Multistate Survival Models Research Articles

Sense of purpose in life and extending the cognitive healthspan: evidence from multistate survival modeling

ABSTRACT Having a sense of purpose in life predicts better maintenance of cognitive function in older adulthood and reduced risk of mild cognitive impairment (MCI) and dementia. However, little research has examined its influence on the rate of cognitive decline and length of cognitive healthspan. This study evaluated the role of sense of purpose on the risk and timing of transitions between normal cognition, MCI, and dementia. Older adults from the Memory and Aging Project (MAP; n = 1821) and the Health and Retirement Study (HRS; n = 10,542) were followed annually for 19 years and biennially for 12 years, respectively. Multistate survival models assessed whether sense of purpose predicted transitions across normal cognition, MCI, dementia, and death. More purposeful older adults had lower risk of developing MCI (HR = 0.82 in MAP; HR = 0.93 in HRS), higher likelihood of cognitive improvement, and longer cognitively healthy life expectancies. Results suggest sense of purpose may extend the cognitive healthspan.

Mapping 15-year depressive symptom transitions in late life: population-based cohort study.

The longitudinal course of late-life depression remains under-studied. To describe transitions along the depression continuum in old age and to identify factors associated with specific transition patterns. We analysed 15-year longitudinal data on 2745 dementia-free persons aged 60+ from the population-based Swedish National Study on Aging and Care in Kungsholmen. Depression (minor and major) was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; subsyndromal depression (SSD) was operationalised as the presence of ≥2 symptoms without depression. Multistate survival models were used to map depression transitions, including death, and to examine the association of psychosocial (social network, connection and support), lifestyle (smoking, alcohol consumption and physical activity) and clinical (somatic disease count) factors with transition patterns. Over the follow-up, 19.1% had ≥1 transitions across depressive states, while 6.5% had ≥2. Each additional somatic disease was associated with a higher hazard of progression from no depression (No Dep) to SSD (hazard ratio 1.09; 1.07-1.10) and depression (Dep) (hazard ratio 1.06; 1.04-1.08), but also with a lower recovery (HRSSD-No Dep 0.95; 0.93-0.97 [where 'HR' refers to 'hazard ratio']; HRDep-No Dep 0.96; 0.93-0.99). Physical activity was associated with an increased hazard of recovery to no depression from SSD (hazard ratio 1.49; 1.28-1.73) and depression (hazard ratio 1.20; 1.00-1.44), while a richer social network was associated with both higher recovery from (HRSSD-No Dep 1.44; 1.26-1.66; HRDep-No Dep 1.51; 1.34-1.71) and lower progression hazards to a worse depressive state (HRNo Dep-SSD 0.81; 0.70-0.94; HRNo Dep-Dep 0.58; 0.46-0.73; HRSSD-Dep 0.66; 0.44-0.98). Older people may present with heterogeneous depressive trajectories. Targeting the accumulation of somatic diseases and enhancing social interactions may be appropriate for both depression prevention and burden reduction, while promoting physical activity may primarily benefit recovery from depressive disorders.

Applying a multistate survival model to explore the role of fine particles in promoting frailty in the Medicare cohort.

Fine particle pollution is a well-established risk to human health. Observational epidemiology generally treats events as though they are independent of one another and so do not examine the role air pollution may play in promoting the progression of disease. Multistate survival models account for the complex pathway of disease to death. We employ a multistate survival model to characterize the role of chronic exposure to PM2.5 in affecting the rate at which Medicare beneficiaries transition to first hospitalization for cardiovascular disease and then subsequently death. We use an open cohort of Medicare beneficiaries and PM2.5 concentrations estimated with photochemical model predictions, satellite-based observations, land-use data, and meteorological variables. The multistate model included three transitions: (1) entry to cardiovascular hospital admission; (2) entry to death; and (3) cardiovascular hospital admission to death. The transition intensity was modeled using a Cox proportional hazards model. For a 1 µg/m3 increase in annual mean PM2.5, we estimate a nationally pooled hazard ratio of 1.022 (95% confidence interval [CI] = 1.018, 1.025) for the transition from entry to first cardiovascular hospital admission; 1.054 (95% CI = 1.039, 1.068) for the transition from entry to death; 1.036 (95% CI = 1.027, 1.044) for the transition from first cardiovascular hospital admission to death. The hazard ratios exhibited some heterogeneity within each of nine climatological regions and for each of the three transitions. We find evidence for the role of PM in both promoting chronic illness and increasing the subsequent risk of death.

