Piecewise Exponential Model Research Articles

Development and Validation of a Prediction Model for Kidney Failure in Long-Term Survivors of Childhood Cancer.

Kidney failure is a rare but serious late effect following treatment for childhood cancer. We developed a model using demographic and treatment characteristics to predict individual risk of kidney failure among 5-year survivors of childhood cancer. Five-year survivors from the Childhood Cancer Survivor Study (CCSS) without history of kidney failure (n = 25,483) were assessed for subsequent kidney failure (ie, dialysis, kidney transplantation, or kidney-related death) by age 40 years. Outcomes were identified by self-report and linkage with the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5,045) served as a comparator. Piecewise exponential models accounting for race/ethnicity, age at diagnosis, nephrectomy, chemotherapy, radiotherapy, congenital genitourinary anomalies, and early-onset hypertension estimated the relationships between potential predictors and kidney failure, using area under the curve (AUC) and concordance (C) statistic to evaluate predictive power. Regression coefficient estimates were converted to integer risk scores. The St Jude Lifetime Cohort Study and the National Wilms Tumor Study served as validation cohorts. Among CCSS survivors, 204 developed late kidney failure. Prediction models achieved an AUC of 0.65-0.67 and a C-statistic of 0.68-0.69 for kidney failure by age 40 years. Validation cohort AUC and C-statistics were 0.88/0.88 for the St Jude Lifetime Cohort Study (n = 8) and 0.67/0.64 for the National Wilms Tumor Study (n = 91). Risk scores were collapsed to form statistically distinct low- (n = 17,762), moderate- (n = 3,784), and high-risk (n = 716) groups, corresponding to cumulative incidences in CCSS of kidney failure by age 40 years of 0.6% (95% CI, 0.4 to 0.7), 2.1% (95% CI, 1.5 to 2.9), and 7.5% (95% CI, 4.3 to 11.6), respectively, compared with 0.2% (95% CI, 0.1 to 0.5) among siblings. Prediction models accurately identify childhood cancer survivors at low, moderate, and high risk for late kidney failure and may inform screening and interventional strategies.

Estimating child maltreatment cases that could be alcohol-attributable in New Zealand.

Children are an important group harmed by others' alcohol consumption. This study (1) compared the risk of occurrence of child maltreatment among children exposed versus not exposed to parents with an alcohol-attributable hospitalization or service use for mental health/addiction and (2) conducted sensitivity analyses to estimate the cases of child maltreatment that could be attributable to alcohol under two different conditions in New Zealand. A cohort study conducted among children 0-17 years and their parents (years 2000-2017) using the Statistics New Zealand Integrated Data Infrastructure. The New Zealand Health Survey 2017 was also used. New Zealand. 58 359 children aged 0-17 years and their parents. Survival analysis based on a Bayesian piecewise exponential model was used to estimate the risk of time to first substantiated child maltreatment event (identified from social service, hospital, mortality and police data) related to exposure to parents with an alcohol-attributable hospitalization or who used a mental health/addiction service (versus no exposure). Potential confounders were included for parents and children. The sensitivity analyses (i) estimated an alcohol-attributable admissions/service use fraction for maltreatment in 2017 and (ii) calculated a population-attributable fraction using the relative risk from the cohort and prevalence of hazardous drinking (AUDIT 8+) among parents in 2017. There was a 65.1% [1.65; 95% confidence interval (CI) = 1.46-1.86] increased risk of child maltreatment if a child was exposed to parents who had an alcohol-attributable hospitalized or mental health/addictions service use. The sensitivity analyses estimated that in 2017 14.6% (CI = 14.0-15.3%) and 11.4% (95% CI = 8.4-14.3%) of the documented cases of child maltreatment in New Zealand could be attributable to parents with severe or hazardous consumption. In New Zealand, exposure to parents with an alcohol-attributable hospitalization or service use is a risk factor for substantiated child maltreatment.

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial

The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

The association of diastolic arterial pressure and heart rate with mortality in septic shock: a retrospective cohort study

