Nelson-Aalen Estimator Research Articles

The Tri-Steps Model of Critical Conditions in Intensive Care: Introducing a New Paradigm for Chronic Critical Illness.

Background: The prevailing model for understanding chronic critical illness is a biphasic model, suggesting phases of acute and chronic critical conditions. A major challenge within this model is the difficulty in determining the timing of the process chronicity. It is likely that the triad of symptoms (inflammation, catabolism, and immunosuppression [ICIS]) could be associated with this particular point. We aimed to explore the impact of the symptom triad (inflammation, catabolism, immunosuppression) on the outcomes of patients hospitalized in intensive care units (ICUs). Methods: The eICU-CRD database with 200,859 ICU admissions was analyzed. Adult patients with the ICIS triad, identified by elevated CRP (>20 mg/L), reduced albumin (<30 g/L), and low lymphocyte counts (<0.8 × 109/L), were included. The cumulative risk of developing ICIS was assessed using the Nelson-Aalen estimator. Results: This retrospective cohort study included 894 patients (485 males, 54%), with 60 (6.7%) developing ICIS. The cumulative risk of ICIS by day 21 was 22.5%, with incidence peaks on days 2-3 and 10-12 after ICU admission. Patients with the ICIS triad had a 2.5-fold higher mortality risk (p = 0.009) and double the likelihood of using vasopressors (p = 0.008). The triad onset day did not significantly affect mortality (p = 0.104). Patients with ICIS also experienced extended hospital (p = 0.041) and ICU stays (p < 0.001). Conclusions: The symptom triad (inflammation, catabolism, immunosuppression) during hospitalization increases mortality risk by 2.5 times (p = 0.009) and reflects the chronicity of the critical condition. Identifying two incidence peaks allows the proposal of a new Tri-steps model of chronic critical illness with acute, extended, and chronic phases.

Risk factors for suicide in patients with pancreatic ductal adenocarcinoma: A population‐based study

AbstractBackgroundPatients diagnosed with pancreatic ductal adenocarcinoma (PDAC) face a notable risk of suicide. However, comprehensive population‐based studies on suicide risk in PDAC patients have been lacking. This study seeks to explore the suicide risk in PDAC patients and identify the specific risk factors associated with suicide‐related mortality.MethodsA cohort of 101,382 PDAC patients was extracted from the Surveillance, Epidemiology, and End Results database, spanning from January 1, 2000, to December 31, 2017. The study employed the standardized mortality ratio (SMR) to assess the relative risk of suicide in PDAC patients compared to the general US population. The Nelson–Aalen estimator and the Fine and Grey method were utilized to pinpoint the risk factors linked to suicide‐specific mortality.ResultsPDAC patients exhibited a 3.51‐fold higher risk of suicide compared to the general US population. This risk demonstrated an upward trend over the years. Notably, individuals aged 70–74 years faced a significantly elevated risk of suicide (SMR = 5.14, 95% CI: 3.10–8.03). Furthermore, there were distinct peaks in suicide risk at 1–4‐ and 25–28‐month post‐diagnoses (SMR = 15.04 and 2.72, respectively). Factors, such as gender, chemotherapy status, and marital status, emerged as significant independent predictors of suicide‐specific mortality in PDAC patients.ConclusionsThis study highlights a heightened suicide risk among PDAC patients in comparison to the general US population. It underscores the crucial need for continuous monitoring of the psychological well‐being of all PDAC patients. Additionally, considering the elevated risk, the application of antidepressant therapy could be beneficial for those identified as having a higher risk of suicide.

The joint effects of genetic liability and the death of close relatives on risk for major depression and alcohol use disorder in a Swedish national sample.

To determine whether genetic risk factors for major depression (MD) and alcohol use disorder (AUD) interact with a potent stressor - death of spouse, parent, and sibling - in predicting episodes of, respectively, MD and AUD. MD and AUD registrations were assessed from national Swedish registries. In individuals born in Sweden 1960-1970, we identified 7586, 388 459, and 34 370 with the loss of, respectively, a spouse, parent, and sibling. We started following subjects at age 18 or the year 2002 with end of follow-up in 2018. We examined time to event - a registration for MD within 6 months or AUD within a year - on an additive scale, using the Nelson-Aalen estimator. Genetic risk was assessed by the Family Genetic Risk Score (FGRS). In separate models controlling for the main effects of death of spouse, parent, and sibling, FGRS, and sex, significant interactions were seen in all analyses between genetic risk for MD and death of relative in prediction of subsequent MD registration. A similar pattern of results, albeit with weaker interaction effects, was seen for genetic risk for AUD and risk for AUD registration. Genetic risk for bipolar disorder (BD) and anxiety disorders (AD) also interacted with event exposure in predicting MD. Genetic risk for both MD and AUD act in part by increasing the sensitivity of individuals to the pathogenic effects of environmental stressors. For prediction of MD, similar effects are also seen for genetic risk for AD and BD.

Comparison of nonparametric estimators of the expected number of recurrent events.

