Extended Cox Regression Model Research Articles

Effect of common maintenance drugs on the risk and severity of COVID-19 in elderly patients.

Maintenance drugs are used to treat chronic conditions. Several classes of maintenance drugs have attracted attention because of their potential to affect susceptibility to and severity of COVID-19. Using claims data on 20% random sample of Part D Medicare enrollees from April to December 2020, we identified patients diagnosed with COVID-19. Using a nested case-control design, non-COVID-19 controls were identified by 1:5 matching on age, race, sex, dual-eligibility status, and geographical region. We identified usage of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), statins, warfarin, direct factor Xa inhibitors, P2Y12 inhibitors, famotidine and hydroxychloroquine based on Medicare prescription claims data. Using extended Cox regression models with time-varying propensity score adjustment we examined the independent effect of each study drug on contracting COVID-19. For severity of COVID-19, we performed extended Cox regressions on all COVID-19 patients, using COVID-19-related hospitalization and all-cause mortality as outcomes. Covariates included gender, age, race, geographic region, low-income indicator, and co-morbidities. To compensate for indication bias related to the use of hydroxychloroquine for the prophylaxis or treatment of COVID-19, we censored patients who only started on hydroxychloroquine in 2020. Up to December 2020, our sample contained 374,229 Medicare patients over 65 who were diagnosed with COVID-19. Among the COVID-19 patients, 278,912 (74.6%) were on at least one study drug. The three most common study drugs among COVID-19 patients were statins 187,374 (50.1%), ACEI 97,843 (26.2%) and ARB 83,290 (22.3%). For all three outcomes (diagnosis, hospitalization and death), current users of ACEI, ARB, statins, warfarin, direct factor Xa inhibitors and P2Y12 inhibitors were associated with reduced risks, compared to never users. Famotidine did not show consistent significant effects. Hydroxychloroquine did not show significant effects after censoring of recent starters. Maintenance use of ACEI, ARB, warfarin, statins, direct factor Xa inhibitors and P2Y12 inhibitors was associated with reduction in risk of acquiring COVID-19 and dying from it.

Childhood infections and autism spectrum disorders and/or intellectual disability: a register-based cohort study

ObjectiveTo explore the associations between childhood infections and subsequent diagnoses of autism spectrum disorder (ASD), intellectual disability (ID), and their co-occurrence.MethodsThe association between specialized care for any infection, defined by ICD-codes, and later ASD or ID was investigated in a register-based cohort of 556,732 individuals born 1987–2010, resident in Stockholm County, followed from birth to their 18th birthday or December 31, 2016. We considered as potential confounders children’s characteristics, family socioeconomic factors, obstetric complications, and parental histories of treatment for infection and psychiatric disorders in survival analyses with extended Cox regression models. Residual confounding by shared familial factors was addressed in sibling analyses using within-strata estimation in Cox regression models. Sensitivity analyses with the exclusion of congenital causes of ASD/ID and documented risk for infections were also performed.ResultsCrude estimates indicated that infections during childhood were associated with later ASD and ID with the largest risks observed for diagnoses involving ID. Inclusion of covariates, exclusion of congenital causes of ASD/ID from the population, and sibling comparisons highlighted the potential for confounding by both heritable and non-heritable factors, though risks remained in all adjusted models. In adjusted sibling comparisons, excluding congenital causes, infections were associated with later “ASD without ID” (HR 1.24, 95%CI 1.15–1.33), “ASD with ID” (1.57, 1.35–1.82), and “ID without ASD” (2.01, 1.76–2.28). Risks associated with infections varied by age at exposure and by age at diagnosis of ASD/ID.ConclusionsInfections during childhood may contribute to a later diagnosis of ID and ASD.

Evaluation of Time-Varying Biomarkers in Mortality Outcome in COVID-19: an Application of Extended Cox Regression Model.