The effects of diastolic arterial pressure (DAP) and heart rate (HR) on the prognosis of patients with septic shock are unclear, and whether these effects persist over time is unknown. We aimed to investigate the relationship between exposure to different intensities of DAP and HR over time and mortality at 28days in patients with septic shock. In this cohort study, we obtained data from the Medical Information Mart for Intensive Care IV, which includes the data of adult patients (≥ 18years) with septic shock who underwent invasive blood pressure monitoring. We excluded patients who received extracorporeal membrane oxygenation (ECMO) or glucocorticoids within 48h of ICU admission. The primary outcome was mortality at 28days. Piece-wise exponential additive mixed models were used to estimate the strength of the associations over time. In total, 4959 patients were finally included. The median length of stay in the ICU was 3.2days (IQR: 1.5-7.1days), and the mortality in the ICU was 12.9%, with a total mortality at 28days of 15.9%. After adjustment for baseline and time-dependent confounders, both daily time-weighted average (TWA) DAP and HR were associated with increased mortality at 28days and strong association, mainly in the early to mid-stages of the disease. The results showed that mortality in patients with septic shock was lowest at a DAP of 50-70mm Hg and an HR of 60-90 beats per minute (bpm). Throughout, a significant increase in the risk of death was found with daily exposure to TWA-DAP ≤ 40mmHg (hazard ratio 0.99, 95% confidence interval (CI) 0.94-1.03) or TWA-HR ≥ 100bpm (hazard ratio 1.16, 95% CI 1.1-1.21). Cumulative and interactive effects of harmful exposure (TWA-DAP ≤ 40mmHg and TWA-HR ≥ 100bpm) were also observed. The optimal ranges for DAP and HR in patients with septic shock are 50-70mmHg and 60-90bpm, respectively. The cumulative and interactive effects of exposure to low DAP (≤ 40mmHg) and tachycardia (≥ 100bpm) were associated with an increased risk of death.

An Optimal Assessment Schedule after Definitive Locoregional Treatment in Locally Advanced Head and Neck Cancer Using Parametric Modeling

<h3>Purpose/Objective(s)</h3> Surveillance plan after definitive treatment in head and neck cancer (HNC) is determined arbitrarily in daily clinical practice. This study aims to establish an optimal assessment schedule model in locally advanced HNC using a parametric model of standardized event-free survival (EFS) curves. <h3>Materials/Methods</h3> A total of 673 patients with locally advanced HNC (227 nasopharynx (NPC), 237 HPV-positive oropharynx (HPV+ OPC), 47 HPV-negative oropharynx (HPV- OPC), 65 hypopharynx (HPC), and 97 larynx cancer (LC)) who completed definitive locoregional treatment were retrospectively analyzed. EFS was defined as the period from the end of treatment to the date of any event (tumor recurrences or secondary malignancies). EFS curves were estimated using the piecewise exponential model and divided into three phases of regular follow-up. The criterion of a 5% event rate among the remaining patients was used to determine the optimal follow-up time point and interval. <h3>Results</h3> With a median follow-up of 57.8 months (range, 6.4–158.1 months), the event rates of NPC, HPV+ OPC, HPV- OPC, HPC, and LC were 18.9%, 14.8%, 36.2%, 44.6%, and 30.9%, respectively. Using parametric modeling, the optimal follow-up intervals for HPC/LC/NPC were every 2.1/3.2/6.1 months until 16.5 months after treatment, every 3.7/5.6/10.8 months from 16.5 to 25 months, every 9.1/13.8/26.5 months from 25 to 99 months, and open follow-up thereafter. For HPV- OPC, surveillance every 2.7 months until 16.5 months after treatment, every 4.8 months from 16.5 to 25 months, and every 11.8 months from 25 to 99 months were recommended. In contrast, for HPV+OPC, optimal intervals were every 7.7 months until 16.5 months after treatment, every 13.7 months from 16.5 to 25 months, every 33.7 months from 25 to 99 months. The recommended number of follow-up visits was 5, 4, 12, 15, and 10 times for NPC, HPV+ OPC, HPV- OPC, HPC, and LC, respectively. <h3>Conclusion</h3> The optimal assessment schedule for HNC stratified by primary subsites and HPV status was reasonably established using parametric modeling of EFS curves. Due to the limited healthcare resource and increasing number of HNC patients, this evidence-based assessment model will be worthwhile.

Association of Changes in Cancer Therapy Over 3 Decades With Risk of Subsequent Breast Cancer Among Female Childhood Cancer Survivors

Breast cancer is the most common invasive subsequent malignant disease in childhood cancer survivors, though limited data exist on changes in breast cancer rates as primary cancer treatments have evolved. To quantify the association between temporal changes in cancer treatment over 3 decades and subsequent breast cancer risk. Retrospective cohort study of 5-year cancer survivors diagnosed when younger than 21 years between 1970 and 1999, with follow-up through December 5, 2020. Radiation and chemotherapy dose changes over time. Breast cancer cumulative incidence rates and age-specific standardized incidence ratios (SIRs) compared across treatment decades (1970-1999). Piecewise exponential models estimated invasive breast cancer and ductal carcinoma in situ (DCIS) risk and associations with treatment exposures, adjusted for age at childhood cancer diagnosis and attained age. Among 11 550 female survivors (median age, 34.2 years; range 5.6-66.8 years), 489 developed 583 breast cancers: 427 invasive, 156 DCIS. Cumulative incidence was 8.1% (95% CI, 7.3%-9.0%) by age 45 years. An increased breast cancer risk (SIR, 6.6; 95% CI, 6.1-7.2) was observed for survivors compared with the age-sex-calendar-year-matched general population. Changes in therapy by decade included reduced rates of chest (34% in the 1970s, 22% in the 1980s, and 17% in the 1990s) and pelvic radiotherapy (26%, 17%, and 13% respectively) and increased rates of anthracycline chemotherapy exposures (30%, 51%, and 64%, respectively). Adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% every 5 years of primary cancer diagnosis era (rate ratio [RR], 0.82; 95% CI, 0.74-0.90). When accounting for chest radiotherapy exposure, the decline attenuated to an 11% decrease every 5 years (RR, 0.89; 95% CI, 0.81-0.99). When additionally adjusted for anthracycline dose and pelvic radiotherapy, the decline every 5 years increased to 14% (RR, 0.86; 95% CI, 0.77-0.96). Although SIRs of DCIS generally increased over time, there were no statistically significant changes in incidence. Invasive breast cancer rates in childhood cancer survivors have declined with time, especially in those younger than 40 years. This appears largely associated with the reduced use of chest radiation therapy, but was tempered by concurrent changes in other therapies.