We compare the performance of nonparametric estimators for the mean number of recurrent events and provide a systematic overview for different recurrent event settings. The mean number of recurrent events is an easily interpreted marginal feature often used for treatment comparisons in clinical trials. Incomplete observations, dependencies between successive events, terminating events acting as competing risk, or gaps between at risk periods complicate the estimation. We use survival multistate models to represent different complex recurrent event situations, profiting from recent advances in nonparametric estimation for non-Markov multistate models, and explain several estimators by using multistate intensity processes, including the common Nelson-Aalen-type estimators with and without competing mortality. In addition to building on estimation of state occupation probabilities in non-Markov models, we consider a simple extension of the Nelson-Aalen estimator by allowing for dependence on the number of prior recurrent events. We pay particular attention to the assumptions required for the censoring mechanism, one issue being that some settings require the censoring process to be entirely unrelated while others allow for state-dependent or event-driven censoring. We conducted extensive simulation studies to compare the estimators in various complex situations with recurrent events. Our practical example deals with recurrent chronic obstructive pulmonary disease exacerbations in a clinical study, which will also be used to illustrate two-sample-inference using resampling.

KAPLAN-MEIER AND NELSON-AALEN ESTIMATORS FOR CREDIT SCORING

Financial institutions use credit scoring analysis to predict the probability that a customer will default. In this paper, we determine the probability of default using nonparametric survival analysis that are Kaplan-Meier and Nelson-Aalen. The analysis is based on survival function curves, cumulative hazard function curves, mean survival time, and standard error of estimators. Based on the curves of survival function for both Kaplan Meier and Nelson Aalen estimators relatively the same. Based on the curves of cumulative hazard function, mean survival time, and standard error the Nelson-Aalen estimators are slightly higher than Kaplan-Meier.

1234-P: Derivation of a Claims-Computable Major Adverse Cardiovascular Event Estimator (ACME) in Adults with Type 2 Diabetes

Major adverse cardiovascular events (MACE) are a major cause of morbidity and mortality among adults with type 2 diabetes. Currently available risk prediction models estimate long-term risk (typically 10-year) and require clinical data not routinely available in real-world data sources, which limit their use on population level. Using de-identified claims data from OptumLabs® Data Warehouse for enrollees in private and Medicare Advantage health plans linked to 100% sample of Medicare fee-for-service beneficiaries between 2014 and 2021, we derived ACME to estimate annualized risk of non-fatal myocardial infarction, non-fatal stroke, or all-cause mortality in patients with type 2 diabetes aged ≥21 years (N=6,623,526). The Cox proportional hazards model, combined with an estimate of the baseline hazard using the Nelson-Aalen estimator to allow conditional survival predictions, included 28 covariates available in claims (age, sex, cardiovascular comorbidities, and cardiovascular medications). The study population had mean age 68.1 (SD, 10.6) years, 49.8% were women, and 73.0% were non-Hispanic White. ACME’s concordance index was 0.74 (se = 0.0002) and it performed comparably in all racial and ethnic groups. Strongest predictors of MACE were acute myocardial infarction and stroke within the past 3 months, heart failure hospitalization within the past year, and end-stage kidney disease. Overall, 4.2% of patients were predicted to have low (&amp;lt;1%) annualized MACE risk, 62.8% were predicted to have moderate (≥1 to &amp;lt;5%) annualized risk, and 33.0% were predicted to have high (≥5%) annualized risk. Other thresholds can be chosen for individualized applications. ACME can support population risk stratification and health management efforts at the health system and payer levels, participant identification for decentralized pragmatic clinical trials of cardiovascular disease and its prevention, and risk-stratified observational studies using real-world data. Disclosure R.G.Mccoy: Consultant; Emmi. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. J.Brito: None. M.Mickelson: None. E.Polley: None. K.Swarna: None. Y.Deng: None. J.Herrin: Consultant; Johnson &amp; Johnson Medical Devices Companies. J.Ross: Research Support; Johnson &amp; Johnson. D.M.Kent: Research Support; W.L. Gore. B.Borah: Consultant; Boehringer Ingelheim Inc., Exact Sciences. W.Crown: Consultant; Janssen Scientific Affairs, LLC, UnitedHealth Group, Viatris Inc. V.M.Montori: None. Funding Patient-Centered Outcomes Research Institute (DB-2020C2-20306)

Comparison of 5- and 10-year breast cancer risk predictions.

