings support our hypothesis that a multifactorial model must be considered to improve prognosis in the Fontan population.

Filling the "GAP" in Real-World Assessment of Psoriatic Arthritis Disease Activity: Performance Characteristics of a Global/Pain Composite Endpoint.

Some retrospective data sources, such as electronic health records in the USA, report composite outcome measures not fully validated in psoriatic arthritis (PsA). However, they often contain global assessments, such as a Physician Global Assessment (PhGA) and Patient Global Assessment (PatGA), along with patient-reported pain scores, which individually are considered validated in PsA. This research described the performance characteristics of a 3-item global assessment and pain (GAP) composite endpoint using data from the ixekizumab phase3 PsA clinical trial program. Discrimination of GAP was assessed by comparing placebo to active treatment arms. The magnitude of treatment effect and responsiveness were compared to Disease Activity Index for PsA (DAPSA), clinical DAPSA, DAPSA28, and Psoriatic Arthritis Disease Activity Score (PASDAS) using effect size (ES) and standardized response mean (SRM), respectively. Construct validity was evaluated through correlation among the composite endpoints, and with other physician- and patient-reported outcomes. Change in GAP was compared in patients who reached low disease activity (LDA) levels based on DAPSA, cDAPSA, and PASDAS vs those who did not. GAP discriminated between active treatment and placebo with statistically significant separation as early as week1. The largest ES/SRM was seen with GAP (2.29/1.74) and PASDAS (2.47/1.68). GAP had the strongest correlation with PASDAS (0.81-0.92) and showed moderate correlations with patient-assessed physical function, low correlations with physician-assessed skin and nail psoriasis, and low to moderate correlation with physician-assessed enthesitis. A significantly greater improvement in GAP was seen in the groups achieving LDA states compared to those not (p < 0.001). The GAP composite, an abbreviated endpoint comprising measures common in electronic health records, has promising performance characteristics and could be used to address important clinical questions regarding outcomes and impact of PsA in existing datasets. CLINTRIALS. NCT01695239; NCT02349295.

Advancing composite outcome measures: Insights on weighting components from OMERACT 2023

ObjectiveThe OMERACT Composite Working Group hosted a workshop at OMERACT 2023 to explore the complexities of weighting components in the development of composite outcomes. This study presents the methodology and findings of this workshop, exploring the complexities of weighting the individual components of composite outcome measures. MethodsThe workshop featured a multifaceted program, beginning with a plenary session that introduced the concept of composite outcomes, shared a patient's journey with rheumatic disease through a narrative, illustrated a composite outcome for Osteoarthritis Flares, and outlined the five domains selected for this composite outcome. A breakout exercise engaged participants in ranking and assigning weights to these domains, followed by group discussions to reach a consensus on weights. The workshop concluded with another plenary session that discussed various weighting approaches, including discrete choice and conjoint analysis from the ANCA-Associated Vasculitis working group, and outlined future directions for research on composite outcome methods. ResultsThe breakout exercise revealed the challenges in assigning relative importance to different domains, highlighting the variability in participant perspectives. Consensus discussions highlighted the diversity in approaches to weighting, the need for appropriate methods to determine domain weights and the impact of such weights on the interpretation of composite scores. ConclusionThe OMERACT 2023 workshop underscored the significance of a systematic approach to weighting components in composite outcome development. It highlighted the complexity of achieving consensus on the importance of domains and the role of incorporating the perspectives of patient research partners in this process. Future research directions include refining weighting methodologies, moving composites through the OMERACT Filter and enhancing understanding of their implications for clinical trials. The findings contribute to the ongoing discourse on optimizing composite outcome measures in rheumatology and beyond, advocating for a balanced integration of scientific rigour and patient-centeredness in their development.

Impact of Inflammatory Markers and Senescence-Associated Secretory Phenotype in the Gingival Crevicular Fluid on the Outcomes of Periodontal Regeneration.