ESTIMATION OF WORKING LIFE EXPECTANCY: APPLICATION OF A MULTISTATE MARKOV MODEL

Abstract Longer life expectancy in Western countries has led to concerns about sustainable workforces amid the rising costs of securing aging populations. Retirement age is no more a good indicator of the end of the working life, because many older workers move in-and-out of workforce. A more useful measure is working life expectancy (WLE), which is the expected number of remaining years from a given age that a person will work. This measure considers transitions across different employment states. The method adopted for estimation of WLE is along the same line to estimate health expectancy (HE) based on cross-sectional data without considering transitions in different states of work over time. A better approach is based on multi-state survival models considering transitions among states over time using longitudinal data. These models assume a Markov Process to estimate transition probabilities. WLE is the weighted sum of duration of stay in a state weighted by the transition probabilities. The method adopted in IDEAR consortium is a multistate survival model assuming a first-order Markov process in continuous time to estimate transition probabilities. Transition probabilities are estimated by the msm package. This model takes care of interval censoring where the exact dates of transitions from one state to another is not known. WLEs are estimated by using the package elect (van den Hout, 2019) incorporating age as a time dependent variable by using a Gompertz model instead of the exponential model. The method is demonstrated to estimate WLE using Swedish Longitudinal Occupational Survey of Health (SLOSH).

THE IMPORTANCE OF PERSONALITY TRAITS FOR COGNITIVE HEALTHSPAN

Abstract The existing literature consistently finds that personality traits are associated with dementia and with risk of mortality. However, few studies have simultaneously examined the impact of traits on dementia while accounting for death as a competing risk, which is critical as dementia and mortality are dependent outcomes and the likelihood of each increases alongside older age. In response, data were drawn from the Rush Memory and Aging Project (N=1954; baseline mean age=80 years; 74% female; up to 23 annual assessments). We used multi-state survival models to investigate whether traits (conscientiousness, extraversion, and neuroticism) were associated with transitions between cognitive status categories (No Cognitive Impairment, NCI; Mild Cognitive Impairment, MCI; dementia) and death. Further, multinomial regression models estimated cognitive healthspan (i.e., years without cognitive impairment) and total longevity. Adjusting for demographics, depressive symptoms, and APOEε4, personality traits were most important in the transition from NCI to MCI; higher conscientiousness was associated with a ~22% decreased risk of transitioning from NCI to MCI (HR=0.78, 95%CI=0.72, 0.85), whereas higher neuroticism was associated with a ~12% increased risk of transitioning from NCI to MCI (HR=1.12, 95%CI=1.04, 1.21). Life expectancy analyses suggested that participants who were higher in conscientiousness were estimated to live longer without cognitive impairment compared to individuals lower in conscientiousness. Findings were similar, though less pronounced, for individuals higher in extraversion or lower in neuroticism. Importantly, none of the traits appeared to be important for total longevity. Together, these results highlight the importance of personality traits, particularly conscientiousness, for maximizing cognitive healthspan.

