Time Bias Research Articles

Eligibility rate of applicant’s LinkedIn account: a naïve bayes classification and visualization

In the digital era, social media platforms like LinkedIn have become famous for recruitment, and recruiters widely use them to find potential employees. The recruitment process is crucial in organizations, as it involves selecting qualified applicants from a diverse pool. However, the screening process and manual recruitment process entail significant time, high costs, and potential bias. Consequently, it may cause recruiting unqualified applicants and may affect the organizations. Thus, this study aims to classify and generate a list of potential job applicants by analyzing seven attributes of their LinkedIn accounts: title, location, skills, education, language, certification, and years of experience. Data are collected from LinkedIn profiles and then undergo data pre-processing. The naive Bayes (NB) algorithm is implemented as the classification algorithm and sets the classification as “eligible” or “ineligible”. The NB model achieved an accuracy testing of 89.8%, indicating good performance in classifying potential job applicants. At the same time, we measure the similarity cosine score to set the mean of the eligibility. The classification results are visualized for the suitable applicants in descending rank, allowing users to choose the applicants’ classification status efficiently. For the system usability, we managed to get 90% from the recruitment expert.

De-Mystifying the Clone-Censor-Weight Method for Causal Research Using Observational Data: A Primer for Cancer Researchers.

Regulators and oncology healthcare providers are increasingly interested in using observational studies of real-world data (RWD) to complement clinical evidence from randomized controlled trials for informed decision-making. To generate valid evidence, RWD studies must be carefully designed to avoid systematic biases. The clone-censor-weight (CCW) method has been proposed to address immortal time and other time-related biases. The objective of this manuscript is to de-mystify the CCW method for cancer researchers by describing and presenting its core components in an accessible and digestible format, using visualizations and examples from cancer-relevant studies. The CCW method has been applied in diverse settings, including investigations of the effects of surgery within a certain time after cancer diagnosis, the continuation of annual screening mammography, and chemotherapy duration on survival. The method handles complex data wherein the treatment group to which an individual belongs is unknown at the start of follow-up. The three steps of the CCW method involve cloning or duplicating the patient population and assigning one clone to each treatment strategy, artificially censoring the clones when their observed data are inconsistent with the assigned strategy and weighting the cloned and censored population to address selection bias created by the artificial censoring. The CCW method is a powerful tool for designing RWD studies in cancer that are free from time-related biases and successfully, to the extent possible, emulate features of a randomized clinical trial.

Exposure misclassification: an “immortal time” bias in observational studies of training load and injury

Several observational studies of the relationship between training load and injury have found increased risks of injury at low loads. These associations are expected because load is often assessed at the end of the injury follow-up period. As such, athletes who get injured earlier in the follow-up period will have systematically lower loads than athletes who get injured later in the follow-up period. In this commentary, we identify this problem as a type of exposure misclassification occurring from the misalignment of exposure measurement and start of follow-up. This methodological issue has previously been recognized in other areas of epidemiology as “immortal time bias”. We discuss how this bias can be prevented by aligning the measurement of load with the start of follow-up for injury.

Survival Analysis of Conversion Surgery in Borderline Resectable and Locally Advanced Unresectable Pancreatic Ductal Adenocarcinoma Addressing Selection and Immortal Time Bias: A Retrospective Single-Center Study.

The purpose of this study was to provide a detailed evaluation of the oncological advantages of surgery following neoadjuvant chemotherapy (NAC) for patients with borderline resectable (BR) or unresectable (UR) pancreatic ductal adenocarcinoma (PDAC), with a focus on minimizing biases. Recently, NAC has become the standard care for BR or UR locally advanced (UR-LA) PDAC, however, many studies have assessed survival benefits and favorable variables without consideration for biases, particularly immortal time bias. This study included patients diagnosed with BR or UR-LA PDAC at Juntendo University Hospital from 2019 to 2022. To mitigate bias, we applied methods such as propensity score matching (PSM), time-dependent covariate Cox proportional hazard regression analysis (TDC), landmark analysis, and multivariable Cox proportional hazards regression model. The study analyzed 124 patients, dividing them into a surgery group (n = 57) and a chemotherapy-only group (n = 67). After PSM, there were 21 matched pairs. Survival analysis using TDC analysis showed that the surgery group had significantly better overall survival compared with the chemotherapy-only group in both the entire cohort and the matched pairs. Cox regression analysis of the entire cohort also revealed a similar superiority of surgery, while the landmark analysis showed varying results depending on the landmark setting. After careful adjustment for selection and immortal time biases, surgery following NAC appears to significantly extend survival in patients with BR or UR PDAC.