10529 Background: Breast cancer risk assessment is valuable in personalizing risk-reduction and screening approaches for the general population. Maximizing the benefits while reducing the harms associated with current breast cancer screening and risk-reduction recommendations should increase the efficacy of these paradigms. Because healthcare providers have limited time with their patients, we developed a risk prediction model, BRISK, which uses the most important clinical risk factors for breast cancer (in an easily collected format), polygenic risk and mammographic density. We previously validated BRISK 5-year risk predictions and found that it performed better than IBISv7 and BCRAT. Methods: The dataset comprised 241,633 women (mean age at baseline assessment = 56.6 years). We included all races/ethnicities available in the UK Biobank. There were 3726 women affected during the first five years of follow-up and 7482 women affected during the full 10 years of follow-up. We compared the performance of the 5-year and 10-year risk predictions by assessing the association with breast cancer using Cox regression to estimate the hazard ratio (HR) per SD of risk, discrimination using calculating Harrell’s C-index and calibration using logistic regression to estimate the slope and the intercept of the logit of the risk predictions. Nelson–Aalen estimates of the hazard function by quintiles of risk and standardized incidence ratios (SIRs) of the number of breast cancer cases expected were used to illustrate performance. Results: The predictive performance of BRISK was consistent for 5-year and 10-year risk predictions. Discrimination was similar, with a Harrell’s C-index of 0.645 (95% CI = 0.636, 0.654) for the 5-year risk and of 0.638 (95% CI = 0.632, 0.645) for the 10-year risk. We used Nelson_Aalen cumulative hazard estimates to compare breast cancer incidence by risk quintile for both 5 and 10-year risk. Both risk scores overestimated risk in the top two deciles with the 5-year expected risks of 2.8% and 5.0% corresponding to observed risks of 2.3% and 3.3%. The 10-year expected risks for the top two deciles were 5.6% and 9.8% while the corresponding observed risks were 4.6% and 6.4%. Finally, we used clinically actionable thresholds to show the standard incidence ratios (SIR) of 1.77 (95% CI = 1.69, 1.85) for women ≥3% 5-year risk and 2.05 (95% CI = 1.93, 2.18) ≥8% 10-year risk. Conclusions: The BRISK 5-year and 10-year risk prediction perform equally well. There is an overestimation of risk for the top decile in both models. This is important to consider in risk-management conversations between clinician and patient. While the observed risk of the top decile remained above the 3% 5-year risk threshold used in the United States, the top decile observed risk dropped below the 8% 10-year risk threshold used in the United Kingdom. Risk scores are not used in isolation, but it may be preferable to err on the side of overestimation rather than underestimation.

Estimation of median survival time and its 95% confidence interval using SAS PROC LIFETEST

ABSTRACT Estimation of median survival and its 95% confidence interval depends on the choice of the survival function, standard error, and a method for constructing the confidence interval. This paper outlines several available possibilities in SAS® (version 9.4) PROC LIFETEST and compares them on theoretical grounds and using simulated data, with criteria: ability to estimate the 95% CI, coverage probability, interval width, and appropriateness for practical use. Data are generated with varying hazard patterns, N, % censoring, and censoring patterns (early, uniform, late, last visit). LIFETEST was run using the Kaplan–Meier and Nelson–Aalen estimators and the transformations available (linear, log, logit, complementary log–log, and arcsine square root). Using the Kaplan–Meier estimator with the logarithmic transformation as well as with the logit leads to a high frequency of LIFETEST not being able to estimate the 95% CI. The combination of Kaplan–Meier with the linear transformation is associated with poor coverage achieved. For small samples, late/last visit censoring has a negative effect on being able to estimate the 95% CI. Heavy early censoring can lead to low coverage of the 95% CI of median survival for sample sizes up to and including N = 40. The two combinations that are optimal for being able to estimate the 95% CI and having adequate coverage are the Kaplan–Meier estimator with complementary log–log transformation, and the Nelson–Aalen estimator with linear transformation. The former fares best on the third criterion (smaller width) and is also the SAS® default and validates the choice of default.

Impact of cytoreductive nephrectomy (CRN) on overall survival (OS) in metastatic non–clear cell renal cancer (nccRCC).

730 Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for 25% of kidney cancer diagnoses and encompasses a diverse group of kidney tumors with distinct biology for which treatment in the metastatic setting is evolving. The role of CRN for nccRCC population in the current treatment landscape remains unclear. Methods: We retrospectively identified patients (pts) with nccRCC from The National Cancer Database (NCDB) participant user file (PUF) for Kidney and Renal Pelvis Tumors. Pts with de novo metastatic disease diagnosed between 2006 and 2017, received systemic treatment (trt) with immunotherapy (IO) or non-immunotherapy (NIO) and either underwent or could have undergone a CRN were selected. Demographic and disease characteristics were summarized using descriptive statistics. The cumulative incidence of CRN with death without CRN as a competing risk, was estimated using the Nelson-Aalen estimator. The association of each demographic and disease characteristic on the cumulative incidence of CRN was evaluated using univariate Fine-Gray regression. The effect of CRN on survival was visualized using a Simon-Makuch plot. P values were based on Mantel-Byar test. Cox regression with a time-dependent predictor was used to estimate the change in the hazard of death after CRN. Results: We identified 3644 pts, 72% male, mean age 61 ±13 years. Nearly 40% of pts (n=1453) had sarcomatoid histology, followed by 30% with papillary (n=1075). Most pts, 96% (n=3489) received NIO systemic trt and only 9% were treated with IO (n=319). Nearly half of the study population (45%) underwent CRN (n=1642). Of these, 95% received NIO trt (n=1564) and 9% received IO (n=152). Pts who underwent CRN were younger and less likely to have bone, brain or liver metastases. Minority pts were less likely to undergo CRN. Mean time from dx to surgery was 1.1 ±1.7 months. For all pts, mOS was 9 months (95% CI: 8.6-9.4). OS was improved for pts who underwent CRN vs those who did not (11.3 vs 7.5 months, p&lt;0.0001). In multivariate analysis, cytoreductive nephrectomy was associated with a reduction in the risk of death, HR 0.73 (95% CI: 0.68, 0.80, p&lt;.0001). Conclusions: For pts with de novo metastatic nccRCC, CRN is associated with improved outcomes. Further analysis regarding the effect of treatment regimens on survival outcomes is warranted and planned. Prospective randomized trials in the modern treatment era are needed to further assess the timing and impact of CRN on outcomes in pts with metastatic nccRCC. [Table: see text]

Portal vein thrombosis, hepatic decompensation, and survival in patients with porto-sinusoidal vascular disease and portal hypertension.

