Longitudinal Outcomes Research Articles

Hemoglobin A1c control is an independent predictor of circulating troponin concentrations using machine learning

Abstract Diabetes mellitus (DM) is associated with multiple comorbidities that may precipitate cardiac damage and elevated cardiac troponin (cTn) concentrations including renal failure, hyperlipidemia (HLD), hypertension (HTN), coronary artery disease (CAD), and congestive heart failure (CHF). Diabetics >70 years old have a higher likelihood of adverse outcomes including major cardiovascular events and cardiac mortality. However, the risk to younger diabetic patients and the precipitating factor(s) that facilitate cardiac injury in those with DM are unknown. The objective of this study was to investigate factors predictive of cTn concentrations in young, relatively healthy diabetic patients. We collected 1,533 remnant plasma samples from outpatients between 06/22-09/22 with physician ordered hemoglobin A1c testing. cTn was measured using the Abbott ARCHITECT High Sensitivity Troponin-I assay (limit of detection = 1.7 ng/L, imprecision = 4.76% at 50 ng/L). Demographic information (sex, race, BMI) and pertinent medical history (diabetes, HTN, HLD, CAD, CHF) were collected from the electronic medical record, along with estimated glomerular filtration rate (eGFR) and hemoglobin A1c. Exclusion criteria included: patients with missing laboratory data, those undergoing cancer treatment, or a history of myocardial infarction/cardiomyopathy/ cardiac surgery. Troponin results were classified as normal- or high-risk using a cut-off of 10 ng/L for females and 12 ng/L for males, thresholds previously shown to correlate with incidence of cardiovascular disease risk within 15 years. Univariate statistics were calculated using bootstrap resampling. An XGBoost model was trained to predict high-risk troponinemia, and summary statistics were calculated on a held-out test set. Of the 1,135 patients that met inclusion criteria, 621 (54.7%) were female. The median age was 60 years (IQR: 49-69 years) and the median A1c was 6.2% (IQR: 5.8-7.0%). A total of 746 patients (65.7%) had a prior diabetes diagnosis, with 156 patients (13.7%) having prediabetes, 42 patients (3.7%) having Type 1, and 548 patients (48.3%) having Type 2. Median troponin concentration for patients with an A1c <5.7% was 1.6 ng/L (IQR: 0.8-3.4), 5.7-6.4% was 2.2 ng/L (IQR:1.3-4.8), and ≥6.5% was 2.9 ng/L (IQR: 1.6-6.7). Univariate analysis demonstrated significant differences in troponinemia by age (CI of difference: 4.4-8.9 years), A1c (0.2-0.7%), and eGFR (28-38mL/min/1.73m2). The machine learning model demonstrated strong predictive capacity (sensitivity: 0.74, specificity: 0.86, PPV: 0.5, NPV: 0.92, area under ROC curve: 0.91). The features with the greatest impact on area under the ROC curve when removed were eGFR, Age, A1c, and CHF, suggesting a combination of clinical and laboratory variables can be used to predict circulating troponin concentrations in outpatients. Results of both univariate and multivariate analyses suggest that A1c control is an independent contributor to cTn concentrations. Ultimately, this study provides evidence that glucose control may be associated with cardiac damage and future cardiovascular events, warranting longitudinal outcome studies.

Longitudinal Patient-Reported Outcomes and Clinical Outcomes By VES-13 and Comprehensive Geriatric Assessment in Older Adults with Aggressive Non-Hodgkin Lymphomas

Background: Older adults with aggressive non-Hodgkin lymphoma (NHL) can experience durable remissions with therapy but also substantial toxicities and healthcare utilization. The Vulnerable Elders Survey (VES-13) is a 13-item tool assessing age, self-rated health, and ability to perform physical and functional activities (score of 3+ indicates vulnerability). The Fondazione Italiana Linfomi comprehensive geriatric assessment (CGA) assesses age, comorbidities, and ability to perform physical and functional activities and classifies patients as fit, unfit, or frail. Both the VES-13 and CGA hold promise to risk stratify older adults for poor outcomes. Few data are available comparing these tools in assessing risk for poor survival and healthcare utilization, and prior studies have not examined the impact of therapy on longitudinal patient-reported outcomes (PROs). Methods: We conducted a longitudinal prospective study of 105 older adults with aggressive NHL at Massachusetts General Hospital or the Dana-Farber Cancer Institute between 9/2020 and 1/2023. Eligible patients were age >= 65 years at time of treatment initiation receiving combination chemoimmunotherapy. Patients could enroll up until cycle 1 day 8 of therapy. Patients completed questionnaires at baseline and 6 weeks, 12 weeks, 18 weeks, and 6 months post therapy initiation assessing demographics, quality of life (QOL-Functional Assessment of Cancer Therapy-Lymphoma [FACT-Lym]), depression and anxiety (Hospital Depression and Anxiety Scale [HADS]), and physical symptoms (Edmonton Symptom Assessment Scale-revised [ESAS-r]). At baseline patients also completed the VES-13 and underwent CGA evaluated by an oncologist. We utilized linear mixed models to examine longitudinal QOL, depression, anxiety, and physical symptoms. We assessed univariate factors associated with longitudinal QOL. Using Cox regression models controlling for gender, age-adjusted International Prognostic Index (IPI), hypoalbuminemia, Charlson comorbidity index (CCI), and lymphoma subtype, we assessed the relationship of VES-13 and CGA in separate models with overall survival (OS). We also examined factors associated with unplanned hospitalization within 6 months of therapy start using logistic regression. Results: We enrolled 106/163 (65.0%) patients. 1 patient was excluded due to treatment with an ineligible therapy. Patients had a median age of 73 years (range: 65-99, 38.1% >75, 21.9% >=80); most were male gender (64.8%), White race (96.2%), and married/with a life partner (72.4%). The most common lymphoma subtypes were DLBCL (73.0%), DLBCL/high grade B-cell lymphoma with MYC and BCL2 translocations (12.4%), and mantle cell lymphoma (10.5%). The majority (56/104, 53.8%) had an age-adjusted IPI of 2 or 3, over a third (34.3%) had a CCI score of 2+, and 82.9% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 45.7% (48/105) had a VES-13 score of 3+. 40.0%, 9.5%, and 50.5% were fit, unfit, and frail, respectively, on CGA. QOL, depression, anxiety, and physical symptoms all improved over time (Figure 1). QOL improved regardless of age group, VES-13 category (<3 vs 3+), or CGA result (Figure 1). Compared to other patients, those 80+ years with either VES-13 score 3+ (β= -2.90, p=0.045) or frail on CGA (β= -3.68, p=0.007) had a worse QOL trajectory. Income > $50,000 annually (β=2.41; p=0.041) was associated with better QOL trajectory. VES-13 score of 3+ (HR=6.08; p=0.014) and frail on CGA (HR=5.20; p=0.028) were both associated with worse survival. Of those with follow up (N=66), 8 died within 1 year (1-year OS=87.9%), all of whom were both frail on CGA and had VES-13 score 3+. 25.8% (8/31) of the CGA frail patients and 28.6% (8/28) of those with VES-13 3+ died within 1 year. VES-13 score (OR=1.16, p=0.028) was associated with greater likelihood of unplanned hospitalization. Conclusion: Older adults with aggressive NHL often experience improvement in QOL and other PROs with treatment, even across age and frailty categories. VES-13 score and CGA identify patient groups at high risk for early death and poor QOL trajectory, for whom novel therapies and supportive care interventions are warranted. Higher VES-13 score is also associated with higher risk of unplanned hospitalization. Routine assessment of VES-13 and CGA has high potential for early identification of high risk patients and implementation of appropriate interventions.

