Semiparametric Estimators in Competing Risks Regression

Clinical trials and cohort studies that collect survival data frequently involve patients who may fail from one of multiple causes (failure types). These causes are called competing risks. The cumulative incidence function (CIF), or subdistribution, is a commonly reported quantity that describes the crude failure type-specific probability of the study population. The proportional subdistribution hazards model has been widely applied to study the effects of covariates on the CIF. In practice however, the time of failure may be recorded but the cause may be unknown or missing. To avoid bias, we developed two semiparametric estimators of covariate effects: the inverse probability weighted (IPW) estimator and the augmented inverse probability weighted (AIPW) estimator. We showed that these estimators are consistent and asymptotically normal. Their finite sample size properties and robustness were demonstrated through simulations. In many situations, investigators are interested in the marginal survival distribution of latent failure times, rather than the CIF. Because of the identifiability problem in competing risks, we derived an estimator of covariate effects in the Cox proportional hazards model by incorporating the random signs censoring (RSC) principle, which assumes that the main event failure time is independent of the indicator that the main event precedes the competing event. Unlike identifying assumptions that are typically imposed in practice, RSC is verifiable via stochastic ordering in the observed data. We further relaxed the RSC assumption by positing that independence is achieved conditional on some covariates. We showed that the resulting estimator is not only easy to implement but also has desirable asymptotic properties. We evaluated the estimator's finite sample size performance through simulations. Medical datasets were used to illustrate the proposed methods. Public Health Significance: Biomedical and public health studies with time-to-event endpoint are abundant and often influence regulatory decisions. Trustworthiness of the research results not only relies on the design quality, but also on the soundness of the analytical approach used. The methodologies we propose account for two potential sources of bias in the conduct of such studies -- competing risks and missing data

Advancing cognitive engineering methods to support user interface design for electronic health records

Background Despite many decades of research on the effective development of clinical systems in medicine, the adoption of health information technology to improve patient care continues to be slow, especially in ambulatory settings. This applies to dentistry as well, a primary care discipline with approximately 137,000 practitioners in the United States. A critical reason for slow adoption is the poor usability of clinical systems, which makes it difficult for providers to navigate through the information and obtain an integrated view of patient data. Objective In this study, we documented the cognitive processes and information management strategies used by dentists during a typical patient examination. The results will inform the design of a novel electronic dental record interface. Methods We conducted a cognitive task analysis (CTA) study to observe ten general dentists (five general dentists and five general dental faculty members, each with more than two years of clinical experience) examining three simulated patient cases using a think-aloud protocol. Results Dentists first reviewed the patient’s demographics, chief complaint, medical history and dental history to determine the general status of the patient. Subsequently, they proceeded to examine the patient’s intraoral status using radiographs, intraoral images, hard tissue and periodontal tissue information. The results also identified dentists’ patterns of navigation through patient’s information and additional information needs during a typical clinician-patient encounter. Conclusion This study reinforced the significance of applying cognitive engineering methods to inform the design of a clinical system. Second, applying CTA to a scenario closely simulating an actual patient encounter helped with capturing participants’ knowledge states and decision-making when diagnosing and treating a patient. The resultant knowledge of dentists’ patterns of information retrieval and review will significantly contribute to designing flexible and task-appropriate information presentation in electronic dental records

Large variations in the prices of urologic procedures at academic medical centers 1 year after implementation of the Price Transparency Final Rule

IMPORTANCE: Patients with urologic diseases often experience financial toxicity, defined as high levels of financial burden and concern, after receiving care. The Price Transparency Final Rule, which requires hospitals to disclose both the commercial and cash prices for at least 300 services, was implemented to facilitate price shopping, decrease price dispersion, and lower health care costs. OBJECTIVE: To evaluate compliance with the Price Transparency Final Rule and to quantify variations in the price of urologic procedures among academic hospitals and by insurance class. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study that determined the prices of 5 common urologic procedures among academic medical centers and by insurance class. Prices were obtained from the Turquoise Health Database on March 24, 2022. Academic hospitals were identified from the Association of American Medical Colleges website. The 5 most common urologic procedures were cystourethroscopy, prostate biopsy, laparoscopic radical prostatectomy, transurethral resection of the prostate, and ureteroscopy with laser lithotripsy. Using the corresponding Current Procedural Terminology codes, the Turquoise Health Database was queried to identify the cash price, Medicare price, Medicaid price, and commercial insurance price for these procedures. EXPOSURES: The Price Transparency Final Rule, which went into effect January 1, 2021. MAIN OUTCOMES AND MEASURES: Variability in procedure price among academic medical centers and by insurance class (Medicare, Medicaid, commercial, and cash price). RESULTS: Of 153 hospitals, only 20 (13%) listed a commercial price for all 5 procedures. The commercial price was reported most often for cystourethroscopy (86 hospitals [56%]) and least often for laparoscopic radical prostatectomy (45 hospitals [29%]). The cash price was lower than the Medicare, Medicaid, and commercial price at 24 hospitals (16%). Prices varied substantially across hospitals for all 5 procedures. There were significant variations in the prices of cystoscopy (χ23 = 85.9; P = .001), prostate biopsy (χ23 = 64.6; P = .001), prostatectomy (χ23 = 24.4; P = .001), transurethral resection of the prostate (χ23 = 51.3; P = .001), and ureteroscopy with laser lithotripsy (χ23 = 63.0; P = .001) by insurance type. CONCLUSIONS AND RELEVANCE: These findings suggest that, more than 1 year after the implementation of the Price Transparency Final Rule, there are still large variations in the prices of urologic procedures among academic hospitals and by insurance class. Currently, in certain situations, health care costs could be reduced if patients paid out of pocket. The Centers for Medicare & Medicaid Services may improve price transparency by better enforcing penalties for noncompliance, increasing penalties, and ensuring that hospitals report prices in a way that is easy for patients to access and understand