Porto-sinusoidal vascular disease (PSVD) is a novel nomenclature to describe non-cirrhotic portal hypertension and characteristic histology without portal vein thrombosis (PVT). It is a more inclusive definition than the previously well-recognized entity idiopathic non-cirrhotic portal hypertension. There is a paucity of data on PSVD patients. A total of 33 patients diagnosed with PSVD and portal hypertension (PH) between 2005 and 2021 were included. Data were retrieved from electronic medical record system and analyzed. Of the 33 patients, 6 (18%) occurred in post-transplant allograft liver. After a median follow-up of 96months (interquartile range, IQR [52, 139]), 14 deaths occurred (42%), 4 directly related to decompensated liver disease. The Kaplan-Meier survival estimates at 1, 5, and 10years were 94%, 87% and 58%. PVT occurred in 10 patients (30%). The Nelson-Aalen cumulative risk estimate for PVT at 1, 5 and 10years were 16%, 25% and 48%. The median model for end-stage liver disease and Child-Pugh score at initial presentation were 8 (IQR [7-12]) and 5 [5-6], and increased to 13 [8, 18] and 7 [5, 8], respectively, at the end of follow-up. Of the 11 patients who presented with splenomegaly and no specific sign of PH, 7 (64%) developed varices and 3 (27%) ascites at a median follow-up of 100months. PSVD with PH is not a benign entity. Mortality, PVT and hepatic decompensation are common. Patients with PSVD must be closely monitored, including those who only have non-specific clinical signs (e.g., splenomegaly) of PH.

Neuromyelitis optica spectrum disorders with and without associated autoimmune diseases.

We aimed to determinate the frequency of this association and compare the features of neuromyelitis optica spectrum disorder (NMOSD) with and without associated autoimmune diseases (AD) in a Latin American (LATAM) population in clinical practice. We retrospectively reviewed the medical records of patients with NMOSD according to the 2015 diagnostic criteria. Patients from Argentina (n=77), Brazil (n=46), and Venezuela (n=17) were enrolled and classified into two groups as follows: with AD or without AD. Clinical, paraclinical (including aquaporin-4 antibodies (AQP4-ab) status), magnetic resonance imaging (MRI), and prognosis data were analyzed and compared. Kaplan-Meier (KM) and the Nelson-Aalen estimator analyses were performed to estimate both time and the cumulative hazard risk of disability reaching an EDSS≥4; and time for the first recurrence. Out of 140 patients, 33 (23.5%) patients had associated an AD at presentation. The most frequent associated AD was Hashimoto disease (n=10) followed by lupus (n=7) and Sjogren's syndrome (n=6). However, rituximab use (42.4% vs. 21.5%, p=0.02), female gender (82.2% vs. 100%, p=0.006), corticospinal lesions on MRI (0% vs. 12.5%, p=0.01) at onset, and positivity for antinuclear antibodies (21.2% vs. 48.4%, p=0.03) were significantly associated with NMOSD patients with AD in comparison to NMOSD patients without AD. No differences were found in other clinical and paraclinical aspects between groups. KM and Nelson-Aalen estimator analyses did not show differences between groups. NMOSD patients associated with AD were observed in 23.5%. In addition, NMOSD patients with and without associated AD were similar in most evaluated features.

Comparing Direct-to-Implant and Two-Stage Breast Reconstruction in the Australian Breast Device Registry.

There remains a lack of clarity surrounding the benefits, risks, and outcomes between two-stage expander/implant reconstruction and single-stage direct-to-implant (DTI) reconstruction. This study used a national data set to examine real-world outcomes of two-stage and DTI reconstructions. A cohort study was conducted examining patients in the Australian Breast Device Registry (ABDR) from 2015 to 2018 who underwent prosthetic breast reconstruction following mastectomy. DTI and two-stage cohorts after definitive implant insertion were compared. Rate of revision surgery, reasons for revision, and patient-reported outcome measures were recorded. Statistical analysis was undertaken using Fisher exact or chi-square, Wilcoxon rank sum, or t tests; Nelson-Aalen cumulative incidence estimates; and Cox proportional hazards regression. A total of 5152 breast reconstructions were recorded, including 3093 two-stage and 2059 DTI reconstructions. Overall revision surgery rates were 15.6% for DTI (median follow-up, 24.7 months), compared with 9.7% in the two-stage cohort (median follow-up, 26.5 months; P < 0.001). The most common reasons for revision for DTI and two-stage reconstruction were capsular contracture (25.2% versus 26.7%; P = 0.714) and implant malposition (26.7% versus 34.3%; P = 0.045). Multivariate analysis found acellular dermal matrix use ( P = 0.028) was significantly associated with a higher risk of revision. The influence of radiotherapy on revision rates was unable to be studied. Patient satisfaction levels were similar between reconstructive groups; however, patient experience was better in the DTI cohort than in the two-stage cohort. The ABDR data set demonstrated that DTI reconstruction had a higher revision rate than two-stage, but with comparable patient satisfaction and better patient experience. Capsular contracture and device malposition were leading causes of revision in both cohorts. Therapeutic, III.