Longitudinal Patient-Reported Outcomes (PROs) in a Prospective Registry of CAR T-Cell Therapy Recipients

Background Chimeric antigen receptor T-cell therapies (CAR-T) significantly improve survival and health-related quality of life (HRQoL) in clinical trials of relapsed hematologic malignancies. However, the impact of CAR-T on real-world longitudinal patient-reported outcomes (PROs), particularly in the immediate post-CAR-T period during which patients are hospitalized and at risk for acute CAR-T-related toxicities, has not been studied. Further, few CAR-T studies have utilized Patient-Reported Outcomes Measurement Information System (PROMIS) survey instruments, which are recommended to enable comparison of PROs across various CAR-T products and disease types. To characterize real-world HRQoL and symptom burden in patients receiving CAR-T, we integrated PROMIS PRO instruments into a prospective cellular therapy registry. Methods The University of Chicago Cellular Therapy Biobank prospectively administers the PROMIS v1.2 Global Health and PROMIS-29 Profile v2.1 instruments to CAR-T recipients. PRO instruments are administered at the following timepoints, anchored to the day (D) of CAR-T receipt: baseline (at time of apheresis), D+1, D+15, D+28, D+90, D+180, and then every 3 months until the 2-year timepoint. The Biobank was queried for all patients who completed a baseline and at least one post-CAR-T survey. PROMIS T-scores were analyzed by one-way repeated measures ANOVA up to the 12-month timepoint. PROMIS T-scores were longitudinally visualized as mean change from baseline. Minimally important differences (MID) that were clinically significant were defined as T-score changes of at least 2. Statistical analyses were performed in STATA, version 17.0. Results There were 68 patients available for PRO analysis. Median age was 65 years (range, 24-80) and 63% were male. Most patients had large B-cell lymphomas (n = 27, 40%) or multiple myeloma (n = 27, 40%). Median prior lines of therapy were 4 (range, 1-12), with only 3 patients receiving 1 prior therapy. The majority of patients received CD19-targeted products (n = 35, 51%), followed by BCMA-targeted products (n = 27, 40%). Patients lived a median of 36 miles from the CAR-T center (range, 2-544), with 65% living over 30 miles away. Survey completion rates at timepoints were as follows: 73% at D+15, 82% at D+28, 84% at D+90, 76% at D+180, and 95% at 12 months. For PROMIS Global Health, there was a significant longitudinal change in Global Physical Health (p = .002), with a clinically meaningful improvement by D+28 which was no longer observed by D+90 ( Figure 1), but no significant change in Global Mental Health (p = .09). For PROMIS-29 Profile, there were significant longitudinal changes in physical function (p = .0001), fatigue (p = .001), and social role functioning (p = .002), but not anxiety (p = .08), depression (p = .45), sleep (p = .92), or pain (p = .27). There were clinically meaningful improvements in both physical and social role functioning in the first 28 days after CAR-T which were no longer observed by D+90 ( Figure 1). Fatigue significantly worsened in the first 28 days after CAR-T to a clinically meaningful degree, but subsequently improved to better than baseline after D+90 ( Figure 2). With a median follow-up of 9 months (range, 1-28), 40% of patients had post-CAR-T disease progression. Relapses occurred a median of 4.9 months after CAR-T, with 31% of relapses (n = 8) occurring before D+90. There were 10 deaths (15%) at a median of 6.7 months after CAR-T. Conclusions In this real-world prospective PRO analysis, there were clinically meaningful improvements in several HRQoL domains in the first month after CAR-T, namely physical and social functioning, despite significantly worsening fatigue during the same time period. However, these HRQoL improvements diminished after D+28, concurrent with the transition of patients from the CAR-T center to home. These results suggest that intensive support by the inpatient and outpatient care teams may improve physical HRQoL during the immediate post-CAR-T period. In addition, given the low rate of relapses before D+90 in this cohort, worsening patient-reported functioning after D+28 may be driven by changes in care support after discharge to home. Interventions to optimize the post-CAR-T transition to home are warranted, as well as studies utilizing PROMIS PROs to identify patients with deteriorating HRQoL who may benefit from augmented support and/or closer surveillance for relapsed disease.

Comparative Analysis of Methods for Analyzing Clinical Results of Immuno-Oncology Therapy with Delayed Treatment Effects

