Analysis of the Cox Model with Longitudinal Covariates with Measurement Errors and Partly Interval Censored Failure Times, with Application to an AIDS Clinical Trial.

Time-dependent covariates are often measured intermittently and with measurement errors. Motivated by the AIDS Clinical Trials Group (ACTG) 175 trial, this paper develops statistical inferences for the Cox model for partly interval censored failure times and longitudinal covariates with measurement errors. The conditional score methods developed for the Cox model with measurement errors and right censored data are no longer applicable to interval censored data. Assuming an additive measurement error model for a longitudinal covariate, we propose a nonparametric maximum likelihood estimation approach by deriving the measurement error induced hazard model that shows the attenuating effect of using the plug-in estimate for the true underlying longitudinal covariate. An EM algorithm is devised to facilitate maximum likelihood estimation that accounts for the partly interval censored failure times. The proposed methods can accommodate different numbers of replicates for different individuals and at different times. Simulation studies show that the proposed methods perform well with satisfactory finite-sample performances and that the naive methods ignoring measurement error or using the plug-in estimate can yield large biases. A hypothesis testing procedure for the measurement error model is proposed. The proposed methods are applied to the ACTG 175 trial to assess the associations of treatment arm and time-dependent CD4 cell count on the composite clinical endpoint of AIDS or death. Supplementary Information: The online version contains supplementary material available at 10.1007/s12561-023-09372-y.

Semiparametric regression analysis of doubly-censored data with applications to incubation period estimation.

The incubation period is a key characteristic of an infectious disease. In the outbreak of a novel infectious disease, accurate evaluation of the incubation period distribution is critical for designing effective prevention and control measures . Estimation of the incubation period distribution based on limited information from retrospective inspection of infected cases is highly challenging due to censoring and truncation. In this paper, we consider a semiparametric regression model for the incubation period and propose a sieve maximum likelihood approach for estimation based on the symptom onset time, travel history, and basic demographics of reported cases. The approach properly accounts for the pandemic growth and selection bias in data collection. We also develop an efficient computation method and establish the asymptotic properties of the proposed estimators. We demonstrate the feasibility and advantages of the proposed methods through extensive simulation studies and provide an application to a dataset on the outbreak of COVID-19.

Longitudinal study of glomerular hyperfiltration in adults with sickle cell anemia: a multicenter pooled analysis.

Glomerular hyperfiltration is common in young sickle cell anemia patients and precedes development of overt kidney disease. In this multicenter pooled cohort, we characterized hyperfiltration and its decline to normal range in adult patients. Glomerular filtration rate (GFR) was estimated using the creatinine-based 2009 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation omitting race adjustment and the 2021 CKD-EPI equation. Using CKD-EPI-2009, 506 patients had baseline estimated GFR (eGFR) ≥90 mL/min per 1.73 m2, median age of 24 (interquartile range [IQR], 19-34) years and 5.17 years of follow-up. The prevalence of hyperfiltration (eGFR ≥140 and ≥130 mL/min per 1.73 m2 for men and women, respectively) was 38.3%. Using CKD-EPI-2009, baseline hyperfiltration was less likely with older age (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.73-0.83; P < .0001), male sex (OR, 0.32; 95% CI, 0.18-0.58; P = .0002), and higher weight (OR, 0.96; 95% CI, 0.94-0.99; P = .001). Using CKD-EPI-2021, hyperfiltration was similarly less likely with older age (OR, 0.75; 95% CI, 0.70-0.81; P < .0001), male sex (OR, 0.24; 95% CI, 0.13-0.44; P < .0001), and higher weight (OR, 0.97; 95% CI, 0.95-0.99; P = .004). In patients with baseline hyperfiltration, eGFR declined to normal values at a median age of 26.2 years. Using CKD-EPI-2009, this decline was associated with male sex (HR, 2.20; 95% CI, 1.26-3.87; P = .006), systolic blood pressure (hazard ratio [HR], 1.02; 95% CI, 1.01-1.04; P = .01), and hydroxyurea use (HR, 1.74; 95% CI, 1.002-3.03; P = .05). Using CKD-EPI-2021, decline of eGFR to normal was only associated with male sex (HR, 3.39; 95% CI, 2.01-5.69; P < .0001). Decline to normal eGFR range from hyperfiltration occurs earlier in males, those on hydroxyurea, and with higher systolic blood pressure.

Longitudinal study of glomerular hyperfiltration and normalization of estimated glomerular filtration in adults with sickle cell disease.