82. Incidence rates of invasive aspergillosis among lung transplant recipients in timeperiods with universal and targeted antifungal prophylaxis - a nationwide cohort study

Abstract Background The best stategy for prevention of invasive aspergillosis (IA) after lung transplantation (LTX) has not been determined. In 2016, Danish guidelines for IA prophylaxis was changed from 12 weeks of universal prophylaxis with voriconazole to targeted prophylaxis with posaconazole and inhaled amphotericin B for high risk patients. In a previous study we found significantly higher rates of adverse events in the period with universal prophylaxis. The objectives of this study were to compare rates of IA 1) in time periods before and after change of guidelines; 2) during persontime on vs. persontime without antifungal prophylaxis in the total study period. Methods In a Danish nationwide study we included all adult lung transplant recipients (LTXr), 2010–2019. Proven and probable IA were defined using ISHLT criteria. Patients were censored at the first of following events: death, retransplantation, end of 2019, or one year after LTX. The cumulative hazard of IA was calculated using the Nelson Aalen estimator. Rates of IA were analyzed in bi- and multivariate Poisson regression models adjusted for the time period after LTX (0–6 and 6–12 months). Persontime on protocol prophylaxis (start to end + 14 days) was treated as time-updated variable. Results A total of 295 LTXr were followed for 245 person-years, of whom 183/193 vs. 6/102 initiated antifungal prophylaxis during the universal vs. the targeted prophylaxis period (Table 1). IA was diagnosed in 34/193 (17.6%) vs. 15/102 (14.7%) LTXr the first year after transplantation in the universal vs. targeted prophylaxis period. Overall, similar cumulative hazards of IA were observed between the universal and targeted prophylaxis period (p=0.59, Figure 1). The adjusted incidence rate ratio (aIRR) of IA during the universal vs. targeted prophylaxis period was 1.30 (95% CI 0.69–2.44), (Table 2). In the total study period, the aIRR of IA during persontime on vs. persontime without antifungal prophylaxis was 0.87 (95% CI 0.40–1.88), (Table 2). Characteristics of lung transplant recipients in time periods with universal voriconazole and targeted posaconazole and inhaled amphotericin B prophylaxis. Proven and probable invasive aspergillosis including anastomosis infection, trakeobronkitis and pneumonia according to ISHLT criteria. *) Underlying diseases categorized as high risk of invasive aspergillosis. Incidence rates (IR) and incidence rate ratios (IRR) of invasive aspergillosis in lung transplant recipients in two multivariate models. Poisson regression models comparing rates of IA in model 1) during universal prophylaxis time period versus targeted prophylaxis time period and in model 2) during persontime on prophylaxis (start to end + 14 days) versus persontime without prophylaxis in the total study period 2010–2019. Adjusted for time after LTX IRR: Bivariable model including the listed variables in bold and adjustment for time after transplantation (time-updated). Fully adjusted IRR: Multivariable model with adjustment for sex, age, high risk underlying disease, single/double lung transplant, Aspergillus prior to transplantation and time after transplantation (time-updated). Abbreviations: LTX = lung transplant recipients; CI = confidence interval; IR = incidence rates per 100 person-years; IRR = incidence rate ratio; Ref. = reference. Cumulative hazards of invasive aspergillosis the first year after lung transplantation in time periods with universal voriconazole versus targeted posaconazole and inhaled amphotericin B prophylaxis. Conclusion A strategy of targeted prophylaxis, for high risk patients only, may be preferred over universal voriconazole prophylaxis after LTX due to similar rates of IA and lower rates of adverse events. Disclosures Maiken C. Arendrup, DMSci, PhD, MD, Chiesi, Gilead: Honoraria|F2G, Cidara, Scynexis: Grant/Research Support Michael Perch, MD, Boeringer-Ingelheim: Travel grant|PulmonX: Expert Testimony|Roche: Grant/Research Support|Takeda: Expert Testimony|Therakos: Honoraria|Zambon: Advisor/Consultant|Zambon: Expert Testimony Marie Helleberg, PhD, DMSc, AstraZeneca: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Janssen: Advisor/Consultant|Roche: Advisor/Consultant|Sobi: Advisor/Consultant.