The aim of this study was to test the molecular expression profile (senescence-associated secretory phenotype; SASP) in gingival crevicular fluid (GCF) prior to surgery in relation to the distribution of clinical success of periodontal regeneration. Forty consecutive patients presenting sites with residual probing pocket depth (PPD) ≥ 6 mm and intrabony defects ≥ 3 mm were treated through a minimally invasive surgical technique. Pre-operatively, GCF was sampled for inflammatory biomarker analysis related to SASP [interleukin (IL)-1β, IL-6, and IL-12; matrix-metalloproteinases (MMP)-8 and -9]. Better or worse responders were classified depending on the achievement of a composite outcome measure at 1-year [COM; PPD ≤ 4 mm and clinical attachment gain (CAL) gain ≥ 3 mm]. Correlation analyses and logistic regression models were performed. Periodontal regeneration led to significant improvements in mean clinical and radiographic parameters. Teeth achieving COM presented significantly lower amounts of SASP factors compared with non-successful teeth. Higher CAL gain, PPD reduction, and radiographic bone fill were negatively correlated with IL-1β and MMP-8 and -9 (p < 0.001), while IL-12 showed a direct relationship with CAL gain (p = 0.005) and PPD reduction (p = 0.038). Sites expressing higher SASP expression in the GCF before periodontal regeneration achieved worse clinical and radiographic outcomes.

The flapless approach with and without enamel matrix derivatives for the treatment of intrabony defects: A randomized controlled clinical trial.

To compare the clinical and radiographic outcomes of flapless procedure alone or in combination with enamel matrix derivatives (EMD) in the treatment of deep intrabony defects. Forty-six patients re-evaluated after non-surgical therapy were randomly assigned to the test (flapless with EMD) or control group (flapless alone). Clinical measurements were recorded pre-surgery and at 6 and 12 months after surgery, and radiographic measurements were taken pre-surgery and after 12 months. Forty-six patients completed the study. Improvements were observed in both groups at 12 months for mean clinical attachment level (CAL) gain, with significant differences between test (3.9 ± 1.1 mm) and control groups (3.0 ± 1.2) (p = .017). Probing pocket depth (PPD) reduction (4.0 ± 0.7 vs. 3.3 ± 1.4 mm) was also near to statistical significance (p = .051). Also, more sites achieved successful composite outcome measure (final PPD ≤ 4 mm and CAL gain ≥3 mm) for the regenerative treatment in the flapless + EMD group (82.6% vs. 52.2%; p = .028). In terms of radiographic outcomes, EMD yielded a greater defect bone fill than flapless treatment alone (3.0 ± 1.0 mm vs. 1.8 ± 1.5 mm; p < .001). The additional application of EMD during the flapless procedure for intrabony defects slightly improved clinical and radiographic outcomes. gov identification number: NCT05456555.

Composite outcome measures in high-impact critical care randomised controlled trials: a systematic review

BackgroundThe use of composite outcome measures (COM) in clinical trials is increasing. Whilst their use is associated with benefits, several limitations have been highlighted and there is limited literature exploring their use within critical care. The primary aim of this study was to evaluate the use of COM in high-impact critical care trials, and compare study parameters (including sample size, statistical significance, and consistency of effect estimates) in trials using composite versus non-composite outcomes.MethodsA systematic review of 16 high-impact journals was conducted. Randomised controlled trials published between 2012 and 2022 reporting a patient important outcome and involving critical care patients, were included.Results8271 trials were screened, and 194 included. 39.1% of all trials used a COM and this increased over time. Of those using a COM, only 52.6% explicitly described the outcome as composite. The median number of components was 2 (IQR 2–3). Trials using a COM recruited fewer participants (409 (198.8–851.5) vs 584 (300–1566, p = 0.004), and their use was not associated with increased rates of statistical significance (19.7% vs 17.8%, p = 0.380). Predicted effect sizes were overestimated in all but 6 trials. For studies using a COM the effect estimates were consistent across all components in 43.4% of trials. 93% of COM included components that were not patient important.ConclusionsCOM are increasingly used in critical care trials; however effect estimates are frequently inconsistent across COM components confounding outcome interpretations. The use of COM was associated with smaller sample sizes, and no increased likelihood of statistically significant results. Many of the limitations inherent to the use of COM are relevant to critical care research.

A multimodal approach to automated hierarchical assessment of bulbar involvement in amyotrophic lateral sclerosis.