COVID-19 pandemic has created many challenges for clinicians. The monitoring trend for laboratory biomarkers is helpful to provide additional information to determine the role of those in the severity status and death outcome. This article aimed to evaluate the time-varying biomarkers by LOWESS Plot, check the proportional hazard assumption, and use to extended Cox model if it is violated. In the retrospective study, we evaluated a total of 1641 samples of confirmed patients with COVID-19 from October until March 2021 and referred them to the central hospital of Ayatollah Rohani Hospital affiliated with Babol University of medical sciences, Iran. We measured four biomarkers AST, LDH, NLR, and lymphocyte in over the hospitalization to find out the influence of those on the rate of death of COVID-19 patients. The standard Cox model suggested that all biomarkers were prognostic factors of death (AST: HR=2.89, P<0.001, Lymphocyte: HR=2.60, P=0.004, LDH: HR=2.60, P=0.006, NLR: HR=1.80, P<0.001). The additional evaluation showed that the PH assumption was not met for the NLR biomarker. NLR biomarkers had a significant time-varying effect, and its effect increase over time (HR(t)=exp (0.234+0.261×log(t)), p=0.001). While the main effect of NLR did not show any significant effect on death outcome (HR=1.26, P=0.097). The reversal of results between the Cox PH model and the extended Cox model provides insight into the value of considering time-varying covariates in the analysis, which can lead to misleading results otherwise.

Overall Survival and Survival Time by Palliative Performance Scale: A Retrospective Cohort Study in Thailand.

Objectives:The palliative performance scale (PPS) is a useful tool for predicting the survival time of palliative patients and for multidisciplinary teams in designing an appropriate care plan for patients and their families. This study aimed to (1) assess the survival time of palliative patients, (2) examine the factors associated with survival time and (3) investigate the proportion of patients whose survival time matched the time proposed by existing literature, within the Thai population.Materials and Methods:A retrospective cohort study was conducted with data drawn from five hospitals in one of the north-east provinces in Thailand. The study population comprised patients with a palliative diagnosis (ICD10: Z51.5) who had registered in one of the five hospitals between 1 October 2015 and 30 September 2017. Kaplan–Meier survival analysis was used to assess overall survival time and an extended Cox regression model to identify predictors of survival.Results:Of the 2792 registered patients, 1163 were included in the analysis. Most patients were male (55.62%), with a mean age of 64.59 years (±15.38), and were covered by the universal coverage insurance (77.72%). Approximately half (56.23%) of the participants had cancer and about a quarter (27.13%) had an initial PPS result of 30. The overall median survival time was 14 days (mean = 64.08, 95% CI: 12–16). Three significant predictors for survival included sex, hospital and initial PPS score.Conclusion:The survival time of palliative patients was relatively short. Sex, hospital and initial PPS were significant predictors of survival. The median survival time by PPS was similar to the values reported by the previous study but proportion of correct prediction was low. Therefore, it might be necessary to investigate the survival time of palliative patients by country independently.

SURVIVAL ANALYSIS TO DETERMINE AGE TO GIVE FIRST BIRTH IN WOMEN IN EAST JAVA USING EXTENDED COX REGRESSION

The age of a woman when giving birth to her first child needs to be a concern because it is related to the safety of the mother and baby. A woman being too young or too old increases the risk of death for both the mother and baby. Every woman giving birth for the first time is likely to experience psychological disorders such as anxiety and excessive fear during labor, and even postpartum depression. Given the importance and possible extent of the consequences of women giving birth for the first time, this study intended to assess the factors that influence the age at first birth, especially amongst women of childbearing age in East Java. These factors include the age at first marriage, education, and region. The method used was the extended Cox regression model. The analysis shows that the age at first marriage and education are factors that significantly influence the age at first birth. The more mature the age at first marriage, the more mature the age at first birth. Likewise, the higher the educational status, the higher the potential for giving birth to a first child over the age of 23, especially amongst women who graduated high school and university.

Impact of Pretransplant and New-Onset Diabetes After Transplantation on the Risk of Major Adverse Cardiovascular Events in Kidney Transplant Recipients: A Population-based Cohort Study.

Pretransplant diabetes and new-onset diabetes after transplant (NODAT) are known risk factors for vascular events after kidney transplantation, but the incidence and magnitude of the risk of major adverse cardiovascular events (MACE) and cardiac deaths remain uncertain in recent era. A population cohort study of kidney transplant recipients identified using data from linked administrative healthcare databases from Ontario, Canada. The incidence rates of MACE (expressed as events with 95% confidence interval [95% CI] per 1000 person-years were reported according to diabetes status of pretransplant diabetes, NODAT, or no diabetes. Extended Cox regression model was used to examine the association between diabetes status, MACE, and cardiac death. Of 5248 recipients, 1973 (38%) had pretransplant diabetes, and 799 (15%) developed NODAT with a median follow-up of 5.5 y. The incidence rates (95% CI) of MACE for recipients with pretransplant diabetes, NODAT, and no diabetes between 1 and 3 y posttransplant were 38.1 (32.1-45.3), 12.6 (6.3-25.2), and 11.8 (9.2-15.0) per 1000 person-years, respectively. Compared with recipients with pretransplant diabetes, recipients with NODAT experienced a lower risk of MACE (adjusted hazard ratio, 0.59; 95% CI, 0.47-0.74) but not cardiac death (adjusted hazard ratio, 0.97; 95% CI, 0.61-1.55). The rate of MACE and cardiac death was lowest in patients without diabetes. Patients with pretransplant diabetes incur the greatest rate of MACE and cardiac deaths after transplantation. Having NODAT also bears high burden of vascular events compared with those without diabetes, but the magnitude of the increased rate remains lower than recipients with pretransplant diabetes.