1570. Cumulative Antibiotic Exposure and Risk for Candidemia

Abstract Background Broad-spectrum antibiotic use is a known risk factor for candidemia, but the duration and type of antibiotic exposure associated with greatest risk are not well characterized. Measurements of antibiotic days may be useful to assess cumulative burden of selective pressure on the microbiome and risk for candidemia. Methods This retrospective cohort study aimed to quantify the effect of antibiotic exposure on risk for candidemia. The primary outcome was hazard for developing candidemia across an array of antibiotic agents, classes and spectra. We measured antibiotic days of therapy (DOT) for adults admitted to Duke University hospitals 1/1/2016–12/31/2021. We excluded patients with community-onset candidemia, defined as growth of Candida spp. in blood culture collected ≤ 48 hours of admission, because antibiotic exposure prior to arrival was not reliably accessible. Time-to-event analyses were performed using the Nelson-Aalen estimator for modeling cumulative hazard functions to compare the proportion of candidemia observed based on exposure to each antibiotic. Logrank tests were used to evaluate for differences between hazard functions with a pre-specified alpha level of 0.05, and exponential cumulative proportional hazards models were implemented to generalize hazard functions. Results During 164,185 encounters in 105,330 unique patients, we identified candidemia in 237 patients. Prior to developing candidemia, cases received a total of 9,604 antibacterial DOT distributed across 46 unique antibiotic agents (Fig. 1) Carbapenems were associated with increased hazard for candidemia compared to beta-lactams (p&amp;lt; 0.005) (Figs. 2–3). There were 57 encounters for candidemia where meropenem was administered with a median of 10 DOT prior to onset of candidemia. Days of Antibiotic Therapy by Agent and Outcome. Conclusion This work represents a novel approach to quantifying antibiotic exposure as a risk factor for candidemia. In an unadjusted model, we identified carbapenems as a high-risk class; additional analysis with adjusted regression models will help contextualize exposure risk with respect to comorbidity and illness severity. This work may serve as a reference for antibiotic stewards as they promote appropriate antibiotic use, including reducing overuse of broad-spectrum antibiotics. Disclosures Rebekah W. Moehring, MD, MPH, FIDSA, FSHEA, UpToDate, Inc.: Author Royalties Barbara D. Alexander, MD, Astellas: Advisor/Consultant|HealthtrackRx: Advisor/Consultant|HealthtrackRx: Grant/Research Support|Scynexis: Grant/Research Support|UpToDate: Advisor/Consultant Melissa D. Johnson, PharmD, Biomeme: Licensed Transcriptional Signature for Candidemia|Charles River Laboratories: Grant/Research Support|Entasis Therapeutics: Advisor/Consultant|Merck &amp; Co. Inc: Advisor/Consultant|Merck &amp; Co. Inc: Grant/Research Support|Pfizer, Inc.: Advisor/Consultant|Scynexis Inc.: Grant/Research Support|Theratechnologies: Advisor/Consultant.

Registry Data Indicate a Meaningful Chance for Successful Pregnancies after Allogeneic Stem Cell Transplantation: Results from the German Stem Cell Transplant Registry (DRST)

Background Long-term survival following allogeneic hematopoietic cell transplantation (alloHCT) has improved significantly over the last decades. Beyond curation, return to a normal social life, including family planning, represents an important goal especially for young adult cancer survivors. However, alloHCT recipients are at high risk for infertility due to precedent chemotherapy, total body irradiation, transplant-related morbidity and long-term immunosuppressive medication. Nevertheless, spontaneous pregnancies following alloHCT were reported occasionally. Systematic studies on fertility preservation and pregnancies after alloHCT are very rare and do not cover the most recent era of transplantation. To fill this gap, we conducted a national multicenter study to investigate the pregnancy rate after alloHCT and their outcomes and to analyze potential risk factors in female transplant recipients. Methods Retrospectively, we evaluated data on disease and transplant characteristics from all women of childbearing age (18-40 years), who received an alloHCT in Germany between 2003 and 2018. Data were retrieved from the German Registry for Stem Cell Transplantation (DRST). Follow-up data were introduced into a competing risk model in order to calculate rates of pregnancies and first live birth per person-year after alloHCT. "First live birth” and "death w/o prior live birth” were considered as competing risks. Cumulative hazards were estimated with the Nelson-Aalen estimator. To perform a risk factor analysis for the expected incidence rate we used multivariable Poisson regression. In addition, we performed structured guideline interviews with those women who consented in providing detailed information about conception, course of pregnancy, and children's health. Results In total, 2,654 women met the eligibility criteria and 74 pregnancies were reported in 50 women. Pregnancies were reported at a median of 4.7 years (0.7-14.7 years) following alloHCT. Women who conceived pregnancy had a median age of 24 years (range 18 to 34) at alloHCT. Underlying diseases were AML/MDS in 19 patients, bone marrow failure syndromes in 17 patients, Lymphoma/ALL in 8 patients, and CML in 6 patients. Most patients underwent non-myeloablative or RIC (NMA/RIC) conditioning (76%). Total body irradiation (TBI) was part of the conditioning regimen in 12 patients (24%) of whom 4 patients received a cumulative TBI dose ≥8 Gray. Notably, acute GVHD grade II-IV had been reported in 11 women and chronic GvHD in 14 women. Factors associated with a better chance of pregnancy were younger age at alloHCT (p<0.001), TBI with <8 Gray (p<0.020), NMA/RIC conditioning (p= 0.032) and non-malignant transplant indications such as hemoglobinopathy/bone marrow failure syndrome (p=0.006). Fifty-three of 74 pregnancies resulted in live births. Based on competing risk analyses this translated into an annual rate of 0.45% (95% CI: 0.31 to 0.59 %) first-livebirths after alloHCT. This rate is 6 times lower than the corresponding first-birth rate of 3% for german women between 18 and 40 years of age. Detailed informations on conception and outcomes were obtained for 52 pregnancies. Forty out of 52 (77%) pregnancies occurred spontaneously, while assisted reproductive technologies (ART) were used in the remaining women. Techniques that resulted in successful pregnancies were: IVF (n=2), ICSI (n=2), ovarian tissue cryopreservation (n=2), oocyte donation (n=6). Preterm deliveries (29%) and low birth weight (21%) were higher as compared to reference data for the general population. Conclusions Our data strongly indicate that female alloHCT survivors should be educated about the realistic possibility to become pregnant after HCT. Lower age at alloHCT (<35 years), non-myeloablative or reduced-intensity conditioning, cumulative doses of TBI <8 Gray and non-malignant transplant indications increase the chances to preserve fertility. Interdisciplinary fertility counseling before alloHCT is essential to inform about the possibilities of assisted reproductive technologies. Nevertheless, the chances for spontaneous pregnancies should not be underestimated, and patients should be aware of this to avoid unexpected or unwanted pregnancies. Further research is needed to better understand and tailor procedural choices for conditioning regimens with respect to fertility preservation.