As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement leads to progressive declines of speech and swallowing functions, significantly impacting social, emotional, and physical health, and quality of life. Standard clinical tools for bulbar assessment focus primarily on clinical symptoms and functional outcomes. However, ALS is known to have a long, clinically silent prodromal stage characterized by complex subclinical changes at various levels of the bulbar motor system. These changes accumulate over time and eventually culminate in clinical symptoms and functional declines. Detection of these subclinical changes is critical, both for mechanistic understanding of bulbar neuromuscular pathology and for optimal clinical management of bulbar dysfunction in ALS. To this end, we developed a novel multimodal measurement tool based on two clinically readily available, noninvasive instruments-facial surface electromyography (sEMG) and acoustic techniques-to hierarchically assess seven constructs of bulbar/speech motor control at the neuromuscular and acoustic levels. These constructs, including prosody, pause, functional connectivity, amplitude, rhythm, complexity, and regularity, are both mechanically and clinically relevant to bulbar involvement. Using a custom-developed, fully automated data analytic algorithm, a variety of features were extracted from the sEMG and acoustic recordings of a speech task performed by 13 individuals with ALS and 10 neurologically healthy controls. These features were then factorized into 10 composite outcome measures using confirmatory factor analysis. Statistical and machine learning techniques were applied to these composite outcome measures to evaluate their reliability (internal consistency), validity (concurrent and construct), and efficacy for early detection and progress monitoring of bulbar involvement in ALS. The composite outcome measures were demonstrated to (1) be internally consistent and structurally valid in measuring the targeted constructs; (2) hold concurrent validity with the existing clinical and functional criteria for bulbar assessment; and (3) outperform the outcome measures obtained from each constituent modality in differentiating individuals with ALS from healthy controls. Moreover, the composite outcome measures combined demonstrated high efficacy for detecting subclinical changes in the targeted constructs, both during the prodromal stage and during the transition from prodromal to symptomatic stages. The findings provided compelling initial evidence for the utility of the multimodal measurement tool for improving early detection and progress monitoring of bulbar involvement in ALS, which have important implications in facilitating timely access to and delivery of optimal clinical care of bulbar dysfunction.

Prepandemic Resilience to Trauma and COVID-19 Infection in Older Women.

Prior work suggests that psychological resilience to trauma may protect not only mental but also physical health. This study examined the relationship of prepandemic psychological resilience to lifetime trauma with self-reported COVID-19 infection and symptoms during the early years of the COVID-19 pandemic. Data are from 18,670 longitudinal cohort participants in the Nurses' Health Study II. Based on prior evidence that trauma and subsequent distress can increase infection risk and severity, and that psychological assets may offset this risk, we hypothesized higher versus lower psychological resilience to prior trauma would be associated with lower risk for COVID-19 infection. Prepandemic resilience was assessed via self-report between 2017 and 2019 based on self-reported lifetime trauma exposure and psychological health. COVID-19 infection and symptoms were self-reported on seven questionnaires administered between May 2020 and October 2021, from which we derived a composite outcome measure of probable COVID-19 infection, defined as having 3+ COVID-19 symptoms (out of 9) and/or a positive COVID-19 test result at any single assessment. Multivariable regression revealed significant associations between higher prepandemic resilience scores and lower risk for probable COVID-19 infection, adjusting for sociodemographic and COVID-19-related risk factors (risk ratio [RR] = 0.90 [95% confidence interval {CI}, 0.87-0.93]). Considering subcomponents of the composite COVID-19 infection measure separately, prepandemic resilience was significantly associated with lower risk of reported symptoms (RR = 0.83 [95% CI, 0.79-0.88]), but not with a positive test result alone (RR = 0.96 [95% CI, 0.91-1.01]). Identifying protective factors for infection risk may help inform psychosocial interventions to improve health outcomes.