Glomerular hyperfiltration is common in sickle cell disease (SCD) and precedes proteinuria and declining kidney function. We evaluated hyperfiltration in SCD patients and its "normalization." Routine visit data were collected retrospectively from adult SCD patients in a single centre from 2004 to 2013. Baseline was defined as first available serum creatinine and hyperfiltration as estimated glomerular filtration rates (eGFR) >130 ml/min/1·73 m2 for women and >140 ml/min/1·73 m2 for men. Normalization of hyperfiltration was eGFR reduction to 90-130 ml/min/1·73 m2 for women or 90-140 ml/min/1·73 m2 for men. Among 292 patients, median age was 27 years [interquartile range (IQR):20·0-38·0], and 56·8% had baseline hyperfiltration. Baseline hyperfiltration was inversely associated with age [odds ratio (OR):0·86, 95% confidence interval (CI): 0·82-0·90; P < 0·0001], male sex (OR:0·16, 95% CI: 0·07-0·41; P = 0·0001), haemoglobin (OR:0·76, 95% CI 0·61-0·94; P = 0·01), weight (OR:0·96, 95% CI: 0·93-0·99; P = 0·004), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACE-I/ARB) use (OR:0·08, 95% CI: 0·01-0·75; P = 0·03), and positively with hydroxycarbamide use (OR:2·99, 95% CI: 1·18-7·56; P = 0·02). Of 89 hyperfiltration patients without baseline proteinuria, 10 (11·2%) developed new-onset proteinuria [median 1·05 years (IQR:0·63-2·09)]. Normalization of hyperfiltration was less likely with higher baseline eGFR [hazard ratio (HR):0·90, 95% CI: 0·86-0·95; P < 0·0001] and more likely in males (HR:6·35, 95% CI:2·71-14·86, <0·0001). Hyperfiltration is common in adult SCD patients, particularly when younger. Decline to normal values is more likely in males, possibly representing kidney function loss rather than improvement in hyperfiltration.

Semiparametric regression analysis of partly interval-censored failure time data with application to an AIDS clinical trial.

Failure time data subject to various types of censoring commonly arise in epidemiological and biomedical studies. Motivated by an AIDS clinical trial, we consider regression analysis of failure time data that include exact and left-, interval-, and/or right-censored observations, which are often referred to as partly interval-censored failure time data. We study the effects of potentially time-dependent covariates on partly interval-censored failure time via a class of semiparametric transformation models that includes the widely used proportional hazards model and the proportional odds model as special cases. We propose an EM algorithm for the nonparametric maximum likelihood estimation and show that it unifies some existing approaches developed for traditional right-censored data or purely interval-censored data. In particular, the proposed method reduces to the partial likelihood approach in the case of right-censored data under the proportional hazards model. We establish that the resulting estimator is consistent and asymptotically normal. In addition, we investigate the proposed method via simulation studies and apply it to the motivating AIDS clinical trial.

Regression Analysis of Case-cohort Studies in the Presence of Dependent Interval Censoring.

The case-cohort design is widely used as a means of reducing the cost in large cohort studies, especially when the disease rate is low and covariate measurements may be expensive, and has been discussed by many authors. In this paper, we discuss regression analysis of case-cohort studies that produce interval-censored failure time with dependent censoring, a situation for which there does not seem to exist an established approach. For inference, a sieve inverse probability weighting estimation procedure is developed with the use of Bernstein polynomials to approximate the unknown baseline cumulative hazard functions. The proposed estimators are shown to be consistent and the asymptotic normality of the resulting regression parameter estimators are established. A simulation study is conducted to assess the finite sample properties of the proposed approach and indicates that it works well in practical situations. The proposed method is applied to an HIV/AIDS case-cohort study that motivated this investigation.

Semiparametric regression analysis of case-cohort studies with multiple interval-censored disease outcomes.

Interval-censored failure time data commonly arise in epidemiological and biomedical studies where the occurrence of an event or a disease is determined via periodic examinations. Subject to interval-censoring, available information on the failure time can be quite limited. Cost-effective sampling designs are desirable to enhance the study power, especially when the disease rate is low and the covariates are expensive to obtain. In this work, we formulate the case-cohort design with multiple interval-censored disease outcomes and also generalize it to nonrare diseases where only a portion of diseased subjects are sampled. We develop a marginal sieve weighted likelihood approach, which assumes that the failure times marginally follow the proportional hazards model. We consider two types of weights to account for the sampling bias, and adopt a sieve method with Bernstein polynomials to handle the unknown baseline functions. We employ a weighted bootstrap procedure to obtain a variance estimate that is robust to the dependence structure between failure times. The proposed method is examined via simulation studies and illustrated with a dataset on incident diabetes and hypertension from the Atherosclerosis Risk in Communities study.

Rapid decline in estimated glomerular filtration rate in sickle cell anemia: results of a multicenter pooled analysis.

Not available.

Semiparametric inference for a two-stage outcome-dependent sampling design with interval-censored failure time data.