Hematological and biochemical markers influencing breast cancer risk and mortality: Prospective cohort study in the UK Biobank by multi-state models

BackgroundBreast cancer is the most common cancer and the leading cause of cancer-related death among women. However, evidence concerning hematological and biochemical markers influencing the natural history of breast cancer from in situ breast cancer to mortality is limited. MethodsIn the UK Biobank cohort, 260,079 women were enrolled during 2006–2010 and were followed up until 2019 to test the 59 hematological and biochemical markers associated with breast cancer risk and mortality. The strengths of these associations were evaluated using the multivariable Cox regression models. To understand the natural history of breast cancer, multi-state survival models were further applied to examine the effects of biomarkers on transitions between different states of breast cancer. ResultsEleven biomarkers were found to be significantly associated with the risk of invasive breast cancer, including mainly inflammatory-related biomarkers and endogenous hormones, while serum testosterone was also associated with the risk of in-situ breast cancer. Among them, C-reactive protein (CRP) was more likely to be associated with invasive breast cancer and its transition to death from breast cancer (HR for the highest quartile = 1.46, 95 % CI = 1.07–1.97), while testosterone and insulin-like growth factor-1 (IGF-1) were more likely to impact the early state of breast cancer development (Testosterone: HR for the highest quartile = 1.31, 95 % CI = 1.12–1.53; IGF-1: HR for the highest quartile = 1.17, 95 % CI = 1.00–1.38). ConclusionSerum CRP, testosterone, and IGF-1 have different impacts on the transitions of different breast cancer states, confirming the role of chronic inflammation and endogenous hormones in breast cancer progression. This study further highlights the need of closer surveillance for these biomarkers during the breast cancer development course.

Modeling the multi-state natural history of rare diseases with heterogeneous individual patient data: A simulation study.

Multi-state survival models are used to represent the natural history of a disease, forming the basis of a health technology assessment comparing a novel treatment to current practice. Constructing such models for rare diseases is problematic, since evidence sources are typically much sparser and more heterogeneous. This simulation study investigated different one-stage and two-stage approaches to meta-analyzing individual patient data (IPD) in a multi-state survival setting when the number and size of studies being meta-analyzed are small. The objective was to assess methods of different complexity to see when they are accurate, when they are inaccurate and when they struggle to converge due to the sparsity of data. Biologically plausible multi-state IPD were simulated from study- and transition-specific hazard functions. One-stage frailty and two-stage stratified models were estimated, and compared to a base case model that did not account for study heterogeneity. Convergence and the bias/coverage of population-level transition probabilities to, and lengths of stay in, each state were used to assess model performance. A real-world application to Duchenne Muscular Dystrophy, a neuromuscular rare disease, was conducted, and a software demonstration is provided. Models not accounting for study heterogeneity were consistently out-performed by two-stage models. Frailty models struggled to converge, particularly in scenarios of low heterogeneity, and predictions from models that did converge were also subject to bias. Stratified models may be better suited to meta-analyzing disparate sources of IPD in rare disease natural history/economic modeling, as they converge more consistently and produce less biased predictions of lengths of stay.

Availability of Cognitive Resources in Early Life Predicts Transitions Between Cognitive States in Middle and Older Adults From Europe.

The existing literature highlights the importance of reading books in middle-to-older adulthood for cognitive functioning; very few studies, however, have examined the importance of childhood cognitive resources for cognitive outcomes later in life. Using data from 11 countries included in the Survey of Health, Ageing, and Retirement in Europe (SHARE) data set (N = 32,783), multistate survival models (MSMs) were fit to examine the importance of access to reading material in childhood on transitions through cognitive status categories (no cognitive impairment and impaired cognitive functioning) and death. Additionally, using the transition probabilities estimated by the MSMs, we estimated the remaining years of life without cognitive impairment and total longevity. All models were fit individually in each country, as well as within the pooled SHARE sample. Adjusting for age, sex, education, and childhood socioeconomic status, the overall pooled estimate indicated that access to more books at age 10 was associated with a decreased risk of developing cognitive impairment (adjusted hazard ratio = 0.79, confidence interval: 0.76-0.82). Access to childhood books was not associated with risk of transitioning from normal cognitive functioning to death, or from cognitive impairment to death. Total longevity was similar between participants reporting high (+1 standard deviation [SD]) and low (-1 SD) number of books in the childhood home; however, individuals with more access to childhood books lived a greater proportion of this time without cognitive impairment. Findings suggest that access to cognitive resources in childhood is protective for cognitive aging processes in older adulthood.