Introduction: CAR-T therapy is a groundbreaking therapy that involves modifying patient's T cells to recognize and combat cancer cells. This therapy requires a period of CAR-T manufacture following apheresis, delaying the actual receipt of the CAR-T. During this period the patient may receive bridging therapy. CAR-T therapies are increasingly being studied in randomized controlled clinical trials and delays potentially affect the proportional hazards assumption, reduce log-rank test statistical power, and complicate reporting and interpretation. To address this, we assessed available statistical methods for analyzing immune-oncology outcomes, specifically CAR-T therapy's delayed treatment effects, with a focus on current and emerging tools to improve analysis and reporting. Methods: We systematically reviewed and compared existing and emerging tools to evaluate survival analysis methods suitable for assessing outcomes in CAR-T studies. These methods included standard, stratified, and weighted log-rank tests, cox proportional hazards (time dependent), parametric survival (weibull, etc.), time-dependent covariates, landmark analysis, joint modeling and restricted mean survival time (RMST). We simulated trial results, highlighted features, underlying assumptions, and interpretability. Results: Results were based on a simulated dataset (N=240) and revealed distinct characteristics and implications of each method used to analyze data (Table). Standard log-rank tests, which give equal weight to all time points and assumes proportional hazards, resulted in less discerning outcome measurements compared to weighted techniques such as censored weighted estimation/constant piecewise weighted (CWE/CPW) and Fleming-Harrington which do not assume proportional hazards and can be weighted towards early or late events. RMST summarized average time until progression, which may be a more intuitive measure for clinicians and patients and was presented along with other analytical techniques. Cox proportional hazards modeling provided ratios to quantify and compare efficacy across different time points. Parametric survival models captured survival dynamics and offered precise estimation of survival probabilities at specific intervals. Time-dependent covariates accounted for time-varying factors influencing treatment response, while landmark analysis evaluated treatment efficacy beyond a specific duration and was used in combination with other analytical techniques. Joint modeling simultaneously assessed treatment effects on both longitudinal and survival outcomes, accounting for their interdependencies. Stratification identified patient subgroups with differential treatment responses and outcomes, enabling precise reporting of categorical CAR-T treatment approaches. Conclusions: Our comparative analysis of analytical techniques underscores the critical role of selecting an appropriate approach in the context of CAR-T therapies. Conventional methods such cox regression and the standard log-rank test, while useful in most contexts, may underestimate key outcomes associated with CAR-T therapy due to violations of proportional hazard assumption. Weighted techniques, which can be weighted towards early or late events, may provide a more nuanced picture, and better accommodate CAR-T therapies. Similarly, the RMST offers an intuitive average time to progression, offering complementary insights to other methods. These findings highlight the importance of careful method selection in survival analysis for CAR-T therapy studies. Rigorous, tailored analytical approaches will be crucial in accurately determining the efficacy of these promising therapies and informing future clinical study designs. By considering these methods, researchers can gain deeper insights regarding CAR-T therapy and improve the design and analysis of clinical trials, ultimately advancing the understanding and application of this transformative therapy.

Clonal Hematopoiesis Associated with Rheumatoid Arthritis

Introduction: Clonal hematopoiesis (CH) becomes common with age and can play a role in the pathophysiology of inflammatory diseases by modifying immune cell function. CH is characterized by the presence of somatic mutations in genes such as DNMT3A and TET2 (CH of indeterminate potential, CHIP), and as mosaic chromosomal alterations (mCAs). While CHIP, particularly in the context of TET2 mutations, can promote inflammation in cardiovascular diseases, the association between clonal hematopoiesis and autoimmunity has not been comprehensively studied to date. Rheumatoid arthritis (RA) is one of the most common autoimmune diseases primarily affecting joints. Seropositive RA is defined by the presence of anti-cyclic citrullinated peptide antibodies (ACPA) and/or rheumatoid factor (RF), whereas seronegative RA is a more heterogeneous inflammatory disease entity involving patients with clinical RA manifestations in the absence of ACPA and RF. Understanding of the association between CH and inflammatory processes may yield novel insights into prevention and management of autoimmune diseases. Methods: To comprehensively evaluate the association between CH and autoimmune diseases, we identified CHIP variants in whole exome sequencing (WES) data from the FINRISK study (N=10 129). We also detected mCAs and CHIP in the nationwide FinnGen study (N=340 173), where we manually identified CHIP carriers as outliers in SNP intensity plots at known CHIP loci in DNA microarray data. Only known CHIP loci with variant prevalence comparable to UK Biobank WES data and significant positive associations with age and hematological malignancies were included for downstream analyses. To further characterize the link between CHIP and RA phenotypes, we performed targeted panel sequencing of 69 myeloid driver genes in 675 RA patient blood samples (91% collected at diagnosis) and 60 healthy controls. We studied the association between CH and RA in multivariable models excluding participants with prevalent hematologic malignancies and adjusting for sex, age, smoking, and principal components of ancestry. We performed uni- and multivariable analyses to evaluate the link between CHIP and RA patient phenotypes. Results: We identified CHIP in 381 (3.8%) FINRISK participants. As expected, the prevalence of CHIP increased with age, and CHIP variants were associated with prevalent and incident hematologic malignancies. C-reactive protein values were higher in participants with CHIP (P<0.001). In multivariable models, CHIP status (OR 1.98, 1.13-3.45, P=0.017) was more common in participants with questionnaire-based history of RA (N=151) (Fig 1A). In the FinnGen study, CHIP carrier status was associated with prevalent autoimmune diseases (OR 1.26, 1.05-1.53, P=0.015). We validated the association between prevalent RA (N=10 990) and CHIP carrier status (N=2 393) in the FinnGen study (OR 1.58, 1.18-2.13, P=0.002) (Fig 1A). In particular, CHIP (OR 2.17, 1.40-3.36, P<0.001), and GNB1 variants (OR 4.71, 1.87-11.82, P=0.001) were associated with the seronegative RA, whereas DNMT3A was associated with seropositive RA (OR 1.83, 1.08-3.09, P=0.024). We observed no association between autosomal mCAs and RA. Using targeted panel sequencing, we found CHIP in 22% (146/675) of RA patients. RA patients with CHIP variants were older than those without a CHIP variant (median, 69 vs 63 years, P<0.001). Erythrocyte sedimentation rate (ESR) was higher in those with CHIP (median, 42.5 vs 26.0 mm/h, P=0.043). RA patients with TET2 variants were more likely to have seronegative disease compared with TET2 wild-type patients (proportion of seronegative patients, 56% vs 33%, OR 2.62; P=0.008) (Fig 1B). The association remained significant (OR 2.38, 1.14-4.96, P=0.02) when adjusting for age, sex, and smoking. Evaluation of longitudinal disease outcomes by CHIP status are currently ongoing. Conclusion: CHIP variants were more common in participants with prevalent RA in two population-level cohorts, and the association was specific to seronegative RA in the large FinnGen cohort. In newly diagnosed RA patients, TET2 mutations were more common in seronegative than in seropositive RA. While the causality and the functional basis of these observations remain to be explored in future studies, our results provide additional evidence for the association between CHIP and inflammation in various disease contexts, including autoimmune diseases.