Prognostic Model for De Novo and Recurrent Metastatic Breast Cancer.

PURPOSEMetastatic breast cancer (MBC) has a heterogeneous clinical course. We sought to develop a prognostic model for overall survival (OS) that incorporated contemporary tumor and clinical factors for estimating individual prognosis.METHODSWe identified patients with MBC from our institution diagnosed between 1998 and 2017. We developed OS prognostic models by Cox regression using demographic, tumor, and treatment variables. We assessed model predictive accuracy and estimated annual OS probabilities. We evaluated model discrimination and prediction calibration using an external validation data set from the National Comprehensive Cancer Network.RESULTSWe identified 10,655 patients. A model using age at diagnosis, race or ethnicity, hormone receptor and human epidermal growth factor receptor 2 subtype, de novo versus recurrent MBC categorized by metastasis-free interval, Karnofsky performance status, organ involvement, frontline biotherapy, frontline hormone therapy, and the interaction between variables significantly improved predictive accuracy (C-index, 0.731; 95% CI, 0.724 to 0.739) compared with a model with only hormone receptor and human epidermal growth factor receptor 2 status (C-index, 0.617; 95% CI, 0.609 to 0.626). The extended Cox regression model consisting of six independent models, for < 3, 3-14, 14-20, 20-33, 33-61, and ≥ 61 months, estimated up to 5 years of annual OS probabilities. The selected multifactor model had good discriminative ability but suboptimal calibration in the group of 2,334 National Comprehensive Cancer Network patients. A recalibration model that replaced the baseline survival function with the average of those from the training and validation data improved predictions across both data sets.CONCLUSIONWe have generated and validated a robust prognostic OS model for MBC. This model can be used in clinical decision making and stratification in clinical trials.

Validation of the ELN 2017 Classification for AML with Intermediate Risk Cytogenetics with or without NPM1 -Mutations and High or Low Ratio FLT3-ITD s