Mate-guarding success depends on male investment in a butterfly.

Males of many insects, including butterflies, produce mate-guarding devices, such as mating plugs, to prolong guarding and prevent future female matings in the male's absence. In a few butterflies, large external mate-guarding devices, that is, sphragides, occur. Gór et al. (Behaviour, 160, 2023 and 515-557) found conspicuously large size and morphological variation of mate-guarding devices within a single population of the potentially polyandrous Clouded Apollo (Parnassius mnemosyne, L.) butterfly. They termed the externally visible male-produced devices as Copulatory opening APpendices (CAP) consisting of small devices, termed small CAPs and the much larger shield (i.e. sphragis). Our aim was to reveal CAP replacement dynamics within females during their lifetime and to understand how male investment into small CAPs or shields was (i) related to CAP persistence on the female, that is securing paternity, (ii) associated with female quality, measured as size and (iii) with actual adult sex ratio. We investigated a univoltine Clouded Apollo population to estimate CAP replacement risks, using multistate survival models, in an extensive observational study through 6 years based on mark-recapture. Shields were the most frequent mate-guarding devices and were more persistent than small CAPs, often lasting for life, excluding future matings. Thus, most females bearing a shield were deprived of postcopulatory female choice, and the genetic variance in their offspring could be reduced compared to those bearing small CAPs, thus mating more often. The ratio of shields to all CAPs gradually decreased towards the end of the flight period. Males were more prone to produce a shield when mating females with wider thoraces and when the ratio of males (i.e. competition) was higher in the population. To our best knowledge, this is the first quantitative study to investigate potential factors on which male investment in mate-guarding devices may depend, and how the variation in these devices impacts CAP persistence on females.

Obesity in Late-Life as a Protective Factor Against Dementia and Dementia-Related Mortality.

We estimated the conversion from cognitively normal to mild cognitive impairment (MCI) to probable dementia and death for underweight, normal, overweight, and obese older adults, where the timing of examinations is associated with the severity of dementia. We analyzed six waves of the National Health and Aging Trends Study (NHATS). Body mass (BMI) was computed from height and weight. Multi-state survival models (MSMs) examined misclassification probability, time-to-event ratios, and cognitive decline. Participants (n = 6078) were 77years old, 62% had overweight and/or obese BMI. After adjusting for the effects of cardiometabolic factors, age, sex, and race, obesity was protective against developing dementia (aHR=.44; 95%CI [.29-.67]) and dementia-related mortality (aHR=.63; 95%CI [.42-.95]). We found a negative relationship between obesity and dementia and dementia-related mortality, a finding that has been underreported in the literature. The continuing obesity epidemic might complicate the diagnosis and treatment of dementia.

#4680 PATIENT OUTCOMES AND DYNAMICS OF THE AUSTRALIAN KIDNEY TRANSPLANT WAITLIST: SUSPENSIONS, RETURNING TO WAITLIST, TRANSPLANTATION AND DEATHS