90 Novel approach for childhood Sjögren’s Disease therapies: multistakeholder design of a series of N-of-1 trials

OBJECTIVES/GOALS: Childhood Sjögren’s disease (cSD) is a rare autoimmune disease. Despite the profound impact on children and their families, pediatric-specific clinical trials to inform therapeutic strategies in cSD are lacking. In 2022 we participated in the Trial Innovation Network (TIN) Design Lab with the purpose of designing a series of N-of-1 trials for cSD. METHODS/STUDY POPULATION: New medications have the potential to be safe/effective treatments for cSD but must be evaluated in randomized trials. To overcome limitations of traditional parallel-group designs given the rarity of cSD, we developed an N-of-1 trial approach. Our proposal was selected by the Tufts TIN Design Lab. The Design Lab multi-stakeholder process involved parents of and patients with cSD, pediatric and adult rheumatologists, and experts in clinical trial design and outcomes. We engaged all stakeholders in protocol development to maximize the impact of the proposed approach on clinical care, ensure a successful recruitment plan, and inform the choice of endpoints as there are no widely accepted cSD outcome measures to determine treatment efficacy. RESULTS/ANTICIPATED RESULTS: Using the Design Lab methodology, we clarified the N-of-1 study goals and engaged in an iterative process to develop a “briefing book” that ensured a sound premise for our study. We reviewed and accumulated published literature to support our focus on mucosal/glandular manifestations, identified potential interventions to be used in the N-of-1 trials, and enumerated possible outcomes, including outcomes important to patient/parents. This work culminated in a full-day Design Lab event that included multiple stakeholders who provided expertise from different perspectives on the full drug development pathway. Study design feedback focused on three specific areas. 1) Inclusion and exclusion criteria; 2) Identification of outcome measures; 3) Treatment and washout periods. DISCUSSION/SIGNIFICANCE: To address the critical need and move treatment of cSD forward, we are designing a prototype N-of-1 trial in children with rheumatic disease. We will continue to engage stakeholders by using a series of Delphi surveys and an in-person meeting to create composite outcome measures to test cSD therapies in personalized trials.

The IRELAnD study—investigating the role of early low-dose aspirin in diabetes mellitus: a double-blinded, placebo-controlled, randomized trial

Although aspirin therapy is being increasingly advocated with the intention of risk modification for a wide range of pregnancy complications, women with prepregnancy diabetes mellitus are commonly excluded from clinical trials. The primary aim of this study was to examine the effect of aspirin therapy on a composite measure of adverse perinatal outcome in pregnancies complicated by pregestational diabetes mellitus. A double-blinded, placebo-controlled randomized trial was conducted at 6 university-affiliated perinatology centers. Women with type 1 diabetes mellitus or type 2 diabetes mellitus of at least 6 months' duration were randomly allocated to 150-mg daily aspirin or placebo from 11 to 14 weeks' gestation until 36 weeks. Established vascular complications of diabetes mellitus, including chronic hypertension or nephropathy, led to exclusion from the trial. The primary outcome was a composite measure of placental dysfunction (preeclampsia, fetal growth restriction, preterm birth <34 weeks' gestation, or perinatal mortality). The planned sample size was 566 participants to achieve a 35% reduction in the primary outcome, assuming 80% statistical power. Secondary end points included maternal and neonatal outcomes and determination of insulin requirements across gestation. Data were centrally managed using ClinInfo and analyzed using SAS 9.4. The 2 treatment groups were compared using t tests or chi-square tests, as required, and longitudinal data were compared using a repeated-measures analysis. From February 2020 to September 2022, 191 patients were deemed eligible, 134 of whom were enrolled (67 randomized to aspirin and 67 to placebo) with a retrospective power of 64%. A total of 101 (80%) women had type 1 diabetes mellitus and 25 (20%) had type 2 diabetes mellitus. Reaching the target sample size was limited by the impact of the COVID-19 pandemic. Baseline characteristics were similar between the aspirin and placebo groups. Treatment compliance was very high and similar between groups (97% for aspirin, 94% for placebo). The risk of the composite measure of placental dysfunction did not differ between groups (25% aspirin vs 21% placebo; P=.796). Women in the aspirin group had significantly lower insulin requirements throughout pregnancy compared with the placebo group. Insulin requirements in the aspirin group increased on average from 0.7 units/kg at baseline to 1.1 units/kg by 36 weeks' gestation (an average 83% within-patient increase), and increased from 0.7 units/kg to 1.3 units/kg (a 181% within-patient increase) in the placebo group, over the same gestational period (P=.002). Serial hemoglobin A1c levels were lower in the aspirin group than in the placebo group, although this trend did not reach statistical significance. In this multicenter, double-blinded, placebo-controlled randomized trial, aspirin did not reduce the risk of adverse perinatal outcome in pregnancies complicated by prepregnancy diabetes mellitus. Compared with the placebo group, aspirin-treated patients required significantly less insulin throughout pregnancy, indicating a beneficial effect of aspirin on glycemic control. Aspirin may exert a plausible placenta-mediated effect on pregestational diabetes mellitus that is not limited to its antithrombotic properties.

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups.

It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years. We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction. In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.