IntroductionNucleophosmin 1-mutations (NPM1) and internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene (FLT3-ITDs) are the most frequently detected molecular abnormalities in patients with AML and are used for risk assessment and stratification of post-remission therapy. In the 2017 ELN recommendations (Döhner et al, Blood 2017) FLT3-ITD mutations are grouped according to the ratio of the mutant (mt) to wild type (wt) alleles into low ratio (LR) and high allelic ratio (HR) mutations using a cut-off of 0.5. AML with intermediate risk (IR) cytogenetic abnormalities and NPM1 -mutant FLT3- wt AML is grouped together with NPM1 -mutant and LR FLT3-ITD as favorable risk AML, only NPM1 -wt HR FLT3-ITD AML is considered adverse risk. Since validation studies have not been published so far for the 2017 ELN recommendations, we analyzed survival of patients with IR cytogenetic abnormalities who were treated in randomized controlled trials on intensive induction chemotherapy of the Study Alliance Leukemia (SAL) in the past two decades.MethodsWe performed a retrospective study on all patients who had received intensive induction chemotherapy for newly diagnosed AML within randomized SAL trials with available data on ELN 2017 classification. All molecular studies were performed centrally in one laboratory. Cox regression analyses were fitted with baseline risk factors including genetic markers for the full analysis set. Interaction tests were used to determine the impact of gene-gene interactions. Extended Cox regression models with a time-dependent covariate modeling the time of allogeneic hematopoietic stem cell transplantation (alloHCT) were used to study the role of alloHCT for patients who had reached first complete remission (CR1).ResultsIn total, data on 1610 IR-patients was evaluable. The median age at first diagnosis of AML was 55 years (range, 18 to 87 years), both sexes were equally represented and 72% of patients had normal karyotype AML. Eighty-three percent of patients had de novo AML, 12% secondary AML and 3% therapy-related AML. The median follow-up was 81 months (interquartile range, 63 to 103 months). Numbers of patients in the respective genetic subgroups defined by the 2017 ELN classifications and 5-year overall survival (5-yr-OS) probabilities from diagnosis were as follows (see also Figure 1): 418 patients with FLT3-ITD wt NPM1 mt AML with 50% 5-yr-OS and 119 patients with LR FLT3-ITD with NPM1 mt AML with 41% 5-yr-OS were classed together as favorable AML, 741 patients with FLT3-ITD wt NPM1 wt AML with 27% 5-yr-OS, 170 patients with HR FLT3-ITD with NPM1 mt AML with 31% 5-yr-OS, and 70 patients with LR FLT3-ITD with NPM1 wt AML also with 31% 5-yr-OS were classed as intermediate risk AML and finally 92 patients with HR FLT3-ITD with NPM1 wt AML with 20% 5-yr-OS were classed as adverse risk AML. In any combination NPM1 mutations had a protective effect. Interaction tests indicated that the combination of an NPM1 -mutation and LR FLT3-ITD increased the risk of mortality compared to the single mutations (Wald-test for interaction, p=0.08).When alloHCT in first complete remission was analyzed in an extended Cox regression analysis as time-dependent covariate, the impact differed among patients assigned to the three risk groups defined by the 2017 ELN recommendations: Results indicated that alloHCT had no impact on overall survival in patients with favorable AML HR 1.0 (95%-CI, 0.8 - 1.2), but a beneficial impact in patients with intermediate risk AML HR 0.8 (95%-CI 0.7 - 0.9) or high risk AML HR 0.7 (95%-CI 0.5 - 1.0).ConclusionsThe risk classification of the 2017 ELN recommendations according to NPM1 and FLT3-ITD genotypes was validated in this large retrospective analysis including data from 1610 patients with newly diagnosed AML with intermediate risk cytogenetic abnormalities or normal karyotype. The time-dependent analysis of alloHCT indicated that patients with favorable AML should not receive alloHCT as post-remission therapy in CR1, whereas patients with intermediate risk or high risk AML would benefit from alloHCT in CR1. [Display omitted] DisclosuresSchetelig:Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria. Rollig:Janssen: Research Funding; Bayer: Research Funding. Kayser:TEVA: Honoraria; Novartis: Honoraria, Speakers Bureau. Stoelzel:medac: Other: Travel support. Bug:Amgen: Honoraria; Janssen: Other: Travel Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel funding; Astellas: Other: Travel Funding; Jazz Pharmaceuticals: Other: Travel Funding. Mayer:Novartis: Research Funding; Eisai: Research Funding. Thiede:Novartis: Consultancy, Speakers Bureau; Roche: Consultancy; Agendix: Employment; Bayer: Consultancy, Speakers Bureau.

Association between timely targeted therapy initiation and clinical outcomes in patients with advanced HER2+ gastroesophageal adenocarcinoma.

e16048 Background: Delayed treatment initiation is associated with increased mortality in early-stage cancers. Few studies have examined the impact of timely initiation in advanced cancers. Timely targeted therapy initiation can be especially challenging due to the additional biomarker testing required to identify patients eligible for these treatments. We examined the impact of timely targeted therapy initiation on survival among patients with metastatic HER2+ gastroesophageal adenocarcinoma (GEA). Methods: We performed a retrospective cohort study of patients with metastatic HER2+ GEA treated with first line systemic therapy between 1/2011 and 12/2017 using the nationwide Flatiron Health EHR-derived deidentified database. Timely targeted therapy, defined as initiation of the anti-HER2 monoclonal antibody trastuzumab up to 14 days after first line chemotherapy initiation, was entered as a time-varying exposure on the day of initiation. Patients who initiated trastuzumab after the 14-day cut point or who lacked documentation of having received trastuzumab were classified as having non-timely targeted therapy initiation. Extended Cox regression models were used to compare progression-free (PFS) and overall survival (OS) from the date of first line treatment initiation, adjusted for potential confounders. Pre-planned sensitivity analyses assessed alternative “timeliness” definitions as well as the impact of any trastuzumab administration, regardless of the timing of initiation. Results: We included 459 patients with metastatic HER2+ GEA; 293 (63.8%) received trastuzumab, of whom 223 (76.1%) initiated in a timely manner. The median age was 65.0 years, and patients were predominantly male (82.4%) and non-Hispanic White (78.2%) with an ECOG performance status of 0-1 (85.9%). Relative to non-timely initiation, timely targeted therapy was associated with significantly higher OS (2-year OS 29.6% vs 14.6%; adjusted HR 0.72, 95% CI 0.57-0.91, p = 0.006) and PFS (2-year PFS 8.3% vs 3.9%; adjusted HR 0.78, 95% CI 0.62-0.98, p = 0.030). Results remained similar in sensitivity analyses 1) using alternative “timeliness” definitions (up to 70 days after chemotherapy initiation), and 2) comparing any trastuzumab administration, regardless of the timing of initiation, to no trastuzumab administration (OS - adjusted HR 0.75, 95% CI 0.60-0.95, p = 0.018; PFS - adjusted HR 0.81, 95% CI 0.64-1.02, p = 0.069). Conclusions: OS and PFS were higher among patients with metastatic HER2+ GEA treated with trastuzumab, regardless of the timing of targeted therapy initiation. Although our results provide reassurance to clinicians that delays in targeted therapy may not be detrimental to patient outcomes, efforts should still be made to ensure that all patients with metastatic HER2+ GEA receive first line trastuzumab.