Unintended hysterotomy extension during caesarean delivery: risk factors and maternal morbidity

We conducted an observational retrospective cohort study to evaluate the risk factors and the maternal morbidity associated with unintended extensions of the hysterotomy during caesarean delivery. We evaluated 2707 women who underwent low-transverse caesarean deliveries in 2011 at an academic, tertiary-care hospital. Hysterotomy extensions were identified through operative reports. Of the 2707 caesarean deliveries, 392 (14.5%) had an unintended hysterotomy extension. On the multivariable regression modelling, neonatal weight (OR 1.42; 95%CI 1.17–1.73), the arrest of labour [first-stage arrest (2.42; 1.73–3.38); second-stage arrest (5.54; 3.88–7.90)] and a non-reassuring foetal status (1.65; 1.20–2.25) were significantly associated with hysterotomy extensions. Hysterotomy extensions were significantly associated with an increased morbidity including an estimated blood loss >1200 millilitres (2.06; 1.41–3.02), a decline in postoperative haemoglobin ≥3.7 g/dL (2.07; 1.35–3.17), an evaluation for lower urinary tract injury (5.58; 3.17–9.81), and a longer operative time (8.11; 6.33–9.88). Based on these results, we conclude that unintended hysterotomy extensions significantly increase the maternal morbidity of caesarean deliveries.Impact statement What is already known on this subject? Maternal morbidity associated with caesarean delivery (CD) is significantly greater than that in vaginal delivery. Unintended extensions of the hysterotomy occur in approximately 4–8% of CDs and are more common after a prolonged second stage of labour. The morbidity associated with hysterotomy extensions has been incompletely evaluated. What do the results of this study add? We demonstrate a rate of hysterotomy extension in a general obstetric population of approximately 15%, which is higher than previously reported estimates, and represents a potential doubling of the rate of the unintended hysterotomy extensions in recent years. The most significant risk factor for a hysterotomy extension was a second-stage labour arrest with a fourfold increase in the frequency of extensions. A hysterotomy extension is a significant independent risk factor for an intraoperative haemorrhage, a drop in postoperative haemoglobin, an intraoperative evaluation for lower urinary tract injury, and longer CD operative times. What are the implications of these findings for clinical practice and/or further research? A second-stage arrest is a strong independent risk factor for a hysterotomy extension. Recent re-evaluations of the labour curve that extend the second stage of labour will likely increase the frequency of CDs performed after a prolonged second stage. In these scenarios, obstetricians should be prepared for an unintended hysterotomy extension and for the possibility of a longer procedure with the increased risks of blood loss and the need for evaluation of the lower urinary tract

Age-related endolysosome dysfunction in the rat urothelium.

Lysosomal dysfunction is associated with a number of age-related pathologies that affect all organ systems. While much research has focused on neurodegenerative diseases and aging-induced changes in neurons, much less is known about the impact that aging has on lower urinary tract function. Our studies explored age-dependent changes in the content of endo-lysosomal organelles (i.e., multivesicular bodies, lysosomes, and the product of their fusion, endolysosomes) and age-induced effects on lysosomal degradation in the urothelium, the epithelial tissue that lines the inner surface of the bladder, ureters, and renal pelvis. When examined by transmission electron microscopy, the urothelium from young adult rats (~3 months), mature adult rats (~12 months), and aged rats (~26 months old) demonstrated a progressive age-related accumulation of aberrantly large endolysosomes (up to 7μm in diameter) that contained undigested content, likely indicating impaired degradation. Stereological analysis confirmed that aged endolysosomes occupied approximately 300% more volume than their younger counterparts while no age-related change was observed in multivesicular bodies or lysosomes. Consistent with diminished endolysosomal degradation, we observed that cathepsin B activity was significantly decreased in aged versus young urothelial cell lysates as well as in live cells. Further, the endolysosomal pH of aged urothelium was higher than that of young adult (pH 6.0 vs pH 4.6). Our results indicate that there is a progressive decline in urothelial endolysosomal function during aging. How this contributes to bladder dysfunction in the elderly is discussed