Planted seedling survival in a post-wildfire landscape: From experimental planting to predictive probabilistic surfaces

Across the southwestern United States, high-severity wildfire is causing increasingly large areas of tree mortality and removing the seed sources required for the natural regeneration of these formerly conifer-dominated landscapes. Planting tree seedlings can accelerate reforestation, but in the semi-arid southwestern US, the survival of planted conifer seedlings is typically low. Our research examined how post-fire planting success is influenced by climate, topographic, biotic, and microclimate factors. We present data on a seedling planting experiment within the footprint of the 2011 Las Conchas Fire in northern New Mexico. We planted 768 tree seedlings of four species: ponderosa pine (Pinus ponderosa), piñon (P. edulis), southwestern white pine (P. strobiformis), and Douglas-fir (Pseudotsuga menziesii) in an area burned at high-severity and densely populated by New Mexico locust (Robinia neomexicana) and other shrub species. We established experimental plots stratified by aspect, either northerly or southerly, and cover, either planted under New Mexico locust or in the open, and collected topographical and microclimate measurements over three years. Mean survival over the 3-year period for all species in all treatments was 20%. Using microclimate variables and site-level topographical indices in a piecewise exponential model, we first determined how these factors influenced seedling survival of four conifer tree species, finding that topographical indices describing incoming solar radiation, variables related to vapor pressure deficit, i.e., seasonal maximums, and presence of New Mexico locust increased hazard for all species while variables related to shade, moisture availability, and slope reduced hazard. Following our planting experiment, an additional 1145 ponderosa pine seedlings, planted by USFS, were surveyed for survival and the topographical indices at their locations were recorded. Adding these seedlings' survival data to our experimentally planted ponderosa pine seedlings, we used boosted regression tree models to determine survival probability for ponderosa pine as a product of topographical indices, then extrapolated these findings to the wider landscape, producing a spatial projection of probabilistic seedling survival as a function of readily available topographical data, with a mean AUC value of 0.63. Both sets of analyses highlight the importance of landscape heterogeneity in shaping microclimatic environments and affecting seedling survival in a predictable manner, with areas receiving less solar radiation and more moisture promoting seedling survival. Our results demonstrate that by using fine-scale microtopography that shapes microclimatic environments, future plantings can increase conifer tree seedling survival in high-severity post-wildfire landscapes.

Evaluation of Optimal Assessment Schedules for Surveillance After Definitive Locoregional Treatment of Locally Advanced Head and Neck Cancer

In clinical practice, assessment schedules are often arbitrarily determined after definitive treatment of head and neck cancer (HNC), producing heterogeneous and inconsistent surveillance plans. To establish an optimal assessment schedule for patients with definitively treated locally advanced HNC, stratified by the primary subsite and HPV status, using a parametric model of standardized event-free survival curves. This was a retrospective study including 2 tertiary referral hospitals and a total of 673 patients with definitive locoregional treatment of locally advanced HNC (227 patients with nasopharyngeal cancer [NPC]; 237 patients with human papillomavirus-positive oropharyngeal cancer [HPV+ OPC]; 47 patients with HPV-negative [HPV-] OPC; 65 patients with hypopharyngeal cancer [HPC]; and 97 patients with laryngeal cancer [LC]). Patients had received primary treatment in 2008 through 2019. The median (range) follow-up duration was 57.8 (6.4-158.1) months. Data analyses were performed from April to October 2021. Tumor recurrence and secondary malignant neoplasms. Event-free survival was defined as the period from the end of treatment to occurrence of any event. Event-free survival curves were estimated using a piecewise exponential model and divided into 3 phases of regular follow-up. A 5% event rate criterion determined optimal follow-up time point and interval. The median (range) age of the 673 patients at HNC diagnosis was 58 (15-83) years; 555 (82.5%) were men; race and ethnicity were not considered. The event rates of NPC, HPV+ OPC, HPV- OPC, HPC, and LC were 18.9% (43 of 227), 14.8% (35 of 237), 36.2% (17 of 47), 44.6% (29 of 65), and 30.9% (30 of 97), respectively. Parametric modeling demonstrated optimal follow-up intervals for HPC, LC, and NPC, respectively, every 2.1, 3.2, and 6.1 months; 3.7, 5.6, and 10.8 months; and 9.1, 13.8, and 26.5 months until 16.5, 16.5 to 25.0, and 25.0 to 99.0 months posttreatment (open follow-up thereafter). For HPV- OPC, assessment was recommended every 2.7, 4.8, and 11.8 months until 16.5, 16.5 to 25.0, and 25 to 99 months posttreatment, respectively. In contrast, HPV+ OPC optimal intervals were every 7.7, 13.7, and 33.7 months until 16.5, 16.5 to 25.0, and 25 to 99 months posttreatment, respectively. Five, 4, 12, 15, and 10 follow-up visits were recommended for NPC, HPV+ OPC, HPV- OPC, HPC, and LC, respectively. This retrospective cohort study using parametric modeling suggests that the HNC assessment schedules should be patient tailored and evidence based to consider primary subsites and HPV status. Given limited health care resources and rising detection rates and costs of HNC, the guidelines offered by these findings could benefit patients and health systems and aid in developing future consensus guidelines.