Effect of immortal time bias on the association between immune-related adverse events and oncological outcomes following immune checkpoint inhibitors therapy for head and neck squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) are pharmacological agents indicated for recurrent and metastatic head and neck squamous cell carcinoma (HNCSCC). Immune-related adverse events (irAEs) have been reported as predictors of therapeutic response to ICIs. However, previous studies have not adequately addressed the immortal time bias. Therefore, we aimed to investigate the association between the onset of irAEs and oncological outcomes, accounting for immortal time bias. We conducted a retrospective study involving 130 patients with HNSCC who were treated with ICIs. The objective response, progression-free survival (PFS), and overall survival (OS) were assessed using logistic regression analysis, the Kaplan-Meier method, and the Cox proportional hazard (PH) model. The immortal time bias was considered using a landmark analysis and an extended Cox (EC) model. The odds ratios for response and disease control were smaller in the landmark than in the naïve analyses. In the landmark analysis, the 1-year PFS rates were 47.6% and 27.2% for irAE+ and irAE- patients, respectively (p = 0.049), and the 1-year OS rates were 85.7% and 66.5%, respectively (p = 0.006). Regarding PFS, the adjusted HRs for irAEs were 0.49 (95% confidence interval (CI) 0.28-0.85) in the PH analysis and 0.75 (95% CI 0.40-1.40) in the EC analysis. As for OS, the adjusted HRs for irAEs were 0.36 (95% CI 0.19-0.66) in the PH analysis and 0.51 (95% CI 0.27-0.95) in the EC analysis. IrAEs were an independent prognostic factor for OS but not PFS. Without considering the immortal time bias, the association between irAEs and oncologic outcomes in patients with HNSCC treated with ICIs was overestimated. Therefore, the balance between the benefits and risks of ICI therapy must be carefully weighed in clinical settings.

Physical, but not laboratory, treatment-related adverse events are associated with favorable outcomes of enfortumab vedotin for advanced urothelial carcinoma: A landmark analysis.

While the occurrence of immune-related adverse events has been recognized as a prognostic marker in patients receiving immune checkpoint inhibitors, the prognostic significance of treatment-related adverse events (trAEs) in patients undergoing antibody-drug conjugates such as enfortumab vedotin (EV) is controversial. We reviewed 106 patients with advanced urothelial carcinoma who were treated with EV therapy at 10 institutions between 2021 and 2023. Associations of clinical parameters with overall survival and progression-free survival were assessed using the Cox proportional hazards model. For the assessment of trAEs, landmark analysis was conducted to minimize immortal time bias. Of 106 patients, 55 (51.9%) experienced disease progression and 44 (41.5%) died during the follow-up period. Any grade and grade ≥3 trAEs occurred in 94 (88.7%) and 44 (41.5%) patients, respectively. Common trAEs included skin disorders (74.5%), gastrointestinal disorders (62.3%), fatigue (50.0%), peripheral neuropathy (36.8%), and hematological disorders (37.7%). One patient died of interstitial pneumonia (grade 5). According to landmark analysis using 88 patients who survived for 2 months or more, trAEs were significantly associated with longer survival. Furthermore, when trAEs were classified into "physical trAEs" such as skin disorders and "laboratory trAEs" such as hematological disorders, the former were associated with longer survival while the latter were associated with shorter survival. Physical, but not laboratory, trAEs are associated with favorable outcomes of EV therapy for advanced urothelial carcinoma. Both managing trAEs and utilizing them as prognostic markers are key points in the use of antibody-drug conjugates such as EV.

Association Between Antibiotic and Outcomes of Chemoimmunotherapy for Extensive-Stage Small Cell Lung Cancer: A Multicenter Retrospective Study of 132 Patients.