Prognostic and Therapeutic Implications of TP53 expression in Chronic Myelomonocytic Leukaemia: Results of a Multicentre Study

Thetumor suppressor TP53 is among the most mutated genes in cancer, including many hematological malignancies in which it usually imparts more aggressive, chemo-refractory, and poor prognosis diseases. TP53 mutations are, though, remarkably rare in chronic myelomonocytic leukemia (CMML): affecting 2.4% of cases in a recent study ( Gurney et al, Leukemia 2023). We found pathogenic TP53 mutations ( TP53MT) in only 1.1% of 640 genotyped UK CMML patients. As expected, TP53MT conferred worse leukemia-free (LFS: median 23 v 28 mo, p=0.031) and overall (OS: 26 v 29 mo, p=0.015) survival compared with TP53WTcases. The clinical relevance in CMML of TP53 expression, however, remains unexplored. To address this we studied 92 TP53WT CMML patients (discovery cohort) from the National Taiwan University Hospital (Taipei, Taiwan) with available RNA-seq on presentation bone marrow (BM), each with extensive longitudinal clinical, laboratory and outcome data. Validation cohorts comprised 33 RNA-sequenced patients from The Christie (Manchester, UK) and 24 from Hospital Morales Meseguer (Murcia, Spain). For all cohorts, RNA-seq data from healthy controls (HCs) were available. Patients in the discovery cohort were divided into low and high TP53 expression groups, determined by the maximally selected rank statistics. TP53low patients (n=15) displayed significantly lower expression than HCs, while TP53high (n=77) had expression levels comparable to HCs. Thus, although most CMML patients are TP53WT, a subset has down-regulated TP53 expression and potential for altered p53 (and downstream) functions. TP53low and TP53high patients did not differ in clinical features or concurrent genetic alterations, although in all cohorts TP53low patients showed a trend towards poorer response to hypomethylating agents (HMA). TP53 low patients displayed significantly worse outcomes than TP53high patients (LFS 7 v 19 mo, p=0.002; OS 11 v 26 mo, p=0.001). Moreover, TP53 expression further stratified prognosis within different CMML-specific prognostic scoring system (CPSS)-molecular risk groups (Fig 1) . Time-dependent ROC analysis indicated TP53 expression as complementary to current risk stratification systems. In multivariable analysis, low TP53 expression remained prognostically detrimental. Survival analyses were consistent in both validation cohorts. GSEA and IPA analyses revealed that compared with HCs or TP53high, TP53low cells exhibited depleted expression of p53-dependent pathways, including MYC targets, E2F targets, G2/M checkpoints, and DNA repair. Interestingly, these are all among the most upregulated pathways in TP53MT (v TP53WT) samples across multiple cancers in TCGA data ( Donehower et al, Cell Rep 2019), indicating distinct roles for p53 in regulating these pathways in a TP53WT context, and that the driving biology of TP53low CMML is distinct from (and not functionally equivalent to) that of oncogenic TP53 mutations. TP53low patients demonstrated significantly enhanced TNF-alpha and inflammatory response signals, highlighting other distinctive pathobiology of the TP53low subgroup. In line with our clinical observation, single-sample GSEA showed significant enrichment of HMA resistance signatures in TP53low patients, potentially contributing to the dismal prognosis in this group. We next investigated whether this could be exploited therapeutically. We treated primary CMML BM cells ex vivo with azacitidine and NSC-207895, an MDMX inhibitor with p53 activating properties, observing clear and substantial synergy for combination therapy in samples from 10 of 11 patients. There was a trend towards inverse correlation between TP53 expression and empirical synergy scores (r=-0.35), suggesting potential for p53 activation to enhance HMA sensitivity in CMML, with broad efficacy, perhaps preferentially in adverse risk TP53low cases. In summary, we have identified and validated, across three cohorts from three countries, that a subgroup of CMML patients display aberrantly low TP53 expression, associated with HMA resistance and worse survival. Transcriptomic analyses revealed distinctive biology driving this novel TP53low subgroup (Fig 2), mandating further mechanistic study. Importantly we report consistent and substantial synergy for combining pharmacological p53 activation with HMA, presenting a novel targeted approach to improve HMA response for this unmet clinical need.

Longitudinal Differences By Treatment Arm in Health-Related Quality of Life Among High Risk Pediatric Hodgkin's Lymphoma Patients Treated on the Children's Oncology Group Ahod 1331 Study

Introduction: Brentuximab vendotin (BV) with AVE-PC demonstrated superior efficacy to ABVE-PC for pediatric patients with high-risk HL in the AHOD 1331 trial. However, there are no data regarding the impact on health-related quality of life (HRQoL) with the addition of BV into the treatment of pediatric HL. Methods: Eligibility for AHOD 1331 (NCT 02166463) included previously untreated HL with high risk disease, defined as stage IIB +bulk, IIIB, IVA, or IVB classic HL. Participants were randomized to either BV-AVE-PC (“BV” arm) or ABVE-PC (standard arm). Among the first 309 participants enrolled in a prespecified longitudinal patient-reported outcomes sub study, 280 were age 11+ years and eligible to self-report HRQoL using the seven-item Child Health Ratings Inventories (CHRIs)-Global scale. HRQoL was assessed prior to treatment (T1), at cycle 2 (T2), at cycle 5 (T3), and at the end of treatment (T4). A clinically meaningful increase in HRQoL was considered a change of 7 points in the CHRIs-Global score (CHRIs), translating to a 1/3 standard deviation. Multivariable linear regression estimated the association between demographic/clinical variables and HRQoL at T1. Linear mixed models estimated the change in HRQoL relative to T1 with a time*treatment arm interaction to estimate differences in the change in HRQoL across treatment arm. This model was adjusted for age, sex, race/ethnicity, stage, large mediastinal adenopathy (LMA), B-symptoms at diagnosis, and a time-varying covariate for involved site radiation prior to T4. Results: Participant and disease characteristics were balanced by treatment arm; mean age at enrollment was 15.6 years (SD= 1.9), 52% were female, 60.4% had LMA, and 58% were stage IV. 93% of participants completed the CHRIs at T1, 92% at T2, 89% at T3, and 74% at T4. At T1, female sex (mean (SD) 64.1 (20.2) vs 71.3 (23.3) p=0.004) and fever (60.8 (23.0) vs. 71.9 (20.4) p=0.024) were associated with worse HRQoL. At each time point after pre-treatment (T1), HRQoL was higher, on average, in the BV arm compared to the standard arm (Figure 1). By T2, participants in the BV arm experienced a statistically and clinically significant increase in HRQoL compared to pre-treatment (T1) (Table 1; β=7.3 95%CI 3.2, 11.4; p≤0.001), which was greater than the change experienced in the standard arm (difference in change β=5.1 95%CI -0.2, 10.3; p=0.057). At T3 and T4 the BV arm continued to experience statistically significant improvements in HRQoL relative to T1 (T3 β=5.3 95%CI 0.8, 9.9; p=0.022; T4 β=14.6 95%CI 10.3, 18.9; p≤0.001). The standard arm did not experience a statistically or clinically significant increase in HRQoL from T1 until T4 (β=9.3 95%CI 4.7, 11.5; p<0.001). Conclusion: Patients with high-risk pediatric HL treated with BV-AVE-PC experienced more rapid and sustained improvement in HRQoL compared to patients treated with ABVE-PC. These data also demonstrate the feasibility and importance of incorporating HRQoL assessments into pediatric clinical trials.