Recurrent events analysis with piece-wise exponential additive mixed models

Recurrent events analysis plays an important role in many applications, including the study of chronic diseases or recurrence of infections. Historically, many models for recurrent events have been variants of the Cox model. In this article we introduce and describe the application of the piece-wise exponential Additive Mixed Model (PAMM) for recurrent events analysis and illustrate how PAMMs can be used to flexibly model the dependencies in recurrent events data. Simulations confirm that PAMMs provide unbiased estimates as well as equivalence to the Cox model when proportional hazards are assumed. Applications to recurrence of staphylococcus aureus and malaria in children illustrate the estimation of seasonality, bivariate non-linear effects, multiple timescales and relaxation of the proportional hazards assumption via time-varying effects. The R package pammtools is extended to facilitate estimation and visualization of PAMMs for recurrent events data.

Time-varying intensity of oxygen exposure is associated with mortality in critically ill patients with mechanical ventilation

BackgroundThere is no consensus exists regarding the association between oxygen exposure (arterial oxygen tension or fraction of inspired oxygen) and outcomes for patients with mechanical ventilation. Additionally, whether the association remains persistent over time is unknown. We aimed to explore the association between exposure to different intensities of oxygen exposure over time and 28-day mortality in patients with mechanical ventilation.MethodsWe obtained data from the Medical Information Mart for Intensive Care IV (MIMIC-IV), which included adult (≥ 18 years) patients who received invasive mechanical ventilation for at least 48 h. We excluded patients who received extracorporeal membrane oxygenation (ECMO) or who initiated ventilation more than 24 h after ICU admission. The primary outcome was 28-day mortality. Piece-wise exponential additive mixed models were employed to estimate the strength of associations over time.ResultsA total of 7784 patients were included in the final analysis. Patients had a median duration of invasive mechanical ventilation of 8.1 days (IQR: 3.8–28 days), and the overall 28-day mortality rate was 26.3%. After adjustment for baseline and time-dependent confounders, both daily time-weighted average (TWA) arterial oxygen tension (PaO2) and fraction of inspired oxygen (FiO2) were associated with increased 28-day mortality, and the strength of the association manifested predominantly in the early-middle course of illness. A significant increase in the hazard of death was found to be associated with daily exposure to TWA-PaO2 ≥ 120 mmHg (Hazard ratio 1.166, 95% CI 1.059–1.284) or TWA-FiO2 ≥ 0.5 (Hazard ratio 1.496, 95% CI 1.363–1.641) during the entire course. A cumulative effect of harmful exposure (TWA-PaO2 ≥ 120 mmHg or TWA-FiO2 ≥ 0.5) was also observed.ConclusionPaO2 and FiO2 should be carefully monitored in patients with mechanical ventilation, especially during the early-middle course after ICU admission. Cumulative exposure to higher intensities of oxygen exposure was associated with an increased risk of death.

Characteristics associated with composite surgical failure over 5 years of women in a randomized trial of sacrospinous hysteropexy with graft vs vaginal hysterectomy with uterosacral ligament suspension