Abstract Background and Aims People on the kidney waitlist are less informed about potential temporary or permanent suspensions. Disparities may exist among those who are suspended and who return to the waitlist. In Australia, average wait times vary be state/territory and blood group, but overall is X years. We aimed to describe and evaluate factors associated with waitlist transitions and subsequent outcomes after entering the waitlist for deceased donor kidney transplant. Method We included all incident patients waitlisted for their first transplant from deceased donors in Australia during 2006-2019. We described all clinical transitions after entering the kidney waitlist including: active on waitlist; suspended; kidney transplant; graft failure; and death. We predicted the restricted mean survival time from waitlist entry until first transplant with 5 year time horizon and summarized the annual percentages in each clinical state until 5 years. We used flexible parametric multi-state survival models to evaluate factors associated with transitions after entering the waitlist until first transplant, reporting the hazard ratio (HR) for each transition. We used Cox proportional hazards models to evaluate factors associated with death while waiting and first transplant, reporting HR for these outcomes. Results Of 8,466 people who entered the kidney waitlist, 6,741 people received their first transplant (6,163 deceased donor; 506 living donor; 99 paired kidney exchange donors), 381 people died while waiting (31 active on waitlist; 350 suspended) and 1,344 were still waiting for a transplant (844 active on waitlist; 500 suspended). Nearly two-thirds (63%) were not suspended while waiting, but 2,111(25%) were suspended once and 1,016(12%) were suspended ≥2 times. Of those suspended, 47% spent a total of <6 months off-waitlist. Predicted mean time from waitlist entry to transplant increased with number of suspensions, from 1.9 years (95% CI:1.8-1.9 years) in patients not suspended to 3.0 years (95% CI:2.8-3.2 years) in patients suspended once or more. For the entire cohort, the 1-year probability of transplant was 41%(95%CI:40-42%), active on waitlist was 42%(95%CI:41-43%), suspended was 11%(95%CI:10-12%) and death was 1.4% (95%CI:1.2-1.7%) (Fig. 1). At 5-years, this increased to 63% (95%CI:62-64%) transplanted, 5% (95%CI:4-5%) active on waitlist, 10% (95%CI:9-11%) suspended and 13% (95%CI:12-14%) died. Several patient factors were associated being suspended and returning to the waitlist, as well as with receiving transplant and death while waiting (Fig. 2). Having been suspended from the waitlist, increased the likeliness of further suspensions by 4.2 times (95%CI: 3.8-4.6; p < 0.001) and returning to the waitlist by 50% (95%CI: 36-65%; p < 0.001) but decreased the likeliness of receiving a transplant by 29% (95%CI: 62-82%; p < 0.001). Being previously suspended once reduced the risk of death while waiting by 31% (HR: 0.69, 95%CI: 0.52-0.91; p < 0.01), likely a paradox of being well enough to return to waitlist at least once. Socio-demographic factors were modifiers of returning to the waitlist after suspension. Males of Australian or New Zealand ethnicity (non-Indigenous) were 13% (95%CI: 4-23%) more likely to return to the waitlist compared to females of the same ethnicity (p < 0.01). However, males of Aboriginal, Torres Strait Islander, Māori or Pacific Islander ethnicity had the same likeliness of returning to the waitlist as their female counterparts (p = 0.08). Conclusion The dynamics of the transplant waiting list were not straightforward. About one-third of patients were suspended at least once and wait 1 year longer for a transplant compared with those not suspended. Our findings will provide evidence to support more informed discussions about the patient journey from waitlist to transplantation, and aid in shared decision making.

Impact of offspring and their educational level on readmission and death among older adults with chronic obstructive pulmonary disease: a nationwide cohort study using multistate survival models

BackgroundIt is well described that there is social inequality in the disease course of chronic obstructive pulmonary disease (COPD), but the impact of social relations is less explored. We aimed...

Determining the impact of ex-vivo lung perfusion on hospital costs for lung transplantation: A retrospective cohort study.