To evaluate the impact of antibiotic (ATB) exposure on the outcome of chemoimmunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). In this multicenter retrospective study, 132 patients with ES-SCLC who received chemoimmunotherapy were included from three hospitals in China. Patients receiving ATB within 30 days prior to initiating ICI therapy (p-ATB) and those receiving concurrent ICI therapy until cessation (c-ATB)were compared to those who did not (n-ATB). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and immune-related adverse events (irAEs) were assessed. To avoid immortal time bias, c-ATB was analyzed as a time-dependent covariate in the Cox proportional hazards model. Among the 132 patients, 25 were included in the p-ATB group and 26 in the c-ATB group, while 81 patients were categorized in the n-ATB group. Multivariate analysis revealed no significant differences in PFS (aHR = 1.028, 95% CI: 0.666-1.589, p = 0.900) and OS (aHR = 0.957, 95% CI: 0.549-1.668, p = 0.877) between the p-ATB and n-ATB groups. Similarly, p-ATB had no significant impact on ORR (p = 0.510) or irAEs (p = 0.516). The use of c-ATB had no significant effect on either PFS (aHR: 1.165, 95% CI: 0.907-1.497; p = 0.232) or OS (aHR: 1.221, 95% CI: 0.918-1.624; p = 0.171) by multivariate analysis. p-ATB has no significant impact on PFS, OS, ORR, or the incidence of irAEs in ES-SCLC patients receiving chemoimmunotherapy. Similarly, c-ATB does not seem to affect PFS or OS.

Evaluating the performance of open-source and proprietary processing of actigraphy sleep estimation in children with suspected sleep disorders: A comparison with polysomnography.

Evaluate the performance of actigraphy-based open-source and proprietary sleep algorithms compared to polysomnography in children with suspected sleep disorders. In a sleep clinic, 110 children (5-12 years, 54% female, 50% Black, 82% with sleep disorders) wore wrist-placed ActiGraph GT9X during overnight polysomnography. Actigraphy data were scored as sleep or wake using open-source GGIR and proprietary ActiLife software. Discrepancy and epoch-by-epoch analyses were conducted to assess agreement between algorithms and polysomnography, along with equivalence testing. The open-source vanHees2015 algorithm showed good accuracy (79.5% ± 12.0%), sensitivity (81.1% ± 13.5%), and specificity (66.0% ± 23.8%) for sleep detection but was outperformed by the proprietary ActiLife algorithms. The magnitude and trend of bias for total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset were similar between algorithms. Total sleep time and sleep efficiency were statistically equivalent for the Cole-Kripke (Actilife) and vanHees2015 algorithms compared to the Sadeh (Actilife) algorithm. The Cole-Kripke (ActiLife) demonstrated higher sensitivity (90.5%) to detect sleep but lower specificity (61.2%) than Cole-Kripke (GGIR) (sensitivity: 62.7%, specificity: 79.9%). Sadeh and Cole-Kripke estimated sleep outcomes were not statistically equivalent between implementations in ActiLife and GGIR. The open-source vanHees2015 algorithm performed well but slightly worse than the proprietary ActiLife algorithms in children. The open-source nature vanHees2015 makes it ideal for clinical pediatric use. Implementation of the Sadeh and Cole-Kripke algorithms in the proprietary ActiLife and open-source GGIR software yield different sleep estimates, so comparisons between studies using these different implementations should be avoided.

Impact of arteriovenous fistula formation on trajectory of kidney function decline: a target trial emulation

Abstract Background Prior nonrandomised studies have suggested nephroprotective effects of arteriovenous fistula (AVF) formation, but these are plausibly susceptible to immortal time and selection biases. Methods We studied patients attending nephrology clinics in the West of Scotland during 2010-2022 with an eGFR ≤15mL/min/1.73m2 and no prior AVF. Using target trial emulation and a sequential trial design, we simulated a hypothetical trial that would randomise patients to either undergo AVF formation immediately or not to undergo AVF formation. The primary outcome was the difference in eGFR slope for the first six months of follow-up, estimated using a mixed-effects model. The secondary outcomes were 5-year absolute risks of dialysis and death, estimated using the Aalen-Johansen and Kaplan-Meier estimators respectively. Results 1,364 unique patients (mean age 51.1, 55.7% male) contributed 3,125 person-trials, with 561 in the AVF and 2,564 in the no AVF group. Mean eGFR was 12.6mL/min/1.73m2 and the median number of eGFR measurements per person-trial was 7 (IQR 4 – 12). Slope of eGFR decline did not differ significantly between the AVF and no AVF groups (between group difference -0.67mL/min/1.73m2/year, 95%CI -1.43, 0.10). The 5-year absolute risk of dialysis was 87% (95%CI 84, 91) in the AVF group and 75% (95%CI 73, 77) in the no AVF group and the 5-year survival probability was 77% (95%CI 70, 83) in the AVF group and 67% (95%CI 64, 69) in the no AVF group. Conclusions In this study of patients with advanced CKD, there was no evidence of a nephroprotective effect of AVF formation.