The course of depressive symptoms and mortality in older patients with cancer

Objective The Geriatric Depression Scale (GDS-15), a self-report questionnaire, emphasizes the psychological dimension of depression. We aimed to investigate whether GDS-15 scores were associated with mortality in older patients with cancer and describe the course of individual symptoms on the GDS-15. Methods An observational, multicenter, prospective study of 288 patients 70 years or older with cancer followed over 24 months. The patients were assessed with the GDS-15 at inclusion, and after four and 12 months. An extended Cox regression model assessed the association between time-dependent GDS-15 scores and mortality. Results After adjusting for cancer-related prognostic factors, a one-point increase in GDS-15 sum score increased risk of death by 12%. GDS-15 mean score increased during the first four months of the study, as did odds for the presence of the GDS-15 symptoms ‘feel you have more problems with memory than most’, ‘not feel full of energy’, and ‘think that most people are better off than you’. The most prevalent and persistent GDS-15 symptom was ‘prefer to stay at home, rather than going out and doing new things’, and ‘not to be in good spirits most of the time’ was the least prevalent. Conclusions More severe depressive symptoms, as measured by the GDS-15, were associated with higher mortality in older patients with cancer. The importance of emotional distress and how to alleviate it should be investigated further in these patients.

Body Weight, Physical Activity, and Risk of Cancer in Lynch Syndrome.

Simple SummaryLifestyle modifies cancer risk in the general public. How lifestyle modifies cancer risk in individuals carrying the inherited pathogenic gene variants in DNA mismatch repair genes (Lynch syndrome) remains understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, physical activity, and cancer risk among Finnish Lynch syndrome carriers (n = 465, 54% women). The results of our study indicated that longitudinal weight gain increases cancer risk, whereas being highly physically active during adulthood could decrease cancer risk in men. Further, women were observed to be less prone to lifestyle-related risk factors than men. The results emphasize the role of weight maintenance and high-intensity physical activity throughout the lifespan, especially in men with Lynch syndrome.Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in body weight and PA using extended Cox regression models. The longitudinal weight change was associated with an increased risk of all cancers (HR 1.02, 95% CI 1.00–1.04) and CRC (HR 1.03, 1.01–1.05) in men. The near-term weight change was associated with a lower CRC risk in women (HR 0.96, 0.92–0.99). Furthermore, 77.6% of the participants retained their PA category over time. Men in the high-activity group had a reduced longitudinal cancer risk of 63% (HR 0.37, 0.15–0.98) compared to men in the low-activity group. PA in adulthood was not associated with cancer risk among women. These results emphasize the role of weight maintenance and high-intensity PA throughout the lifespan in cancer prevention, particularly in men with LS.

Do Group Memberships Online Protect Addicts in Recovery Against Relapse?

The Social Identity Model of Recovery (SIMOR) suggests that addiction recovery is a journey through time where membership in various groups facilitates success. With the help of computational approaches, we now have access to new resources to study whether a wide variety of different online communities can be part of the addiction recovery journey. In this work, we study the effects of two main social factors on recovery success: first, multiple group membership defined in terms of richness of online community engagement; second, active participation operationalized as the evenness in engagement with these groups. We then model recovery from addiction by applying the extended Cox regression model which accounts for the effect of these two factors on time to relapse. We applied our analysis to a dataset of 457 recovering opioid addicts that self-announced the date of their recovery, indicating that at least 219 (48%) addicts relapsed during the recovery period. We find that multiple group membership - in terms of the number of other forums that a subject had posted in - as well as active participation - in terms of how evenly their posts were spread amongst the different forums - reduced the risk of relapse. We discuss our findings with regards to the opportunity, but also risk, that online group membership poses for recovering opioid addicts, as well as the possible contribution that computational social science methods can make to the study of addiction and recovery.