Clinical outcomes up to 9 years after [18F]flutemetamol amyloid-PET in a symptomatic memory clinic population

BackgroundPrevious studies demonstrated increases in diagnostic confidence and change in patient management after amyloid-PET. However, studies investigating longitudinal outcomes over an extended period of time are limited. Therefore, we aimed to investigate clinical outcomes up to 9 years after amyloid-PET to support the clinical validity of the imaging technique.MethodsWe analyzed longitudinal data from 200 patients (Mage = 61.8, 45.5% female, MMMSE = 23.3) suspected of early-onset dementia that underwent [18F]flutemetamol-PET. Baseline amyloid status was determined through visual read (VR). Information on mortality was available with a mean follow-up of 6.7 years (range = 1.1–9.3). In a subset of 108 patients, longitudinal cognitive scores and clinical etiological diagnosis (eDx) at least 1 year after amyloid-PET acquisition were available (M = 3.06 years, range = 1.00–7.02). VR − and VR + patients were compared on mortality rates with Cox Hazard’s model, prevalence of stable eDx using chi-square test, and longitudinal cognition with linear mixed models. Neuropathological data was available for 4 patients (mean delay = 3.59 ± 1.82 years, range = 1.2–6.3).ResultsAt baseline, 184 (92.0%) patients were considered to have dementia. The majority of VR + patients had a primary etiological diagnosis of AD (122/128, 95.3%), while the VR − group consisted mostly of non-AD etiologies, most commonly frontotemporal lobar degeneration (30/72, 40.2%). Overall mortality rate was 48.5% and did not differ between VR − and VR + patients. eDx at follow-up was consistent with baseline diagnosis for 92/108 (85.2%) patients, with most changes observed in VR − cases (VR − = 14/35, 40% vs VR + = 2/73, 2.7%, χ2 = 26.03, p < 0.001), who at no time received an AD diagnosis. VR + patients declined faster than VR − patients based on MMSE (β = − 1.17, p = 0.004), episodic memory (β = − 0.78, p = 0.003), fluency (β = − 1.44, p < 0.001), and attention scores (β = 16.76, p = 0.03). Amyloid-PET assessment was in line with post-mortem confirmation in all cases; two cases were VR + and showed widespread AD pathology, while the other two cases were VR − and showed limited amyloid pathology.ConclusionIn a symptomatic population, we observed that amyloid-status did not impact mortality rates, but is predictive of cognitive functioning over time across several domains. Also, we show particular validity for a negative amyloid-PET assessment, as these patients did not receive an AD diagnosis at follow-up.

Longitudinal outcome monitoring in patients with chronic gastroduodenal symptoms investigated using the Gastric Alimetry system: study protocol

IntroductionThe Gastric Alimetry platform offers a multimodal assessment of gastric function through body surface gastric mapping (BSGM) and concurrent symptom-tracking via a validated App. We aim to perform a longitudinal...

Prevalence, characteristics, and impact on health outcomes of frailty in elderly outpatients with diabetes: A cross-sectional study.

The aims of this study were to determine the prevalence of frailty and its relationship with health outcomes in elderly outpatients attending a Diabetes Specialist Clinic. This study was a cross-sectional study. A total of 168 elderly patients (aged 65 years and above) attending the Diabetes Specialist Clinic of a Three-A hospital of Sichuan province were recruited from January 2021 to February 2021, and follow-up was conducted 1 year after day of screening. Baseline characteristics of patients were collected and frail status were assessed at recruitment. The longitudinal outcomes included hospitalization, fall, mortality, emergency visit, and clinic visit. The presence of frailty was determined by the 5-item FRAIL scale, which ranges from 0 to 5 and are categorized as frail (3-5), prefrail (1-2), and robust (0). A phone questionnaire was carried out to obtain health outcomes. Logistic regression analyses was used to evaluate adverse health outcomes at 1 year follow-up. Of the 168 outpatients, 28.0% was robust, 49.4% was prefrail, and 22.6% was frail. Frailty (both prefrail and frail status) was more prevalent in those patients, which were 75 years old and above (57.0%; P < .001), insulin dependent (45.6%; P = .008), and those had diabetic complications (43.8%; P = .005), previous admission (68.6%; P = .016), and co-morbidities (36.4%; P = .001). In the following year after recruitment, 19.1% of robust patients were hospitalized, while the proportion was 45.8% for prefrail patients and 65.8% for frail patients. Prefrail (OR [odds ratio] = 2.35, 95% confidence interval (CI) 1.63-2.88; P = .028) and frail (OR = 4.63, 95% CI 2.52-5.81; P = .005) patients were more likely to be hospitalized. Frail (OR = 3.37, 95% CI 2.68-4.04; P < .001) patients were more inclined to fall while prefrail patients (OR = 1.03, 95% CI 0.82-1.56; P = .371) were not. Moreover, prefrail (OR = 3.37, 95% CI 2.31-5.72; P = .017) and frail (OR = 4.29, 95% CI 3.16-5.54; P = .006) patients were more likely to return to the clinic. There is a high incidence of frailty among elderly patients attending a Diabetes Specialist Clinic. Frailty is a predictor of hospitalization, fall, and clinic visits within 1 year.