Among women with symptomatic uterovaginal prolapse undergoing vaginal surgery in the Vaginal hysterectomy with Native Tissue Vault Suspension vs Sacrospinous Hysteropexy with Graft Suspension (Study for Uterine Prolapse Procedures Randomized Trial) trial, sacrospinous hysteropexy with graft (hysteropexy) resulted in a lower composite surgical failure rate than vaginal hysterectomy with uterosacral suspension over 5 years. This study aimed to identify factors associated with the rate of surgical failure over 5 years among women undergoing sacrospinous hysteropexy with graft vs vaginal hysterectomy with uterosacral suspension for uterovaginal prolapse. This planned secondary analysis of a comparative effectiveness trial of 2 transvaginal apical suspensions (NCT01802281) defined surgical failure as either retreatment of prolapse, recurrence of prolapse beyond the hymen, or bothersome prolapse symptoms. Baseline clinical and sociodemographic factors for eligible participants receiving the randomized surgery (N=173) were compared across categories of failure (≤1 year, >1 year, and no failure) with rank-based tests. Factors with adequate prevalence and clinical relevance were assessed for minimally adjusted bivariate associations using piecewise exponential survival models adjusting for randomized apical repair and clinical site. The multivariable model included factors with bivariate P<.2, additional clinically important variables, apical repair, and clinical site. Backward selection determined final retained risk factors (P<.1) with statistical significance evaluated by Bonferroni correction (P<.005). Final factors were assessed for interaction with type of apical repair at P<.1. Association is presented by adjusted hazard ratios and further illustrated by categorization of risk factors. In the final multivariable model, body mass index (increase of 5 kg/m2: adjusted hazard ratio, 1.7; 95% confidence interval, 1.3-2.2; P<.001) and duration of prolapse symptoms (increase of 1 year: adjusted hazard ratio, 1.1; 95% confidence interval, 1.0-1.1; P<.005) were associated with composite surgical failure, where rates of failure were 2.9 and 1.8 times higher in women with obesity and women who are overweight than women who have normal weight and women who are underweight (95% confidence intervals, 1.5-5.8 and 0.9-3.5) and 3.0 times higher in women experiencing >5 years prolapse symptoms than women experiencing ≤5 years prolapse symptoms (95% confidence interval, 1.8-5.0). Sacrospinous hysteropexy with graft had a lower rate of failure than hysterectomy with uterosacral suspension (adjusted hazard ratio, 0.6; 95% confidence interval, 0.4-1.0; P=.05). The interaction between symptom duration and apical repair (P=.07) indicated that failure was less likely after hysteropexy than hysterectomy for those with ≤5 years symptom duration (adjusted hazard ratio, 0.5; 95% confidence interval, 0.2-0.9), but not for those with >5 years symptom duration (adjusted hazard ratio, 1.0; 95% confidence interval 0.5-2.1). Obesity and duration of prolapse symptoms have been determined as risk factors associated with surgical failure over 5 years from transvaginal prolapse repair, regardless of approach. Providers and patients should consider these modifiable risk factors when discussing treatment plans for bothersome prolapse.

Mortality rate of Boer, Central Highland goat and their crosses in Ethiopia: Nonparametric survival analysis and piecewise exponential model.

BackgroundAnalysis of survival data by linear or logistic model ignores censoring and skewness inherent in the mortality data. The objective of this study is to estimate the morbidity and mortality rates of kids and adult goats, identify important risk factors for mortality using survival analysis and summarise important causes of goat death.MethodsNonparametric survival analysis and a piecewise exponential model (PEM) were used.ResultsThe mortality rates of kids and adult goats were 0.629 and 0.302 per animal year, respectively. The 25th, 50th and 75th percentiles of survival time of kids were 5, 162 and 1300 days, respectively, and those of adults and goats were 280, 828 and 1,735 days, respectively. Gastrointestinal‐related diseases, pneumonia, weak kid, agalactia, mismothering and heartwater (cowdriosis) were the most important causes of mortality. Constant piecewise exponential regression analysis of risk factors indicated that breed, kid birth weight, doe post‐partum weight (PPWT), birth type, birth year and precipitation variables were associated with (p‐value < 0.05) kid mortality rate. Pure Boer kids compared with Central Highland goat cross with Boer goats were 2.505 times at a higher probability of mortality (p‐value < 0.001). A 1‐kg increase in kid birth weight and dam PPWT reduces mortality probability by 32.5% (p‐value = 0.000) and 6.4% (p‐value < 0.001), respectively. Twin birth kids had a 1.512 times higher rate of mortality (p‐value = 0.001) than single‐born kids. A 1‐ml increment of 15 days of average precipitation significantly reduced kid mortality by 7.8% (p‐value < 0.001).ConclusionVaccination, extensive control of ticks and the use of proper comfortable housing to reduce the stress of goats are recommended. Scheduling a mating programme (May to early July) to match the kidding period to the less kid mortality seasons (end of the long rainy season) of flocks is also important to reduce kid mortality.