NCMP-26. PATIENTS WITH ANTI-HU/ANNA1 PARANEOPLASTIC NEUROLOGICAL DISORDERS DEVELOP PROGRESSIVE DISABILITY BUT HAVE INCREASED SURVIVAL

Abstract ANNA-1/Hu-IgG paraneoplastic neurological disorders (PND) are rare and factors associated with disability and survival outcomes are unknown. We aimed to 1) examine disability and survival in ANNA1/Hu-IgG PND and 2) compare survival to a control group of small cell lung cancer (SCLC) without PND. METHODS This is a retrospective cohort study of ANNA1/Hu-IgG+ with PND and a control cohort of SCLC without PND (n=1513). Cox proportional hazard models examined clinical predictors of disability and survival. Kaplan-Meier curves examined time to mortality and mRS>2. Cox proportional hazard models compared survival between ANNA1/Hu-IgG PND and SCLC without PND, adjusting for age, sex, cancer stage, and brain metastases. RESULTS Forty-five patients with ANNA/Hu1-IgG PND were included (73% female, mean age=63 years [SD=13]). Phenotypes included; neuropathy (16, 36%), ataxia (11, 24%), encephalitis (10, 22%), myasthenic syndromes (3, 7%), myelopathy (2, 4%), enteric neuropathy (2, 4%), myoclonus (1, 2%). Cancers were identified in 78%; SCLC (26, 74%), non-SCLC (4, 11%), other (5, 14%). Immunosuppressive therapy for PND was given in 53%. At 5-year follow-up, 74% had mRS>2. Limbic encephalitis had greater hazard of mRS>2 at last follow-up (HR=7.76, [95% CI=2.20-27.39], p=0.001). At 5-year follow-up, 58% had died. Survival was not influenced by phenotype nor immunosuppressive treatment. Patients with SCLC and ANNA1/Hu-IgG (n=26) were compared to SCLC without PND (n=1513) and had 54% lower hazard of death (adjusted HR =0.46, [95% CI = 0.28–0.76], p=0.003). In ANNA-1/Hu-IgG PND, most patients experienced disability and greater disability was associated with limbic encephalitis, suggesting a potential modifiable factor. However, patients with SCLC and ANNA1/Hu-IgG PND survived longer than patients with SCLC without ANNA1/Hu-IgG PND, suggesting a possible survival advantage due to earlier cancer detection (lead time bias) and/or increased antitumor immunity.

Immortal Time Bias with NSQIP Readmission.

Immortal Time Bias with NSQIP Readmission.

The hazard of using the Poisson model to cope with immortal time bias in the case of time-varying hazard

BackgroundA time-dependent analysis, usually by means of Poisson and Cox regression models, can be applied to prevent immortal time bias. However, the use of the Poisson model requires the assumption that the event rate is constant over time. This study aims to assess the potential consequences of using the Poisson model to cope with immortal time bias on estimating the exposure-outcome relationship in the case of time-varying risks.MethodsA simulation study was carried out. Survival times were assumed to follow a Weibull distribution, and the Weibull parameters were chosen to identify three different scenarios: the hazard of the event is constant, decreases, or increases over time. A dichotomous time-varying exposure in which patients can change at most once from unexposed to exposed was considered. The Poisson model was fitted to estimate the exposure-outcome association.ResultsSmall changes in the outcome risk over time (as denoted by the shape parameter of the Weibull distribution) strongly affected the exposure-outcome association estimate. The estimated effect of exposure was always lower and greater than the true exposure effect when the event risk decreases or increases over time, and this was the case irrespective of the true exposure effect. The bias magnitude was positively associated with the prevalence of and time to exposure.ConclusionsBiased estimates were obtained from the Poisson model to cope with immortal time. In settings with a time-varying outcome risk, the model should adjust for the trend in outcome risk. Otherwise, other models should be considered.