Fast multiple-trait genome-wide association analysis for correlated longitudinal measurements

Large-scale longitudinal biobank data can be leveraged to identify genetic variation contributing to human diseases progression and traits trajectories. While methods for genome-wide association studies (GWAS) of multiple correlated traits have been proposed, an efficient multiple-trait approach to model longitudinal phenotypes is not currently available. We developed GAMUT, a genome-wide association approach for multiple longitudinal traits. GAMUT employs a mixed-effects model to fit longitudinal outcomes where a fast algorithm for inversion by recursive partitioning of the random effects submatrix is introduced. To evaluate performance of the algorithms introduced and assess their statistical power and type I error, stochastic simulation was conducted. Consistent with our expectation, power was greater for cross-sectional (CS) than longitudinal (LT) effects, particularly with a diminishing LT/CS ratio. With a minimum minor allele count of 3 within genotype by time categories, observed type I error was roughly equal to theoretical genome-wide significance. Additionally, 28 blood-based biomarkers measured at 2 time points on participants of the UK Biobank were used to compare GAMUT against single-trait standard and longitudinal GWAS (including rate of change). Across all biomarkers, we observed 539 (CS) and 248 (LT) significant independent variants for the GAMUT method, and 513 (CS) and 30 (LT) for single-trait longitudinal GWAS, respectively. Only 37 variants were identified by modeling rates of change using standard GWAS.

Association of current substance use treatment with future reduced methamphetamine use in an observational cohort of men who have sex with men in Los Angeles

IntroductionMethamphetamine use is highly prevalent among men who have sex with men (MSM), but knowledge of the long-term dynamics, and how they are affected by substance use treatment, is limited. This study aimed to describe trajectories of methamphetamine use among MSM, and to evaluate the impact of treatment for any kind of substance use on frequency of methamphetamine use. MethodsThis analysis used data from a cohort of MSM in Los Angeles, CA, who participated in semi-annual study visits from 2014 to 2022. The study characterized trajectories of methamphetamine use using a continuous time multistate Markov model with three states. States were defined using self-reported frequency of methamphetamine use in the past six months: frequent (daily), occasional (weekly or less), and never. The model estimated the association between receiving treatment for any kind of substance use and changes in state of frequency of methamphetamine use. ResultsThis analysis included 2348 study visits among 285 individuals who were followed-up for an average of 4.4 years. Among participants who were in the frequent use state, 65 % (n = 26) of those who were receiving any kind of substance use treatment at a study visit had reduced their methamphetamine use at their next visit, compared to 33 % (n = 95) of those who were not receiving treatment. Controlling for age, race/ethnicity, and HIV-status, those who reported receiving current treatment for substance use were more likely to transition from occasional to no use (HR: 1.63, 95 % CI: 1.10–2.42) and frequent to occasional use (HR: 4.25, 95 % CI: 2.11–8.59) in comparison to those who did not report receiving current treatment for substance use. ConclusionsFindings from this dynamic modeling study provide a new method for assessing longitudinal methamphetamine use outcomes and add important evidence outside of clinical trials that substance use treatment may reduce methamphetamine use.

Epidemiology of giardiasis and assemblages A and B and effects on diarrhea and growth trajectories during the first 8 years of life: Analysis of a birth cohort in a rural district in tropical Ecuador.

There are limited longitudinal data on the acquisition of Giardia lamblia infections in childhood using molecular assays to detect and type assemblages, and measure effects of infections on diarrhea risk and childhood growth. We analysed stool samples from a surveillance sample within a birth cohort in a rural district in tropical Ecuador. The cohort was followed to 8 years of age for the presence of G. lamblia in stools by quantitative PCR and A and B assemblages by Taqman assay or Sanger sequencing. We explored risk factors associated with infection using generalized estimating equations applied to longitudinal binary outcomes, and longitudinal panel data analysis to estimate effects of infection on diarrhea and growth trajectories. 2,812 stool samples collected between 1 month and 8 years of age from 498 children were analyzed and showed high rates of infection: 79.7% were infected at least once with peak prevalence (53.9%) at 5 years. Assemblage B was accounted for 56.8% of genotyped infections. Risk factors for infection included male sex (P = 0.001), daycare attendance (P<0.001), having a household latrine (P = 0.04), childhood (P<0.001) and maternal soil-transmitted helminth (P = 0.029) infections, and exposures to donkeys (age interaction P = 0.034). G. lamblia was associated with increased risk of diarrhea (per episode, RR 1.03, 95% CI 1.01-1.06, P = 0.011) during the first 3 years of life and a transient impairment of weight (age interaction P = 0.017) and height-for-age (age interaction P = 0.025) trajectories between 1 and 4 years of age. There was no increased risk of either assemblage being associated with outcomes. Our data show a relatively high edemicity of G. lamblia transmission during childhood in coastal Ecuador, and evidence that infection is associated with a transiently increased risk of diarrhea during the first 3 years of life and impairment of weight and height between 1 and 4 years.

Predictors of persistent poor control and validation of ASSESS score: Longitudinal 5-year follow-up of severe asthma cohort

BackgroundLongitudinal predictors of persistent poor asthma control in severe asthma (SA) cohort remain scarce. The predictive value of the asthma severity scoring system (ASSESS) and their validation in the SA cohort outside the original study and in the Asian population is unknown. ObjectiveTo determine the 5-year longitudinal outcome of SA patients and validate the use of ASSESS score in predicting future outcomes in SA. MethodsProspective longitudinal observational study of patients with severe asthma (SA) attending the multidisciplinary specialist SA clinic from 2011 to 2021. The number of exacerbations and asthma control tests (ACT) were recorded yearly for 5 consecutive years. ASSESS score was computed at baseline, and the area under the receiving operating characteristics curve (AUC) for predicting persistent poor asthma control was generated. ResultsOf the 489 patients recruited into the study, 306 patients with 5-year follow-up data were analyzed. Seventy-three percent had Type-2 inflammation (T2) with increased overall exacerbations over 5 years (rate ratio (RR) 2.55, 95% CI 1.31-4.96, p=0.006) relative to non-T2 SA. In the multivariate model, bronchiectasis, gastroesophageal reflux disease (GERD) and ACT<20, were significantly associated with persistent poor asthma control over 5 -years. ASSESS scores were good at predicting persistent poor asthma control with an AUC of 0.71 (95% CI 0.57-0.84). ConclusionBronchiectasis and GERD are predictors for persistent poor asthma control and targeted traits for precision medicine in SA. The ASSESS score has a good prediction for persistent poor asthma control over 5 years.