LGG-15. Late mortality and morbidity of adult survivors of childhood glioma treated across three decades: a report from the Childhood Cancer Survivor Study

PURPOSE: Pediatric low-grade glioma therapy has evolved to delay or eliminate radiation. The impact of therapy changes on long-term outcomes remains unknown. METHODS: Cumulative incidence of late mortality (death >5 years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions (CHCs, CTCAE grading criteria) were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of glioma diagnosed 1970-1999. Outcomes were evaluated by diagnosis decade and by treatment exposures received ≤5 years following diagnosis (surgery-only, chemotherapy ± surgery, and cranial radiation ± surgery or chemotherapy). Relative risk (RRs) with 95%CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS: Among 2,684 eligible survivors (age at diagnosis (median [range]), 7 years [0-20 years]; time from diagnosis, 24 years [5-48 years]), exposure to cranial radiation decreased [51% (1970s), 45% (1980s), 25% (1990s)] along with late tumor recurrence (>5 & ≤15 years from diagnosis) [9.8% (1970s), 8.8% (1980s), 5.0% (1990s)]. The 15-year cumulative incidence of late mortality was 10.3% (1970s), 6.5% (1980s), and 6.0% (1990s) (p<0.001, comparison of cumulative incidence curves). The 15-year cumulative incidence of grade 3-5 CHCs was 19.7% (1970s), 17.8% (1980s), and 14.2% (1990s) (p<0.0001). A reduction in SN incidence was not observed. In multivariable analyses excluding treatment exposure, later diagnosis (1990s vs. 1970s) was associated with lower risk of late mortality, grade 3-5 CHCs and SNs. Inclusion of treatment exposure in the model attenuated the effect of diagnosis decade. Radiation or chemotherapy exposure increased risk compared to surgery alone for late mortality (radiation RR 4.95, 95%CI 3.79-6.47; chemotherapy RR 2.88, 95%CI 1.85-4.48), CHCs (radiation RR 4.02, 95%CI 3.28-4.94; chemotherapy RR 1.66, 95%CI 1.13-2.45), and SNs (radiation RR 4.02, 95%CI 3.06-6.13, chemotherapy RR 2.08, 95%CI 1.03-4.23)). CONCLUSION: Late mortality and CHCs decreased in childhood glioma survivors diagnosed from 1970-1999 largely due to therapy changes, particularly avoidance of cranial radiation, without increased late recurrence.

Late mortality and morbidity among adult survivors of childhood glioma treated over three decades: A report from the Childhood Cancer Survivor Study.

10007 Background: Therapy for pediatric low-grade glioma has evolved to delay or eliminate the need for cranial radiation. The impact of this change in approach on long-term outcomes remains unknown. Methods: Cumulative incidence of late mortality (death ≥5 years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions (CHCs, graded using CTCAE criteria) were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of glioma diagnosed between 1970 and 1999. Outcomes were evaluated by diagnosis decade (1970s, 1980s, 1990s) and by treatment exposure in the first five years from diagnosis [surgery only, chemotherapy (with or without surgery), and cranial radiation (with or without surgery or chemotherapy)]. Relative Risk (RRs) with 95% CIs estimated long-term outcomes using multivariable piecewise exponential models. Results: Among 2,684 eligible survivors (median age at diagnosis, 7 years [range, 0 to 20 years]; median time from diagnosis, 24 years [range, 5 to 48 years]), the proportion exposed to cranial radiation decreased from 51% (1970s) to 45% (1980s) and 25% (1990s) while the rate of recurrence within &gt; 5 years but ≤15 years of diagnosis decreased from 9.8% (1970s) to 8.8% (1980s) and 5.0% (1990s). The 15-year cumulative incidence rate of all-cause late mortality was 10.3% (1970s), 6.5% (1980s), and 6.0% (1990s) (p &lt; 0.001, comparison of cumulative incidence curves). The 15-year cumulative incidence rates of severe, disabling or life-threatening (grade 3-5) CHCs also decreased between 1970 and 1999: 19.7% (1970s), 17.8% (1980s), and 14.2% (1990s) (p &lt; 0.0001). Lower rates of SN were not observed. In a multivariable analysis adjusted for age at diagnosis, attained age, race, sex and diagnosis decade, later diagnosis (1990s vs. 1970s) was associated with lower risk of late mortality (RR 0.86, 95% CI 0.74-0.99), grade 3-5 CHCs (RR 0.65, 95% CI 0.51-0.82) and SN (RR 0.64, 95% CI 0.44-0.94). In addition, when treatment exposure was added to the multivariable model, the effect of diagnosis decade was attenuated and no longer significant. Exposure to radiation or chemotherapy both increased risk compared to surgery alone: all-cause mortality (radiation RR 4.95, 95% CI 3.79-6.47; chemotherapy RR 2.88, 95% CI 1.85-4.48), grade 3-5 CHCs (radiation RR 4.02, 95% CI 3.28-4.94; chemotherapy RR 1.66, 95% CI 1.13-2.45), SNs (radiation RR 4.02, 95% CI 3.06-6.13, chemotherapy RR 2.08, 95% CI 1.03-4.23)). The effect of delayed radiation (&gt; 1year to ≤5 years from diagnosis) on all-cause late mortality, grade 3-5 CHCs, or SNs was not different compared to radiation within one year of diagnosis. Conclusions: Late mortality and CHCs decreased in childhood glioma survivors diagnosed from 1970-1999 largely due to therapy changes, particularly avoidance of cranial radiation, without increased late recurrence.