Peptide Receptor Radionuclide Therapy Improves Survival in Patients Who Progress After Resection of Gastroenteropancreatic Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). We investigated a 2-decade experience with PRRT to determine whether PRRT confers a survival advantage to patients who progress after surgery versus other therapies. We identified patients from our clinic who had resection/cytoreduction of GEP-NETs, then disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The Kaplan-Meier method assessed progression-free survival (PFS) and overall survival (OS), calculated from progression after surgery (no-PRRT group) or the start of PRRT. Cox regression with time-dependent covariates controlled for immortal time bias and other confounders. Overall, 237 patients progressed after surgery; 95 received PRRT and 142 did not. No differences existed in sex, T or Nstage, tumor grade/differentiation, primary site, or time to progression; 94% of PRRT patients had metastases at diagnosis versus 77% in the no-PRRT group. Median PFS was longer in the PRRT group versus the no-PRRT group (32.4 vs. 11.0 months, p<0.001), as was median OS (49.8 vs. 38.4 months; p=0.009). In subgroup analysis, the PRRT group had improved PFS in small bowel NETs and pancreatic NETs. Time-dependent covariate analysis revealed a lower risk of death associated with PRRT (hazard ratio 0.61, p=0.028) after adjusting for sex, age, Mstage, tumor grade, and primary site. Surgical resection and cytoreduction is an effective treatment for patients with GEP-NETs, but most patients with metastatic disease develop recurrent disease. Surgery followed by PRRT after progression conferred superior PFS and OS over no PRRT/other therapies, and is an effective strategy for managing patients with GEP-NETs.

Medication Exposure and Mortality in Patients With Schizophrenia

The use of antipsychotics, antidepressants, and benzodiazepines may influence the risk of mortality in people with schizophrenia. However, many observational studies have not accounted for immortal time bias (ITB), which occurs when there is a period during which patients in the exposed group are necessarily alive and misclassified as exposed (the period between start of follow-up and initiation of drug). Ignoring ITB may lead to misinterpretation of the association between these drugs and mortality. To examine whether the cumulative dose of antipsychotics, antidepressants, and benzodiazepines is associated with mortality risk in patients with schizophrenia and discuss the potential impacts of ignoring ITB. This cohort study used administrative data from Québec, Canada, including patients aged 17 to 64 years diagnosed with schizophrenia between January 1, 2002, and December 31, 2012. Data analysis was performed from June 22, 2022, to September 30, 2024. The primary outcome was all-cause mortality, with follow-up from January 1, 2013, to December 31, 2017, or until death. Mortality risk was assessed for low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines. Cox proportional hazards regression models with time-fixed exposure (not controlling for ITB) and time-dependent exposure (controlling for ITB) were performed. The cohort included 32 240 patients (mean [SD] age, 46.1 [11.6] years; 19 776 [61.3%] men), of whom 1941 (6.0%) died during follow-up. No dose-response association was found for antipsychotics with mortality using the time-fixed method. However, high-dose antipsychotic use was associated with increased mortality after correcting for ITB (adjusted hazard ratio [AHR], 1.28; 95% CI, 1.07-1.55; P = .008). Antidepressants showed a reduced mortality risk using the time-fixed method, but only at high doses when correcting for ITB (AHR, 0.86; 95% CI, 0.74-1.00; P = .047). Benzodiazepines were associated with increased mortality risk regardless of the method. The findings of this study do not dispute the known efficacy of antipsychotics in schizophrenia, but they call into question the magnitude of long-term mortality benefits.

A Structural Description of Biases That Generate Immortal Time.

Immortal time may arise in survival analyses when individuals are assigned to treatment strategies based on post-eligibility information or selected based on post-assignment eligibility criteria. Selection based on eligibility criteria applied after treatment assignment results in immortal time when the analysis starts the follow-up at assignment. Misclassification of assignment to treatment strategies based on treatment received after eligibility results in immortal time when the treatment strategies are not distinguishable at the start of follow-up. Target trial emulation prevents the introduction of immortal time by explicitly specifying eligibility and assignment to the treatment strategies, and by synchronizing them at the start of follow-up. We summarize analytic approaches that prevent immortal time when longitudinal data are available to emulate the target trial from the time of treatment assignment. The term "immortal time bias" suggests that the source of the bias is the immortal time, but it is selection or misclassification that generates the immortal time, leading to bias.

Performance of consumer wrist-worn type sleep tracking devices compared to polysomnography: a meta-analysis.