Trends of the Oswestry Disability Index in Adult Spinal Deformity Patients: A 3-Year Study

Backgroundand Importance: Patients with adult spinal deformity (ASD) undergoing operative treatment may have varying degrees of improvement in patient-reported outcomes. The Oswestry Disability Index (ODI) assesses improvement in quality of life. We aim to measure longitudinal outcomes of ODI scores over three years to determine if early ODI scores predict late ODI scores and to analyze longitudinal changes in ODI scores. Methods235 patients above the age of 18 who underwent surgical correction of ASD at a single institution from 2016 to 2021 and completed ODI questionnaires at follow-up appointments met inclusion criteria. ODI scores were included from follow-up visits at 0 months (immediately postoperative) and within ±1 month of 3, 6, 12, 18, 24, 30, and 36 months. Percent change in ODI from 0 months was calculated, and unpaired t-tests were conducted. ResultsODI scores increased by 8.8% immediately postoperatively, and the percent change from preoperative ODI scores at each subsequent visit were as follows: -11.1% at 3 months, -21.4% at 6 months, -25.4% at 12 months, -28% at 18 months, -31.3% at 24 months, -25.7% at 30 months, and -36.5% at 36 months. ODI scores at each follow-up visit showed significant improvement from baseline (p<0.001). There was an improvement in scores from 3 to 6 months (p=0.04), but no significant difference in 6-month interval visits following 6 months. ConclusionOur results demonstrate a significant and sustained improvement in ODI scores over 3 years following surgical correction of ASD. ODI scores were stable after 6 months, indicating that ODI scores at 6 months may be predictive of scores out to 3 years postoperatively. Examining individual components of ODI sub-scores and comparing ODI results to other PROMs are critical to better assess long-term outcomes in ASD.

Examining the effect of COVID-19 on hypertrophic cardiomyopathy hospitalizations in the USA: a nationwide propensity-score matched analysis

Abstract Background Impact of COVID-19 infection in patient with underlying cardiovascular conditions has been widely studied, but its impact in patients with cardiomyopathies like hypertrophic cardiomyopathy (HCM) still lack data leading to this population-based analysis. Methods We queried the National Inpatient Sample (2020) to identify adult hospitalizations with HCM in patients with vs without COVID-19. Baseline characteristics, comorbidities, and outcomes of HCM-related admissions with vs. without COVID-19 were analyzed on a propensity score matched [1:2 ratio] sample controlled for age, sex, race, income quartile, insurance payer type, and discharge quarter. Multivariate logistic regression was used to assess the impact of COVID-19 on all-cause mortality and major adverse cardiac events (MACE), a composite of Atrial Fibrillation (AF), Cardiac arrest, and Acute ischemic stroke (AIS). Results After exclusion of samples with missing data, 50400 HCM related hospitalizations were recorded in 2020 of which 2005 (4.0%) had COVID-19. 1:2 propensity matched analysis led to two HCM cohorts, 1970 patients with COVID-19 and 3905 without COVID-19 (Table 1). Of all HCM related admissions, the COVID-19 group comprised majorly of Hypertension (81.5% vs 76.2%; all p&amp;lt;0.001), diabetes (40.9% vs 34.8%; all p&amp;lt;0.001), Obesity (25.9% vs 22.8%; p=0.0090). However, had less burden of Peripheral vascular disease (6.9% vs 10.8%), prior coronary artery bypass graft (3.05 vs 5.0%), smoker (22.3% vs 28.8%), Alcohol abuse (1.8% vs 4.0%) and drug abuse (1.0% vs 3.3%); all p&amp;lt;0.001. In terms of outcome, the length of stay [days, median (IQR); 12(6-3) vs 7 (4-2)] and cost [median (IQR); $120777(54298-30976) vs 111138 (51450-25636)]; all p&amp;lt;0.001 was significantly higher in COVID-19 cohort compared to non-COVID-19 cohort. The HCM cohort admitted with COVID-19 had significantly higher all-cause mortality (15.7% vs 3.8% p&amp;lt;0.001) and cardiac arrest, including ventricular fibrillation (4.6% vs 2.6%; p&amp;lt;0.001) compared to non-COVID-19 patients. However, interestingly, the COVID-19 group revealed lower rates of AF (36.8% vs 41.5) and AIS (2.5% vs 5.9%) in HCM hospitalization compared to non-COVID-19 group; all p&amp;lt;0.001. Multivariate odds revealed nearly 4 times higher risk of all-cause mortality [OR 4.08, 95%CI (2.59-6.42), p&amp;lt;0.001] in the COVID-19 group. However, odd of AF [OR, 95% CI; 0.76 (0.58-1.00), P&amp;lt;0.04] and AIS [OR, 95% CI; 0.41 (0.19-0.89), P&amp;lt;0.02] related admissions were lower which could be attributed to lockdowns due to the pandemic rather than lower risk of these events. Conclusion This large-scale nationwide analysis revealed that HCM patients who were infected with SARS-CoV-2 infection had nearly four times higher odds of all-cause mortality with lower probability of admissions with AF and AIS. Long-term prospective studies are warranted to validate these findings and longitudinal outcomes in HCM patients infected with COVID-19, especially following vaccination.

Influence of loss- and restoration-oriented stressors on grief in times of COVID-19

This study aimed to examine the influence of COVID-specific stressors on cross-sectional and longitudinal bereavement outcomes. According to the Dual Process Model of grief these stress-inducing factors can relate to the loss (loss-oriented stressors) or to manage everyday life (restoration-oriented stressors) and require coping in the grief process. A total of 491 participants (94.1% female; 43.92 years on average; 44.4% loss of a parent) were included at the first measurement time point (T0), of whom 99 individuals also participated in a follow-up assessment 6 months later (T1). Participants frequently reported loss-oriented (on average 7.30 out of 21 queried) and restoration-oriented stressors (on average 6.99 out of 19 queried). Cross-sectionally, higher acute grief intensity was associated with a higher number of loss-oriented stressors, poorer mental well-being, and sociodemographic variables. This effect disappeared longitudinally, with only acute grief intensity and poorer mental well-being at T0 predicting higher prolonged grief at T1. Common resilience factors did not buffer the effects of the pandemic on grief. Loss-oriented stressors seem to be especially relevant for understanding grief and might be a mediator of higher long-term grief. The findings suggest that COVID-specific strains need to be specifically taken into account in the support of bereaved individuals.