Effect of Availability of Transcatheter Aortic-Valve Implantation on Survival for all Patients With Severe Aortic Stenosis

Clinical outcomes for the overall severe aortic stenosis (AS) patient population are not well described because those medically managed are not included in procedural registries, and AS severity is not identifiable from administrative data. We aim to assess whether transcatheter aortic valve implantation (TAVI) availability has been associated with overall changes in survival for the whole AS patient population. This is important because patients with AS in real-world practice may differ from those included in randomized controlled trials, potentially attenuating the purported treatment efficacy estimated in trials. Classic severe AS patients (mean gradient ≥40 mmHg) were identified from an echocardiography database. Survival was defined as time since severe AS diagnosis until death. We first compared survival among all patients before and after TAVI availability in 2008. To further understand mechanism, we then assessed whether any survival changes were attributable to TAVI with extended Cox regression models comparing survival among TAVI, surgical aortic valve replacement, and medically managed patients. 3663 classic severe AS patients were included in the study. Median survival years for all patients were greater during the TAVI-era than Pre-TAVI-era (>11.5 vs 6.8, 5-year-HR = 0.8, time-varying effect p <0.0001), and increased median survival was greatest for patients age 65 to74 (>11.5 vs 9.5, 5-year-HR = 0.7, time-varying effect p = 0.045). TAVI patients age 65 to 74 had the lowest risk of death compared to medically managed patients (HR = 0.2, 95% CI = [0.1, 0.3], p <0.0001). In conclusion, in the TAVI-era, overall survival for patients with severe AS has doubled. This improvement is most marked for patients 65 to 74 years of age.

Suicide among veterans with amyotrophic lateral sclerosis.

The purpose of this study was to estimate the risk of death by suicide for those with amyotrophic lateral sclerosis (ALS) seeking care within the Veterans Health Administration (VHA). This was a retrospective, cohort study. Extended Cox regression models were used to compare the hazard of suicide between the ALS and the unexposed groups. The hazard of suicide was 3.98 times higher for those with ALS than for those without (95% confidence interval [CI],2.64-6.00; P < .0001). After adjusting for covariates, those with ALS remained at increased risk (hazard ratio, 3.48; 95% CI, 2.31-5.24; P < .001). Among those seeking care in the VHA, individuals with ALS are at increased risk for dying by suicide. Additional suicide prevention efforts, including strategies for reducing access to lethal means, are warranted.

Association of diabetes type and chronic diabetes complications with early exit from the labour force: register-based study of people with diabetes in Finland

Aims/hypothesisDiabetes and diabetes complications are a cause of substantial morbidity, resulting in early exits from the labour force and lost productivity. The aim of this study was to examine differences in early exits between people with type 1 and 2 diabetes and to assess the role of chronic diabetes complications on early exit. We also estimated the economic burden of lost productivity due to early exits.MethodsPeople of working age (age 17–64) with diabetes in 1998–2011 in Finland were detected using national registers (Ntype 1 = 45,756, Ntype 2 = 299,931). For the open cohort, data on pensions and deaths, healthcare usage, medications and basic demographics were collected from the registers. The outcome of the study was early exit from the labour force defined as pension other than old age pension beginning before age 65, or death before age 65. We analysed the early exit outcome and its risk factors using the Kaplan–Meier method and extended Cox regression models. We fitted linear regression models to investigate the risk factors of lost working years and productivity costs among people with early exit.ResultsThe difference in median age at early exit from the labour force between type 1 (54.0) and type 2 (58.3) diabetes groups was 4.3 years. The risk of early exit among people with type 1 diabetes increased faster after age 40 compared with people with type 2 diabetes. Each of the diabetes complications was associated with an increase in the hazard of early exit regardless of diabetes type compared with people without the complication, with eye-related complications as an exception. Diabetes complications partly but not completely explained the difference between diabetes types. The mean lost working years was 6.0 years greater in the type 1 diabetes group than in the type 2 diabetes group among people with early exit. Mean productivity costs of people with type 1 diabetes and early exit were found to be 1.4-fold greater compared with people with type 2 diabetes. The total productivity costs of incidences of early exits in the type 2 diabetes group were notably higher compared with the type 1 group during the time period (€14,400 million, €2800 million).Conclusions/interpretationWe found a marked difference in the patterns of risk of early exit between people with type 1 and type 2 diabetes. The difference was largest close to statutory retirement age. On average, exits in the type 1 diabetes group occurred at an earlier age and resulted in higher mean lost working years and mean productivity costs. The potential of prevention, timely diagnosis and management of diabetes is substantial in terms of avoiding reductions in individual well-being and productivity.Graphical abstract

Individual-Level and Clinic-Level Factors Associated With Achieving Glycemic Control in a Large Cohort of People With HIV in Care-Washington, DC.