The use of sleep tracking devices is increasing as people become more aware of the importance of sleep and interested in monitoring their patterns. With many devices on the market, we conducted a meta-analysis comparing sleep-scoring data from consumer wrist-worn sleep tracking devices with polysomnography to validate the accuracy of devices. We retrieved studies from the databases of SCOPUS, EMBASE, Cochrane Library, PubMed, Web of Science, and KoreaMed, and OVID Medline up to March 2024. We compared personal data about participants and information on objective sleep parameters. From 24 studies, data of 798 patient using Fitbit, Jawbone, myCadian watch, WHOOP strap, Garmin, Basis B1, Zulu Watch, Huami Arc, E4 wristband, Fatigue Science Readiband, Apple Watch, or Xiaomi Mi Band 5 were analyzed. There were significant differences in total sleep time {mean difference (MD) -16.854, 95% confidence interval (CI) [-26.332; -7.375]}, sleep efficiency (MD -4.691, 95% CI [-7.079; -2.302]), sleep latency (MD 2.574, 95% CI [0.606; 4.542]), and wake after sleep onset (MD 13.255, 95% CI [4.522; 21.988]) between all consumer sleep tracking devices and polysomnography. In subgroup analysis, there was no significant difference of wake after sleep onset between Fitbit and polysomnography. There was also no significant difference sleep latency between other devices and polysomnography. Fitbit measured sleep latency longer than other devices, and other devices measured wake after sleep onset longer. Based on Begg and Egger's test, there was no publication bias in total sleep time and sleep efficiency. Wrist-worn sleep tracking devices, while popular, are not as reliable as polysomnography in measuring key sleep parameters like total sleep time, sleep efficiency, and sleep latency. Physicians and consumers should be aware of their limitations and interpret results carefully, though they can still be useful for tracking general sleep patterns. Further improvements and clinical studies are needed to enhance their accuracy.

A remote monitoring method for gateway electric energy meters based on electric energy, voltage and current conservation decomposition

Abstract A remote monitoring technique for gateway electricity meters is introduced that leverages conservation principles of electric energy, voltage, and current. It aims to tackle issues related to errors in electric energy meters and transformers that are challenging to distinguish, as well as the high costs associated with on-site testing. The ridge regression is used to solve the formulas for bus power and current conservation to obtain gateway metering points’ error and current loops’ error. The voltage loop error is determined through an averaging method, which is then used to calculate the error in electric energy meters. The voltage consistency method is used to synchronize the time bias between gateway electricity meters, ensuring accurate calculations. The analysis results indicate that the proposed method effectively monitors the operating status of gateway electric energy meters and offers greater accuracy compared to benchmarks. This method can timely discover suspected inaccurate electricity meters, aiding in their maintenance and efficient operation.

Long-term outcomes among patients who respond within the first year to nivolumab plus ipilimumab or nivolumab monotherapy: A pooled analysis in 935 patients

PurposeTo investigate the predictive value of RECIST response within 3, 6, or 12 months on long-term survival, and explore differences between nivolumab+ipilimumab and nivolumab monotherapy, we analyzed pooled 5-year data of 935 responder and non-responder patients at various time points after treatment initiation in CheckMate 069, 066, and 067 studies. Patients and methodsTreatment-naive advanced melanoma patients received nivolumab+ipilimumab or nivolumab monotherapy. To decrease immortal time bias, 3-, 6-, or 12-month overall survival (OS) and progression-free survival (PFS) landmark analyses were performed. Association between characteristics and response was evaluated by univariate and multivariate analyses. ResultsResponse rates at any time were 58 % (239/409) for nivolumab+ipilimumab and 44 % (230/526) for nivolumab monotherapy. In 12-month landmark analyses, 5-year OS rates for responders versus non-responders were 82 % versus 40 % with nivolumab+ipilimumab (HR=0.23 [95 % CI, 0.15–0.35]) and 76 % versus 32 % with nivolumab monotherapy (HR=0.22 [95 % CI, 0.16–0.31]). PFS rates were 83 % versus 32 % and 69 % versus 46 %, respectively. Similar strong associations between response at 3 and 6 months and 5-year OS and PFS were also observed with more than 70 % of the responses observed in the first 3 months. Response rates correlated with baseline LDH and PD-L1 status by multivariate analysis but the association between response and long-term survival was maintained in landmark analyses even among patients with high LDH and low PD-L1 expression. ConclusionClinical response evaluated in the first months of therapy is a strong predictor of long-term survival, even in patients with poor prognostic biomarkers.