Pre-Conditioning Easix Is Associated with Survival after Autologous Hematopoietic Stem Cell Transplant in Mature T-Cell Lymphomas

Introduction: Mature T-cell lymphomas (MTCLs) comprise a group of rare, heterogeneous entities with poor prognosis. Optimal use of autologous (auto) and allogeneic (allo) hematopoietic stem cell transplantation (HSCT) remains an area of active study (Marchi & O'Connor 2019). Prognostic scores help guide clinical decision making and are useful to assess baseline risk in retrospective studies. The Endothelial Activation and Stress Index (EASIX) has shown promise in predicting post-alloHSCT survival (Shouval et al. 2019, Luft et al. 2020). However, we have little data on the association between EASIX and post-HSCT survival specific to the MTCL population. Here, we assess the relationship between EASIX prior to conditioning chemotherapy (EASIX-pre) and post-HSCT survival. Methods: Subjects with MTCL who underwent auto- or alloHSCT were identified from a Montefiore Medical Center database. Data were collected on the following by manual chart review: date of birth, sex, race, ethnicity, MTCL subtype, date of stem cell infusion (D0), stem cell source, conditioning intensity, and survival. To be included in the auto- or alloHSCT cohort, a subject's MTCL subtype had to have auto- or alloHSCT as a recommendation in the NCCN Guidelines Version 2.2022 (Horwitz et al. 2022). Conditioning intensity was determined by the Center for International Blood and Bone Marrow Transplant Research operational definition (Giralt et al. 2009). EASIX prior to conditioning (EASIX-pre) was calculated as (lactate dehydrogenase [U/L] x creatinine [mg/dL])/platelets [109 cells/L] at D-21. To estimate lab values at D-21 we used linear interpolation on data available from D-81 to D-9. Missing numerical variables were imputed using scikit-learn's IterativeImputer with the RandomForestRegressor estimator and default parameters, a method similar to missForest. The Nelson-Aalen estimate of the cumulative hazard and event status at last follow up were included in imputation (White & Royston 2009). Missing categorical variables were placed into an unknown category. Univariable Cox models were made for each variable. Variables whose Cox models had likelihood ratio test p < 0.20 were used for adjustment in multivariable models. Survival was measured from D0 to last follow up. Events included both death and discharge to hospice with unknown date of death. Data were analyzed using Python, lifelines, and sci-kit learn (Davidson-Pilon 2019, Pedregosa et al. 2011). Results: 23 subjects underwent autoHSCT 9/19/2006-3/24/2021. Median follow up among censored subjects was 2.30 years. 9 subjects had peripheral T-cell lymphoma, NOS (PTCL, NOS), 7 had angioimmunoblastic T-cell lymphoma, 4 had ALK-negative anaplastic large cell lymphoma, and 3 had other subtypes. EASIX 10th, 50th, and 90th percentiles were 0.55, 1.51, and 3.68. The univariable model for age at D0 had likelihood ratio test p < 0.20 and was used for adjustment in the multivariable Cox model; other potential adjustment variables did not meet this criterion. EASIX-pre adjusted for age at D0 had HR 1.37 (95% CI 1.06-1.76, p = 0.0155, Fig. 1a). 32 subjects underwent alloHSCT 4/22/2008-4/5/2021. Median follow up among censored subjects was 3.36 years. 16 subjects had adult T-cell leukemia/lymphoma, 6 had hepatosplenic T-cell lymphoma, 4 had mycosis fungoides/Sezary syndrome, 4 had PTCL, NOS, and 2 had other subtypes. EASIX 10th, 50th, and 90th percentiles were 0.55, 1.16, and 2.82. The univariable models for age at D0, race, and conditioning intensity had p < 0.20 and were included for adjustment in a multivariable Cox model. In the multivariable model, EASIX-pre had HR 1.12 (95% CI 1.00-1.26, p = 0.0584, Fig. 1b). Conclusion: In our MTCL cohort, at an alpha level of 0.05, EASIX-pre was independently associated with post-autoHSCT but not post-alloHSCT survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Survival Benefit After Implementation of the New Heart Allocation System amongst Highest Priority Candidates Undergoing Heart Transplant

<h3>Purpose</h3> A key policy change in the new US heart allocation system was splitting the previous highest status (1A) into statuses 1, 2, and 3 to better stratify high acuity patients. We determined if the highest priority candidates under this new system had higher survival benefit from transplantation compared with the highest priority candidates in the prior policy. <h3>Methods</h3> We collected Scientific Registry of Transplant Recipients data on all adult heart transplant candidates listed in seasonally matched pre (2016-2017) and post-policy (2018-2019) cohorts. We fitted a Cox proportional hazards model treating transplant and status as time-dependent covariates to estimate hazard ratios of transplant for each status level. We estimated 1-year survival curves with and without transplantation using these hazard ratios and a non-parametric Nelson-Aalen estimate of the baseline hazard. <h3>Results</h3> There were 3,644 candidates listed in the pre-policy and 3,662 in the post-policy cohort. Post-policy candidates were more likely to be transplanted than those in the pre-policy cohort (66 v 60%, p<0.01) and more likely to be alive (89.7 v 88.0%, p=0.02) at one year. There were no statistically significant differences between cohorts in demographics or hemodynamics. Transplantation for Status 1 recipients improved absolute 1-year survival by 60.7%, a significantly greater survival benefit than the 21.4% improvement for Status 1A recipients in the pre-policy period (HR 0.086 v 0.289, p<0.01, <b>Fig</b>). The survival benefit for Status 2 recipients was similar to Status 1A recipients, improving absolute survival by 21.9% (HR 0.264 v 0.289, p=0.68). <h3>Conclusion</h3> Status 1 recipients under the new policy experience greater survival benefit from transplantation than Status 1A recipients in the previous policy. Since the policy change, more medically urgent patients are stratified into the highest priority status, without significantly compromising post-transplant survival.