Does a History of Unintended Pregnancy Lessen the Likelihood of Desire for Sterilization Reversal?

BackgroundUnintended pregnancy has been significantly associated with subsequent female sterilization. Whether women who are sterilized after experiencing an unintended pregnancy are less likely to express desire for sterilization reversal is unknown.MethodsThis study used national, cross-sectional data collected by the 2006-2010 National Survey of Family Growth. The study sample included women ages 15-44 who were surgically sterile from a tubal sterilization at the time of interview. Multivariable logistic regression was used to examine the relationship between a history of unintended pregnancy and desire for sterilization reversal while controlling for potential confounders.ResultsIn this nationally representative sample of 1,418 women who were sterile from a tubal sterilization, 78% had a history of at least one unintended pregnancy and 28% expressed a desire to have their sterilization reversed. In unadjusted analysis, having a prior unintended pregnancy was associated with higher odds of expressing desire for sterilization reversal (odds ratio [OR]: 1.80; 95% confidence interval [CI]: 1.15-2.79). In adjusted analysis controlling for sociodemographic factors, unintended pregnancy was no longer significantly associated with desire for reversal (OR: 1.46; 95% CI: 0.91-2.34).ConclusionAmong women who had undergone tubal sterilization, a prior history of unintended pregnancy did not decrease desire for sterilization reversal

Second primary malignancies in patients with haematological cancers treated with lenalidomide: a systematic review and meta-analysis

Background Lenalidomide has been standard therapy for multiple myeloma and other haematological malignancies for more than a decade. Previous meta-analyses identified an association between lenalidomide and second primary malignancies (SPM) in patients with multiple myeloma. However, newer randomised controlled trials using lenalidomide for other indications have not reported an increased incidence of SPM. The aim of this study was to investigate the risk of developing SPM with lenalidomide use in all disease settings. Methods We did a systematic review of randomised controlled trials that reported SPM in patients treated with lenalidomide. PubMed, Embase, CENTRAL, Europe PubMed Central, and ClinicalTrials.gov were searched from Jan 1, 2004, to March 18, 2022. Randomised controlled trials with at least one lenalidomide group and one non-lenalidomide group were selected, regardless of the disease setting. Studies with a median follow-up of less than 12 months were excluded. Summary data were extracted by two reviewers (KS and KL) independently and verified by a third reviewer (JF). We then conducted a meta-analysis to assess the risk ratio (RR) of SPM with lenalidomide use across various disease subtypes using a random-effects model. We chose random effects for the primary analysis because of anticipated heterogeneity between different diseases, but we used fixed effects for stratified meta-analysis of multiple myeloma studies. Risk of bias was assessed with the PROTECT tool. The study was registered with PROSPERO, CRD42021257508. Findings Our search yielded 9078 studies, and 38 trials that included 14 058 patients were eligible for meta-analysis after screening, 18 of which were in multiple myeloma. The RR across all malignancies was 1·16 (95% CI 0·96–1·39). However, there was heterogeneity across indications (p=0·020). The RR when lenalidomide was used for multiple myeloma was 1·42 (1·09–1·84). There was no increase in SPM in lymphoma or chronic lymphocytic leukaemia (0·90 [0·76–1·08]) and myelodysplastic syndrome (0·96 [0·23–3·97]) trials. In the setting of multiple myeloma, lenalidomide increased both solid and haematological SPM, both in the no-transplantation and post-transplantation settings. From the 38 trials, 21 (55%) had low risk of bias, 12 (32%) had unclear risk of bias, and five (13%) had high risk of bias. Interpretation Based on the current data, lenalidomide-induced SPM seem to occur exclusively in patients with multiple myeloma. Thus, lenalidomide can be used for other indications without the major concern of a therapy-related neoplasm. In the multiple myeloma setting, lenalidomide is an effective drug, but patients should be monitored both for haematological and solid tumour SPM. This monitoring includes patients that have not received autologous haematopoietic stem-cell transplantation. Further investigations are needed to improve understanding on why lenalidomide only promotes SPM in patients with multiple myeloma