Hypnotics and Mortality in Idiopathic Pulmonary Fibrosis: Hospital and National Data-based Analysis

Patients with idiopathic pulmonary fibrosis (IPF) may suffer from insomnia and use hypnotics. However, the effect of the use of hypnotics on their clinical course remains unclear. Is the use of hypnotics associated with an increased risk of mortality in patients with IPF? This study included 99 and 123 patients with IPF from the Hamamatsu and Seirei hospital-based cohorts, respectively, and 30,218 patients with IPF from the national claims database of Japan (NDB cohort). To analyze the association of hypnotic use with outcomes avoiding immortal time bias, multivariable Cox models with time-dependent covariates and target trial emulation with a new user design were employed for the hospital- and NDB-based cohorts, respectively. In the cohorts studied, the 3-year cumulative incidence of new use of hypnotics after IPF diagnosis was 13.4%-24.1%. In both the hospital-based cohorts, the continuous use of hypnotics was associated with an increased risk of all-cause mortality and disease progression. In the NDB cohort, the continuous use of hypnotics was also associated with an increased risk of all-cause mortality. Subgroup analysis found associations between the continuous use of hypnotics and increased mortality regardless of sex and comorbidities, excluding certain subpopulations. This study found that continuous use of hypnotics was associated with an increased risk of mortality in patients with IPF. Given the relatively high cumulative incidence of hypnotic use in this population, there is an urgent need to reassess the appropriate use of hypnotics for patients with IPF.

Aortic valve replacement and mortality with left ventricular hypertrophy in setting of normal LVEF

Abstract Background Without symptoms, indications for aortic valve replacement (AVR) in severe aortic stenosis (AS) differ for individuals with normal vs. low/decreasing left ventricular ejection fraction (LVEF). Conceptually, the development of left ventricular hypertrophy (LVH) could also indicate ventricular injury and potential benefit with earlier AVR. However, little is known about the comparative effectiveness of AVR in individuals with LVH. As such, unlike low or dropping LVEF, development of LVH is not in itself an indication for AVR in clinical guidelines. Methods Initially, 1,232,492 echocardiography reports from 12 hospitals were identified from 1 January 2000 to 22 November 2022, and previously validated natural language processing modules were then applied to identify aortic gradients, LVEF, and presence of LVH. These reports were linked to mortality data, key comorbidities with a 2-year lookback covariate window, and date of any AVR. We then isolated echocardiograms demonstrating normal flow severe AS, LVEF ≥ 55% and LVH. Chart reviews were conducted to reduce missing data and outcomes were censored on the date of the chart review (October 4, 2023). To assess the association between AVR and mortality, Cox proportional hazards models considering treatment status (ie, AVR or not) were used with the index echocardiogram as time zero. Covariates used in risk-adjustment were chosen a priori based on conditions and laboratory values used in cardiac surgery mortality risk-adjustment, since those variables could plausibly confound the treatment decision. To address immortal time bias, AVR was considered a time-varying covariate. Multiple additional approaches with propensity scores were performed as sensitivity analyses. Results After application of inclusion and exclusion criteria, 4856 unique patients remained for analysis. Of those, 2043 (42.1%) received AVR with 841/2043 (41.2%) receiving surgical AVR and 1202/2043 (58.8%) receiving transcatheter AVR. Patients who received AVR had lower unadjusted mortality than those who did not receive AVR (33.6% vs. 47.1%, p &amp;lt; 0.001). After adjustment, and accounting for time-dependence of AVR, AVR was associated with reduced mortality (HR 0.81, 95% CI 0.73-0.89, p &amp;lt; 0.0001). The sensitivity analyses were all consistent with the primary analysis. Conclusions AVR was associated with reduced mortality for patients with severe AS, preserved LVEF, and LVH. This association persisted even after accounting for time-dependence, which tends to reduce the observed effectiveness of procedures in observational data. With over a million echocardiograms over more than 20 years, this is the largest known analysis of AVR outcomes in individuals with severe AS and LVH. Our findings suggest LVH may be a high-risk phenotype of individuals with AS, similar to dropping LVEF. As such, these results raise the potential of more proactive AVR clinical guidelines in individuals with LVH, even when LVEF is normal.Survival in AVR Vs No AVR