Impact of treatment refusal and abandonment on survival outcomes in pediatric osteosarcoma in Southeast Asia: A multicenter study.

Treatment refusal and abandonment (TxRA) are major barriers to improving outcomes among children with sarcomas of the extremities as curative treatment options bearing on amputation or disfiguring surgery, particularly in countries with limited resources. A multi-institutional retrospective study was conducted to determine the predictive factors for TxRA among patients with osteosarcoma associated with survival outcomes across Southeast Asia (SEA). Pediatric patients with osteosarcoma treated between January 1998 and December 2017 in four SEA pediatric oncology centers from three countries were studied. Nelson-Aalen estimates, Kaplan-Meier method, and Cox's proportion hazard model were applied to address the cumulative incidence, survival outcomes, and to identify prognostic factors associated with TxRA. From a total of 208 patients with osteosarcoma enrolled; 18 (8.7%) patients refused and 41 (19.7%) patients abandoned treatment. Income classification of countries, age at diagnosis, tumor size, disease extent, chemotherapy protocols, and types of surgery were associated with TxRA. Tumor size more than 15cm was an independent risk factor associated with TxRA. The 5-year overall and relapse-free survivals were 49.4% and 50.4%, respectively. However, these rates declined further to 37.9% and 35.8%, respectively, when TxRA were considered as events. Tumor size larger than 15cm and metastatic disease were independent risk factors associated with TxRA-sensitive outcomes. The prevalence of TxRA was high in SEA, particularly in lower middle-income countries. Factors associated with TxRA related to tumor burden. Treatment outcomes could be substantially improved by lowering the refusal and abandonment rates.

Empirical evidences on pricing mechanism in Pakistan: A duration analysis

This study evaluates the price setting behavior across main cities of Pakistan by employing the micro data from retail price survey. The most contemporary research technique of Duration Analysis is employed where survivor functions are estimated by most illustrious nonparametric Kaplan-Meier and Nelson-Aalen Estimators. Hazard Functions for various product groups are also estimated by employing parametric Weibull Hazard Model. Results confirm that perishable food items have shortest duration of one week for most of the spells, where government regulation caused prices to change more frequently. It is found that on average small cities faced lower hazard and thus comparably lesser price change, whereas, months of March, April and October witnessed relatively high hazard rates. The study classifies nine commodity groups into two categories. First is high frequency group and second is increasing hazard group. These classifications are believed to assist policy makers in assessing inflation dynamics in Pakistan. The study significantly contributes to the existing literature, firstly, by applying more scrupulous nonparametric and parametric techniques of Survival analysis. To the best of our knowledge, this technique is not yet applied in Pakistan for examining the price behavior. Secondly, as the price setting mechanism in Pakistan is not studied before by employing the high frequency micro price data, therefore, panel data estimation contribute significantly to the existing literature.

Four-year Prostate-specific Antigen Response Rate as a Predictive Measure in Intermediate-risk Prostate Cancer Treated With Ablative Therapies: The SPRAT Analysis

AimsThere is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radiotherapy (SBRT). The aim of the present study was to explore 4-year prostate-specific antigen response rate (4yPSARR) as an early predictive measure. Materials and methodsIndividual patient data from six institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42–54 months) PSA available were analysed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan–Meier method. Biochemical failure-free survival was analysed according to 4yPSARR, with groups dichotomised based on PSA <0.4 ng/ml or ≥0.4 ng/ml and compared using the Log-rank test. A multivariable competing risk analysis was carried out to predict for biochemical failure and the development of metastases. ResultsSix hundred and thirty-seven patients were included, including 424 (67%) with favourable and 213 (33%) with unfavourable intermediate-risk disease. The median follow-up was 6.2 years (interquartile range 4.9–7.9). The cumulative incidence of biochemical failure and metastasis was 7 and 0.6%, respectively; overall survival at 6 years was 97%. The cumulative incidence of biochemical failure at 6 years if 4yPSARR <0.4 ng/ml was 1.7% compared with 27% if 4yPSARR ≥0.4 ng/ml (P < 0.0001). On multivariable competing risk analysis, 4yPSARR was a statistically significant predictor of biochemical failure-free survival (subdistribution hazard ratio 15.3, 95% confidence interval 7.5–31.3, P < 0.001) and metastasis-free survival (subdistribution hazard ratio 31.2, 95% confidence interval 3.1–311.6, P = 0.003). Conclusion4yPSARR is an encouraging early predictor of outcome in patients with intermediate-risk PCa treated with SBRT. Validation in prospective trials is warranted.