Ex-vivo lung perfusion (EVLP) has improved organ utilization for lung transplantation, but it is not yet known whether the benefits of this technology offset its additional costs. We compared the institutional costs of lung transplantation before vs after EVLP was available to identify predictors of costs and determine the health-economic impact of EVLP. We performed a retrospective, before-after, propensity-score weighted cohort study of patients wait-listed for lung transplant at University Health Network (UHN) in Ontario, Canada, between January 2005 and December 2019 using institutional administrative data. We compared costs, in 2019 Canadian Dollars ($), between patients referred for transplant before EVLP was available (Pre-EVLP) to after (Modern EVLP). Cumulative costs were estimated using a novel application of multistate survival models. Predictors of costs were identified using weighted log-gamma generalized linear regression. A total of 1,199 patients met inclusion criteria (352 Pre-EVLP; 847 Modern EVLP). Mean total costs for the transplant hospitalization were $111,878 ($94,123-$130,767) in the Pre-EVLP era and $110,969 ($87,714-$136,000) in the Modern EVLP era. Cumulative five-year costs since referral were $278,777 ($82,575-$298,135) in the Pre-EVLP era and $293,680 ($252,832-$317,599) in the Modern EVLP era. We observed faster progression to transplantation when EVLP was available. EVLP availability was not a predictor of waitlist (cost ratio [CR] 1.04 [0.81-1.37]; p=0.354) or transplant costs (CR 1.02 [0.80-1.29]; p=0.425) but was associated with lower costs during posttransplant years 1&2 (CR 0.75 [0.58-1.06]; p=0.05) and posttransplant years 3+ (CR 0.43 [0.26-0.74]; p=0.001). At our center, EVLP availability was associated with faster progression to transplantation at no significant marginal cost.

Transitions Between Mild Cognitive Impairment, Dementia, and Mortality: The Importance of Olfaction.

The existing literature suggests that impaired olfaction may be an early marker for cognitive decline. Tracking the earliest stages of the progression to dementia is paramount, and yet the importance of olfactory ability throughout cognitive states and death remains unclear. Drawing data from the Rush Memory and Aging Project (N=1501; 74% female), olfactory ability was assessed using the Brief Smell Identification Test (range=0-16), while cognitive states (unimpaired, mild cognitive impairment [MCI], and dementia) were determined using a 3-step neuropsychological diagnostic protocol at up to 15 annual occasions. Multistate survival models simultaneously estimated the association of olfactory ability on transitions through cognitive states and death, while multinomial regression models estimated cognitively unimpaired and total life expectancies. Higher olfactory scores were associated with a reduced risk of transitioning from unimpaired cognition to MCI (hazard ratio [HR]=0.86, 95% confidence interval [CI]=0.82-0.88) and from MCI to dementia (HR=0.89, 95% CI=0.86-0.93), indicating that 1-unit increase in olfactory scores was associated with an approximate 14% and 11% reduction in risk, respectively. Additionally, higher olfactory scores were associated with a greater likelihood of transitioning backward from MCI to unimpaired cognition (HR=1.07, 95% CI=1.02-1.12). Furthermore, higher baseline olfactory scores were associated with more years of longevity without cognitive impairment. However, olfaction was not associated with the transition to death when accounting for transitions through cognitive states. Findings suggest that higher olfactory identification scores are associated with a decreased risk of transitioning to impaired cognitive states and that associations between olfaction and mortality may occur primarily through the pathway of neurodegeneration.

Vedolizumab more likely to be discontinued than ustekinumab in anti-TNF-experienced patients with fistulizing Crohn's disease.

Data on the performance of newer biologics in patients with fistulizing Crohn's disease (CD) are limited. Our study's objective was to evaluate the response to ustekinumab (UST) and vedolizumab (VDZ) in patients with fistulizing CD. Retrospective cohort. We used natural language processing of electronic medical record data to identify a retrospective cohort of individuals with fistulizing CD at a single academic tertiary-care referral center and then performed a chart review. Individuals were eligible for inclusion if a fistula was present at the time of UST or VDZ initiation. Outcomes included medication discontinuation, surgical intervention, development of a new fistula, and fistula closure. Groups were compared with unadjusted analyses and competing risk analyses using multi-state survival models. In all, 68 patients were included (48 UST and 20 VDZ). Most patients had one fistula (79%) and had prior anti-tumor necrosis factor-α treatment (98% in UST group, 80% in VDZ group, p = 0.01). VDZ was significantly more likely to be discontinued than UST (p < 0.0001), most frequently due to inadequate clinical response. Those on UST had a longer median time to surgery for CD than those on VDZ (p = 0.008). In those without surgical fistula repair, 79% on UST and 100% on VDZ still had an active fistula at 1 year (p = 0.30). In individuals with fistulizing CD, our data suggest that UST has better clinical utility than VDZ based on lower rates of discontinuation, though the sample size is small. These findings highlight the importance of further research on the treatment of perianal fistulizing Crohn's disease.