Optimal management of noncommunicable diseases, including diabetes mellitus (DM), is crucially important as people with HIV (PWH) live longer with antiretroviral therapy. Our objective was to assess patient-level and clinic-level factors associated with achieving hemoglobin A1c (HbA1c) ≤7.0% among PWH and DM. The DC Cohort, an observational clinical cohort of PWH, followed from 2011 to 2019 at 12 sites in Washington, DC. Among PWH with diagnosed DM and elevated HbA1c (>7.0%), we examined the association between achieving HbA1c ≤7.0% and demographic and clinical factors, including time-updated medication data, and clinic-level factors related to services and structure. A multilevel marginal extended Cox regression model was generated to identify factors associated with time to HbA1c ≤7.0%. Over half (52.3%) of 419 participants achieved HbA1c ≤7.0%. Individual-level factors associated with HbA1c ≤7.0% included a diagnosis of DM after enrollment and a longer time since HIV diagnosis [hazard ratio (HR) = 2.65 and 1.13, P < 0.05 for both]. Attending a clinic with an endocrinologist was associated with the outcome [adjusted HR (aHR) = 1.41 95% confidence interval (CI): (1.01 to 1.97)]. In addition, comparing clinics that treat everyone, refer everyone or have a mix of treating and referring, showed an association between attending a clinic that treats everyone [aHR = 1.52 95% CI: (1.21 to 1.90)] or a clinic that refers everyone [aHR = 2.24 95% CI: (1.63 to 3.07)] compared with clinics with a mix in achieving glycemic control. Multiple factors are associated with achieving glycemic control in an urban cohort of PWH. Determining if specific services or structures improve DM outcomes may improve health outcomes for PWH and DM.

Application of Extended Cox Regression Model to Time-On-Wing Data of Aircraft Repairables

Global and local aviation traffic is growing while economic and performance pressures on the industry are increasing. As a consequence, airlines try to maximise their fleet utilization. Airline operators and Maintenance, Repair and Overhaul (MRO) providers therefore require as much insight as possible in factors affecting component reliability and availability. Reliability analysis in literature rarely considers the existence of relations between explanatory variables and time-based component reliability, and includes strict assumptions on independence of events and underlying distributions. This disregards the complex nature of aircraft operations, where the probability of an event may be influenced by various operational and maintenance factors. This paper develops new insights from operational and maintenance data about the impact of operating environment and ageing of components and fleet on reliability of the components by incorporating these factors in an extension of the Cox regression model. Examination of results obtained from analysing historical data of a set of three components with respect to installations and removals indicate that the natural environment at the hub airport, maintenance history of components, the age of the aircraft on which the component is installed and different modification designs are useful significant predictors of the time-on-wing duration of the component.

Time-varying and dose-dependent effect of long-term statin use on risk of type 2 diabetes: a retrospective cohort study

BackgroundWe evaluated the effect of statin use on new-onset type 2 diabetes among individuals without atherosclerotic cardiovascular disease (ASCVD) using nationally representative South Korean claims data (2002–2013, N = 1,016,820).MethodsA total of 13,698 patients (statin users 5273, non-statin users 5273) aged 40–74 years, newly diagnosed with dyslipidemia but without any history of diabetes or ASCVD, were selected in 2005. We followed up the final sample until 2013 and evaluated the cumulative incidence of type 2 diabetes. We used extended Cox regression models to estimate the time-varying adjusted hazard ratios of statin use on new-onset type 2 diabetes. We performed further analyses based on the cumulative defined daily dose of statin received per year to evaluate the degree of risk compared to non-statin users.ResultsOver the mean follow-up period of 7.1 years, 3034 patients developed type 2 diabetes; the number of statin users exceeded that of non-users, demonstrating that statin use significantly increased the risk of new-onset type 2 diabetes. The risk of new-onset type 2 diabetes differed among statin users according to cDDD per year (adjusted HR = 1.31 [95% CI 1.18–1.46] for less than 30 cDDD per year; 1.58 [1.43–1.75] for 30–120 cDDD per year; 1.83 [1.62–2.08] for 120–180 cDDD per year; and 2.83 [2.51–3.19] for more than 180 cDDD per year). The diabetogenic effect of pitavastatin was not statistically significant, but the risk was the largest for atorvastatin. Long-term exposure (≥ 5 years) to statins was associated with a statistically significant increase in the risk of new onset type 2 diabetes in all statin subtypes explored, with the highest magnitude for simvastatin (HR = 1.916, 95% CI 1.647–2.228) followed by atorvastatin (HR = 1.830, 95% CI 1.487–2.252).ConclusionsStatin use was significantly associated with an increased risk of new-onset type 2 diabetes. We also found a dose–response relationship in terms of statin use duration and dose maintenance. Periodic screening and monitoring for incident type 2 diabetes may be warranted in long-term statin users.