Abstract 15617: Association Between Growth Differentiation Factor-15 and Outcomes Among Patients With Heart Failure: A Systematic Literature Review

Background: Growth differentiation factor-15 (GDF-15) is upregulated during myocardial injury and stress, and is an emerging biomarker of adverse outcomes in patients with heart failure (HF). Although systematic literature reviews (SLRs) of GDF-15 and HF have been conducted, few assessed outcomes other than mortality. Aim: This SLR examined the association of GDF-15 levels with a broad range of outcomes in patients with HF. Methods: Following PRISMA guidelines, Embase and Medline were searched to identify articles published 1/1/2014–8/23/2022 reporting outcomes associated with GDF-15 in adults with HF. Both cross-sectional (assessed at the same time as GDF-15) and longitudinal outcomes were included. Results: Sixty-three publications met eligibility criteria: 45 were observational studies and 18 post hoc analyses of randomized controlled trials. A total of 19 outcomes were identified. The most frequently reported longitudinal outcomes were mortality (n=32), composite endpoints (e.g., death ± hospitalization; n=28) and hospitalization (n=11). The most common cross-sectional outcome was biomarkers of kidney function (n=22). Of 27 studies assessing all-cause mortality, 24 conducted multivariable analyses (MVA), of which 22 (91.7%) reported a significant, independent association between higher baseline GDF-15 and all-cause death. Among the 26 studies reporting association between baseline GDF-15 and composite endpoints, 19 used MVA and 13/19 (68.4%) reported at least one significant association. Among 10 studies assessing hospitalization and baseline GDF-15, 8/10 (80%) reported outcomes using MVA, of which 50% found a significant association. Twenty studies assessed the cross-sectional association between baseline GDF-15 levels and measures of kidney function. Of these, 7 used MVA and reported statistically significant associations. Conclusions: The results of the SLR suggest that GDF-15 is an independent predictor of mortality and other adverse, nonfatal outcomes in patients with HF. Better understanding of the potential prognostic role of GDF-15 in HF could improve clinical risk prediction and identify patients with HF who may warrant additional treatment optimization/intensification.

Abstract 19130: Is Early Hospital Discharge Safe After Adult Heart Transplantation?

Introduction: The impact of early hospital discharge (EHD) after adult heart transplantation (HT) on longitudinal outcomes is unclear. Many HT recipients are intentionally kept in the hospital for extended stays for continued clinical monitoring. However, there is growing interest in implementing EHD protocols and initiatives to improve patient throughput, optimize hospital resources and bed capacity, and reduce costs. Hypothesis: This study evaluated the impact of EHD on HT outcomes. Methods: The United Network for Organ Sharing (UNOS) database was utilized to identify adult (≥ 18 years old) HT recipients surviving to hospital discharge between January 2010 and December 2022. EHD was defined as occurring within 7 days of HT. Kaplan-Meier analysis was used to estimate survival probability of EHD recipients at 30-days, 90-days, 1-year, 1-year conditional on 30-day survival and 1-year conditional on 90-day survival. Multivariable Cox regression was used for risk adjustment. Results: Of the 31,638 total HTs performed in the study period, 30,720 (97.1%) survived to hospital discharge of which 1,033 (3.36%) were classified as EHD. In an unadjusted analysis, HT recipients survival rates were: [(30-days: ED 99.5% vs non-EHD 98.4%, log-rank p= 0.004), (90-days: EHD 98.8% vs non-EHD 96.4%, log-rank p&lt; 0.001), (1-year: EHD 96.5% vs non-EHD 92.9%, log-rank p&lt; 0.001), (1-year conditional on 30-day survival: EHD 96.9% vs non-EHD 94.5%, log-rank p&lt; 0.001), and (1-year conditional on 90-day survival: EHD 97.6% vs non-EHD 96.4%, log-rank p= 0.036)] (Figure 1). After risk adjustment, the Hazard Ratio (HR) of mortality for EHD recipients was: [30-days HR: 0.37 (0.15-0.89, p=0.027), 90-days HR: 0.39 (0.22-0.70, p=0.001), 1-year HR: 0.57 (0.39-0.82, p=0.003), 1-year conditional on 30-day survival HR: 0.60 (0.40-0.90, p=0.013), and 1-year conditional on 90-day survival HR: 0.75 (0.47-1.18, p=0.213)]. Conclusions: HT patients with EHD have lower complication rates than non-EHD patients. Although a minority of patients have EHD after HT, these data suggest it can be done safely with excellent longitudinal outcomes. Efforts to share best practices and protocols allowing for EHD may be prudent to broadening this practice nationwide in appropriate cases.

Abstract 15947: Cracking the Code of Cardiovascular Risk: Cardiac Troponin I vs. T in Community Dwelling Adults. Is Specificity at Stake?

Introduction. High sensitive cardiac troponin I and T (hs-cTnI and T) are detectable in most adults. Several studies have identified that hs-cTnI and T perform differently for long-term prediction of incident myocardial infarction (MI). Furthermore, in adults with myopathies, hs-cTnT can lose cardiovascular (CV) specificity which may be more relevant to MI prediction vs heart failure (HF) and CV death (CVD). We hypothesized that a meta-analysis of ambulatory adult studies would demonstrate hs-cTnI is a superior predictor of incident MI, but similar for HF and CVD. Methods. Research articles on hs-cTnI or T for longitudinal outcomes in ambulatory adults were screened from PubMed, EMBASE, and Web of Science inclusive of incident MI, HF or CVD and reporting hazard ratios (HR) and 95% confidence intervals (CI) for hs-cTn on a continuous log scale. Two reviewers evaluated the studies for inclusion, removing overlapping populations and extracting the most adjusted model HR. Pooled effect sizes were calculated with a random-effects model, and heterogeneity was assessed using the I 2 statistic. Subgroup analyses based on hs-cTn type were conducted. Results. A total of 3092 studies were screened and 44 met inclusion criteria. There were 109,553, 80,597, and 141,389 participants for HF, MI, and CVD with hs-cTnI measured, and 90,012, 81,259, and 73,977 participants for HF, MI, and CVD with hs-cTnT measured with a mean age of 61 ± 10 years and a median follow-up of 2.1 – 20 years. The pooled effect size estimate (HR) for HF, MI and CVD was 1.57(1.47, 1.66), 1.27(1.18, 1.37) and 1.41(1.32, 1.50) respectively. Subgroup analyses showed similar HR values for HF (I: 1.49 (1.37, 1.62) and T: 1.64 (1.51, 1.78)), MI (Figure) and CVD (I: 1.32 (1.21, 1.44) and T: 1.49 (1.36, 1.63)). Conclusion. hs-cTnI and T are prognostically similar for incident MI, as well as HF and CVD in ambulatory adults, suggesting similar cardiac specificity, though substantial heterogeneity exists between individual studies.