PHYSICAL ACTIVITY, COGNITIVE HEALTH, AND LONGEVITY IN OLDER ADULTHOOD

Abstract Research suggests that physical activity (PA) protects against cognitive impairment in older adulthood; however, the extent to which PA engagement throughout older adulthood influences the simultaneous risk of transitioning to cognitively impaired states and death is unclear. Applying coordinated data analysis across 14 studies, multi-state survival models (MSM) were independently fit to data from fourteen longitudinal studies (NTotal=52,039). PA was synthesized across studies using the metabolic equivalent of task approach. Adjusting for demographics and chronic conditions, meta-analytic results indicated that engaging in more PA was associated with a reduced risk of transitioning from no cognitive impairment to mildly impaired cognitive functioning (HR=0.94, 95%CI’s=0.89,0.99) and death (HR=0.72, 95%CI’s=0.65,0.80). Based on MSM estimates, multinomial regression models computed total life expectancy stratified by national PA recommendations. Meta-analytic results indicate a positive linear effect of PA, such that more PA is associated with longevity. This presentation will include discussion of knowledge translation efforts.

Factors Affecting the Clinical Course of Follicular Lymphoma: A Multistate Survival Analysis Using Individual Patient Data from Eight Multicenter Randomized Clinical Trials.

Leveraging the Follicular Lymphoma Analysis of Surrogacy Hypothesis database of individual patient data from first-line clinical trials, we studied the clinical course of follicular lymphoma (FL) and investigated clinical factors associated with FL outcomes. We examined 2428 patients from 8 randomized trials using multistate survival models with 4 states: induction treatment, progression, death from FL, and death from other causes. We utilized Aalen-Johansen estimator and Cox models to assess the likelihood of FL outcomes and quantify predictors' effects. Two-year progression, FL-related death, and death from other causes estimates were 26.5%, 3.4% and 1.4%, respectively. FL-associated deaths were the primary cause of mortality within 10 years of follow-up. Male sex (hazard ratio: 1.25; 95% confidence interval: 1.05-1.47), > 4 involved nodal areas (1.51; 1.23-1.86), elevated LDH (1.20; 1.01-1.43), low hemoglobin (1.44; 1.15-1.81), and elevated β-2 levels (1.23; 1.02-1.47) increased risk of progression. CD20-targeting agents reduced risks for progression (0.29; 0.22-0.39), death from FL (0.05; 0.01-0.20), and death from other causes without progression (0.13; 0.05-0.33) and following progression (0.52; 0.30-0.92). Estimated 2-year progression rates were 22.3% and 43.5% with or without CD20-targeting agents, respectively. Two-year FL-associated mortality rate was 8.3% among patients without CD20-targeting agents, 5.4% with B-symptoms, 4.9% with elevated LDH, and 9.1% with low hemoglobin. This study identified independent contributions of baseline clinical factors to distinct outcomes for patients with FL following first-line therapy on a clinical trial. Similar analytical approaches are needed to increase understanding of factors that influence FL outcomes in other settings.

Multi-state survival models with treatment effects and biomarkers: Simulations for study design assessment

BackgroundComparative effectiveness studies of cancer therapeutics in observational data face confounding by patterns of clinical treatment over time. The validity of survival analysis in longitudinal health records depends on study design choices including index date definition and model specification for covariate adjustment. MethodsOverall survival in cancer is a multi-state transition process with mortality and treatment switching as competing risks. Parametric Weibull regression quantifies proportionality of hazards across lines of therapy in real-world cohorts of 12 solid tumor types. Study design assessments compare alternative analytic models in simulations with realistic disproportionality. The multi-state simulation framework is adaptable to alternative treatment effect profiles and exposure patterns. ResultsEvent-specific hazards of treatment-switching and death are not proportional across lines of therapy in 12 solid tumor types. Study designs that include all eligible lines of therapy per subject showed lower bias and variance than designs that select one line per subject. Confounding by line number was effectively mitigated across a range of simulation scenarios by Cox proportional hazards models with stratified baseline hazards and inverse probability of treatment weighting. ConclusionQuantitative study design assessment can inform the planning of observational research in clinical oncology by demonstrating the potential impact of model misspecification. Use of empirical parameter estimates in simulation designs adapts analytic recommendations to the clinical population of interest.