Recurrent heart failure hospitalizations are associated with increased cardiovascular mortality in patients with heart failure in Clinical Practice Research Datalink.

AimsHeart failure (HF) is a leading cause of hospitalization and is associated with high morbidity and mortality post‐diagnosis. Here, we examined the impact of recurrent HF hospitalization (HFH) on cardiovascular (CV) and all‐cause mortality among HF patients.Methods and ResultsAdult HF patients identified in the Clinical Practice Research Datalink with a first (index) hospitalization due to HF recorded in the Hospital Episode Statistics data set from January 2010 to December 2014 were included. Patients were followed up until death or end of study (December 2017). CV mortality as primary and as any reported cause and all‐cause mortality were evaluated. An extended Cox regression model was used for reporting adjusted relative CV mortality rates for time‐dependent recurrent HFHs. Overall, 8603 HF patients with an index hospitalization were included, providing 15 964 patient‐years of follow‐up. Patients were relatively old (median age: 80 years) and were mostly male (54.6%), with main co‐morbidities being hypertension and atrial fibrillation. Recurrent HFHs occurred one, two, three, and more than four times in 1561 (18.2%), 518 (6.02%), 206 (2.4%), and 153 (1.8%) patients, respectively. The median time to mortality was 215 (38–664) days for 50.8% of patients who died for any cause during the study period and 139 (27–531) days for 31.3% who died with CV reasons as primary cause. Compared with those of patients without recurrent HFHs, the adjusted hazard ratios (95% CI) for CV mortality as primary cause were 2.65 (2.35–2.99), 3.69 (3.06–4.43), 5.82 (4.48–7.58), and 5.95 (4.40–8.05) for those with one, two, three, and more than four recurrent HFHs.ConclusionsThere is a strong association between recurrent HFH and CV mortality, with the risk increasing progressively with each recurrent HFH.

Prediagnostic adult body mass index change and esophageal adenocarcinoma survival.

BackgroundWe examined whether body mass index (BMI) changes in adulthood, prior to disease onset, are associated with overall survival among esophageal adenocarcinoma patients.MethodsWe included 285 histologically confirmed patients with a complete baseline BMI questionnaire. Using extended Cox regression models, we obtained adjusted hazard ratios (HRs) for the associations between overall survival and BMI at diagnosis, BMI 6 months before diagnosis, self‐reported average adult BMI, and ΔBMI (BMI 6 months before diagnosis minus average adult BMI), categorized into tertiles <0 kg/m2 (BMI loss), ≥0 and <1.25 kg/m2 (stable BMI), and ≥1.25 kg/m2 (BMI gain). We also assessed interaction between ΔBMI and average adult BMI (≥ kg/m2 versus <27.5 kg/m2) with overall survival.ResultsBody mass index at diagnosis >25 and <35 kg/m2 was associated with better overall survival. Compared to patients with stable BMI in adulthood, patients who gained BMI throughout adulthood had 1.68 times the all‐cause hazard of death (95% CI: 1.17‐2.43; P < .01), independent of diagnosis BMI and percent weight loss 6 months before diagnosis. Compared to patients with average adult BMI < 27.5 who maintained stable adult BMI, patients with average adult BMI ≥ 27.5 kg/m2 who gained BMI had the worst survival (HR = 3.05; 95% CI 1.62‐5.72; P < .01).ConclusionBody mass index gain in adulthood is associated with poor overall survival, and maintaining a normal body weight throughout adulthood is associated with the best overall survival among esophageal adenocarcinoma patients, independent of BMI at diagnosis.