Effect of testing protocol and within-pen prevalence on the detection of Mycoplasma hyopneumoniae DNA in oral fluid samples

Combinations of 2 nucleic acid extractions and 3 Mycoplasma hyopneumoniae (MHP) PCRs (namely Protocol 1, 2, 3, and 4) were compared in terms of the probability of detecting DNA in pen-based oral fluid samples as a function of within-pen MHP prevalence. Oral fluid samples were created by randomly assigning 39 7-week old pigs to one of 5 pens, i.e., negative control pen (3 pigs) and 4 pens of 9 pigs each that differed in the proportion of MHP-inoculated pigs (1, 3, 6, or 9). Deep tracheal swabs were collected twice weekly to establish individual pig MHP infection status and derive within-pen prevalence estimation. On DPI 3, tracheal swabs from 15 of 19 inoculated pigs were MHP DNA positive. Oral fluids (n = 320) were collected daily from − 4 to 59 days post inoculation (DPI). Using a piecewise exponential model to account for within-pen transmission dynamics followed by a mixed-effect logistic regression, the probability of detecting MHP DNA in oral fluids was positively associated with within-pen prevalence (P < 0.0001) and differed among test protocols. MHP DNA was detected in 173 oral fluid samples with Protocol 3 versus 148, 134, and 101 with Protocols 4, 2, and 1, respectively. At 100% within-pen prevalence, the probability of detecting MHP DNA in oral fluids was highest using Protocol 3 (95.7%), followed by Protocols 4 (70.1%), 2 (60.1%), and 1 (34.0%). The fact that PCR protocols performed differently suggests that further improvements in extraction methods and MHP PCRs are possible. In the field, the dynamics of MHP infections should be taken into account if using oral fluid samples in surveillance.

Impact of land use and food environment on risk of type 2 diabetes: A national study of veterans, 2008–2018

BackgroundLarge-scale longitudinal studies evaluating influences of the built environment on risk for type 2 diabetes (T2D) are scarce, and findings have been inconsistent. ObjectiveTo evaluate whether land use environment (LUE), a proxy of neighborhood walkability, is associated with T2D risk across different US community types, and to assess whether the association is modified by food environment. MethodsThe Veteran's Administration Diabetes Risk (VADR) study is a retrospective cohort of diabetes-free US veteran patients enrolled in VA primary care facilities nationwide from January 1, 2008, to December 31, 2016, and followed longitudinally through December 31, 2018. A total of 4,096,629 patients had baseline addresses available in electronic health records that were geocoded and assigned a census tract-level LUE score. LUE scores were divided into quartiles, where a higher score indicated higher neighborhood walkability levels. New diagnoses for T2D were identified using a published computable phenotype. Adjusted time-to-event analyses using piecewise exponential models were fit within four strata of community types (higher-density urban, lower-density urban, suburban/small town, and rural). We also evaluated effect modification by tract-level food environment measures within each stratum. ResultsIn adjusted analyses, higher LUE had a protective effect on T2D risk in rural and suburban/small town communities (linear quartile trend test p-value <0.001). However, in lower density urban communities, higher LUE increased T2D risk (linear quartile trend test p-value <0.001) and no association was found in higher density urban communities (linear quartile trend test p-value = 0.317). Particularly strong protective effects were observed for veterans living in suburban/small towns with more supermarkets and more walkable spaces (p-interaction = 0.001). ConclusionAmong veterans, LUE may influence T2D risk, particularly in rural and suburban communities. Food environment may modify the association between LUE and T2D.

Childbearing among Polish migrant women and their descendants in Sweden: an origin-destination country approach

This paper examines the childbearing behaviour of Polish migrant women and their descendants in Sweden. Also considering stayers in the country of origin, we rely on a country-of-origin and country-of-destination approach in a careful examination regarding the relevance of three hypotheses on migrant fertility: the socialisation, selection, and adaptation hypotheses. We analyse the transitions to first and second births based on a piecewise exponential model, using Swedish register data and the Polish Generations and Gender Survey (GGS) first wave. The results support the socialisation hypothesis, as the Polish stayers and the first-generation Polish migrants have their first child at younger ages and are less likely to remain childless than the other groups but are also more likely to not proceed to a second child, unlike the Swedish natives and the second generation. We find partial support for the selection hypothesis. Descriptively, we observe signs of selection into migration based on education, cohort, and marital status. Additionally, our study shows that the impact of marriage varies between stayers and migrants, in the first-birth transition, suggesting selection into migration when it comes to unobserved characteristics as well. The adaptation hypothesis is also supported, as the fertility behaviour of the second generation more closely resembles that of the Swedish natives than that of the first generation and differs more from that of the Polish stayers in terms of both quantum and timing of the first and second births.