Modeling social interaction dynamics measured with smartphone sensors: An ambulatory assessment study on social interactions and loneliness.

More and more data are being collected using combined active (e.g., surveys) and passive (e.g., smartphone sensors) ambulatory assessment methods. Fine-grained temporal data, such as smartphone sensor data, allow gaining new insights into the dynamics of social interactions in day-to-day life and how these are associated with psychosocial phenomena - such as loneliness. So far, however, smartphone sensor data have often been aggregated over time, thus, not doing justice to the fine-grained temporality of these data. In this article, we demonstrate how time-stamped sensor data of social interactions can be modeled with multistate survival models. We examine how loneliness is associated with (a) the time between social interaction (i.e., interaction rate) and (b) the duration of social interactions in a student population (Nparticipants = 45, Nobservations = 74,645). Before a 10-week ambulatory assessment phase, participants completed the UCLA loneliness scale, covering subscales on intimate, relational, and collective loneliness. Results from the multistate survival models indicated that loneliness subscales were not significantly associated with differences in social interaction rate and duration - only relational loneliness predicted shorter social interaction encounters. These findings illustrate how the combination of new measurement and modeling methods can advance knowledge on social interaction dynamics in daily life settings and how they relate to psychosocial phenomena such as loneliness.

Large socioeconomic gap in period life expectancy and life years spent with complications of diabetes in the Scottish population with type 1 diabetes, 2013-2018.

We report the first study to estimate the socioeconomic gap in period life expectancy (LE) and life years spent with and without complications in a national cohort of individuals with type 1 diabetes. This retrospective cohort study used linked healthcare records from SCI-Diabetes, the population-based diabetes register of Scotland. We studied all individuals aged 50 and older with a diagnosis of type 1 diabetes who were alive and residing in Scotland on 1 January 2013 (N = 8591). We used the Scottish Index of Multiple Deprivation (SIMD) 2016 as an area-based measure of socioeconomic deprivation. For each individual, we constructed a history of transitions by capturing whether individuals developed retinopathy/maculopathy, cardiovascular disease, chronic kidney disease, and diabetic foot, or died throughout the study period, which lasted until 31 December 2018. Using parametric multistate survival models, we estimated total and state-specific LE at an attained age of 50. At age 50, remaining LE was 22.2 years (95% confidence interval (95% CI): 21.6 - 22.8) for males and 25.1 years (95% CI: 24.4 - 25.9) for females. Remaining LE at age 50 was around 8 years lower among the most deprived SIMD quintile when compared with the least deprived SIMD quintile: 18.7 years (95% CI: 17.5 - 19.9) vs. 26.3 years (95% CI: 24.5 - 28.1) among males, and 21.2 years (95% CI: 19.7 - 22.7) vs. 29.3 years (95% CI: 27.5 - 31.1) among females. The gap in life years spent without complications was around 5 years between the most and the least deprived SIMD quintile: 4.9 years (95% CI: 3.6 - 6.1) vs. 9.3 years (95% CI: 7.5 - 11.1) among males, and 5.3 years (95% CI: 3.7 - 6.9) vs. 10.3 years (95% CI: 8.3 - 12.3) among females. SIMD differences in transition rates decreased marginally when controlling for time-updated information on risk factors such as HbA1c, blood pressure, BMI, or smoking. In addition to societal interventions, tailored support to reduce the impact of diabetes is needed for individuals from low socioeconomic backgrounds, including access to innovations in management of diabetes and the prevention of complications.