Challenges of modelling approaches for network meta-analysis of time-to-event outcomes in the presence of non-proportional hazards to aid decision making: Application to a melanoma network.

BackgroundSynthesis of clinical effectiveness from multiple trials is a well-established component of decision-making. Time-to-event outcomes are often synthesised using the Cox proportional hazards model assuming a constant hazard ratio over time. However, with an increasing proportion of trials reporting treatment effects where hazard ratios vary over time and with differing lengths of follow-up across trials, alternative synthesis methods are needed.ObjectivesTo compare and contrast five modelling approaches for synthesis of time-to-event outcomes and provide guidance on key considerations for choosing between the modelling approaches.MethodsThe Cox proportional hazards model and five other methods of estimating treatment effects from time-to-event outcomes, which relax the proportional hazards assumption, were applied to a network of melanoma trials reporting overall survival: restricted mean survival time, generalised gamma, piecewise exponential, fractional polynomial and Royston-Parmar models.ResultsAll models fitted the melanoma network acceptably well. However, there were important differences in extrapolations of the survival curve and interpretability of the modelling constraints demonstrating the potential for different conclusions from different modelling approaches.ConclusionThe restricted mean survival time, generalised gamma, piecewise exponential, fractional polynomial and Royston-Parmar models can accommodate non-proportional hazards and differing lengths of trial follow-up within a network meta-analysis of time-to-event outcomes. We recommend that model choice is informed using available and relevant prior knowledge, model transparency, graphically comparing survival curves alongside observed data to aid consideration of the reliability of the survival estimates, and consideration of how the treatment effect estimates can be incorporated within a decision model.

Protein intake and outcome of critically ill patients: analysis of a large international database using piece-wise exponential additive mixed models

BackgroundProteins are an essential part of medical nutrition therapy in critically ill patients. Guidelines almost universally recommend a high protein intake without robust evidence supporting its use.MethodsUsing a large international database, we modelled associations between the hazard rate of in-hospital death and live hospital discharge (competing risks) and three categories of protein intake (low: < 0.8 g/kg per day, standard: 0.8–1.2 g/kg per day, high: > 1.2 g/kg per day) during the first 11 days after ICU admission (acute phase). Time-varying cause-specific hazard ratios (HR) were calculated from piece-wise exponential additive mixed models. We used the estimated model to compare five different hypothetical protein diets (an exclusively low protein diet, a standard protein diet administered early (day 1 to 4) or late (day 5 to 11) after ICU admission, and an early or late high protein diet).ResultsOf 21,100 critically ill patients in the database, 16,489 fulfilled inclusion criteria for the analysis. By day 60, 11,360 (68.9%) patients had been discharged from hospital, 4,192 patients (25.4%) had died in hospital, and 937 patients (5.7%) were still hospitalized. Median daily low protein intake was 0.49 g/kg [IQR 0.27–0.66], standard intake 0.99 g/kg [IQR 0.89– 1.09], and high intake 1.41 g/kg [IQR 1.29–1.60]. In comparison with an exclusively low protein diet, a late standard protein diet was associated with a lower hazard of in-hospital death: minimum 0.75 (95% CI 0.64, 0.87), and a higher hazard of live hospital discharge: maximum HR 1.98 (95% CI 1.72, 2.28). Results on hospital discharge, however, were qualitatively changed by a sensitivity analysis. There was no evidence that an early standard or a high protein intake during the acute phase was associated with a further improvement of outcome.ConclusionsProvision of a standard protein intake during the late acute phase may improve outcome compared to an exclusively low protein diet. In unselected critically ill patients, clinical outcome may not be improved by a high protein intake during the acute phase.Study registration ID number ISRCTN17829198

Novel Low Complexity BP Decoding Algorithms for Polar Codes: Simplifying on Non-Linear Operations

The parallel nature of the belief propagation (BP) decoding algorithm for polar codes opens up a real possibility of high throughput and low decoding latency during hardware implementation. To address the problem that the BP decoding algorithm introduces high-complexity non-linear operations in the iterative messages update process, this paper proposes to simplify these operations and develops two novel low complexity BP decoding algorithms, namely, exponential BP (Exp-BP) decoding algorithm and quantization function BP (QF-BP) decoding algorithm. The proposed algorithms simplify the compound hyperbolic tangent function by using probability distribution fitting techniques. Specifically, the Exp-BP algorithm simplifies two types of non-linear operations into single non-linear operation using the piece-wise exponential model function, which can approximate the hyperbolic tangent function in the updating formula. The QF-BP algorithm eliminates non-linear operations using the non-uniform quantization in the updating formula, which is effective in reducing computational complexity. According to the simulation results, the proposed algorithms can reduce the computational complexity up to 50% in each iteration with a loss of less than 0.1 dB compared with the BP decoding algorithm, which can facilitate the hardware implementation.