We propose a two-stage outcome-dependent sampling design and inference procedure for studies that concern interval-censored failure time outcomes. This design enhances the study efficiency by allowing the selection probabilities of the second-stage sample, for which the expensive exposure variable is ascertained, to depend on the first-stage observed interval-censored failure time outcomes. In particular, the second-stage sample is enriched by selectively including subjects who are known or observed to experience the failure at an early or late time. We develop a sieve semiparametric maximum pseudo likelihood procedure that makes use of all available data from the proposed two-stage design. The resulting regression parameter estimator is shown to be consistent and asymptotically normal, and a consistent estimator for its asymptotic variance is derived. Simulation results demonstrate that the proposed design and inference procedure performs well in practical situations and is more efficient than the existing designs and methods. An application to a phase 3 HIV vaccine trial is provided.

Rapid decline in estimated glomerular filtration rate is common in adults with sickle cell disease and associated with increased mortality.

We evaluated the prevalence of rapid decline in kidney function, its potential risk factors and influence upon mortality in sickle cell disease (SCD) in a retrospective single-center study. Rapid decline of kidney function was defined as estimated glomerular filtration rate (eGFR) loss of >3·0 ml/min/1·73 m2 per year. A multivariable logistic regression model for rapid eGFR decline was constructed after evaluating individual covariates. We constructed multivariate Cox-regression models for rapid eGFR decline and mortality. Among 331 SCD patients (median age 29 years [interquartile range, IQR: 20, 41]; 187 [56·5%] female) followed for median 4·01 years (IQR: 1·66, 7·19), rapid eGFR decline was noted in 103 (31·1%). History of stroke (odds ratio [OR]: 2·91, 95% confidence interval [CI]: 1·25-6·77) and use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (OR: 3·17, 95% CI: 1·28-7·84) were associated with rapid eGFR decline. The rate of eGFR change over time was associated with mortality (hazard ratio [HR]: 0·99, 95% CI: 0·984-0·995, P = 0·0002). In Cox-regression, rapid eGFR decline associated with mortality (HR: 2·07, 95% CI: 1·039-4·138, P = 0·04) adjusting for age, sex and history of stroke. Rapid eGFR decline is common in SCD and associated with increased mortality. Long-term studies are needed to determine whether attenuating loss of kidney function may decrease mortality in SCD.

Progressive Decline in Estimated GFR in Patients With Sickle Cell Disease: An Observational Cohort Study.

RATIONALE & OBJECTIVE: Progression of chronic kidney disease (CKD) in sickle cell disease (SCD) and its risk factors remain poorly defined. We identified characteristics associated with CKD as well as decline in estimated glomerular filtration rate (eGFR) and presence of proteinuria over time in adults with SCD. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Patients with SCD 18 years or older in a single center from 2004 to 2013. PREDICTORS: Baseline clinical and laboratory measures, comorbid conditions, SCD-related complications, relevant treatments, and severity of genotypes defined as severe (homozygous SCD [HbSS]/sickle-ß0-thalassemia [HbSß0]) or mild (hemoglobin SC disease [HbSC]/sickle-ß+-thalassemia [HbSß+]-thalassemia). OUTCOMES: Presence at baseline of CKD, defined here as eGFR<90mL/min/1.73m2 or proteinuria (≥1+) on urinalysis or current kidney transplant or dialysis therapy; change in eGFR; and presence of proteinuria over time. ANALYTICAL APPROACH: Logistic regression for baseline CKD. Linear mixed-effects model for eGFR decline and generalized linear mixed-effects model for proteinuria during the study period evaluating for interaction with time. Stratified by genotype severity. RESULTS: Among 427 patients, 331 had 2 or more measurements of creatinine. During a median follow-up of 4.01 (interquartile range, 1.66-7.19) years, annual eGFR decline was 2.05mL/min/1.73m2 for severe genotypes (P<0.001) and 1.16mL/min/1.73m2 (P=0.02) for mild genotypes. At baseline, 21.4% of patients with severe genotypes had CKD versus 17.2% of those with mild genotypes. For severe genotypes, angiotensin-converting enzyme-inhibitor/angiotensin receptor blocker use (OR, 6.10; 95% CI, 2.03-18.29; P=0.001) and avascular necrosis (OR, 0.40; 95% CI, 0.16-0.97; P=0.04) were associated with baseline CKD. Among those with mild genotypes, higher hemoglobin level was associated with lower probability of CKD (OR per 1-g/dL greater hemoglobin level, 0.63; 95% CI, 0.43-0.93; P=0.02). Rate of eGFR decline was inversely related to hemoglobin level (ß = 0.46 [SE, 0.23]; P=0.04) within the severe genotype subgroup. No factors were identified to be associated with proteinuria over time. LIMITATIONS: Retrospective observational study, limited direct measures of albuminuria. CONCLUSIONS: Patients with SCD exhibit rapid decline in eGFR over time. Decline in eGFR is associated with markers of disease severity and associated comorbid conditions.

Nephrin as a biomarker of sickle cell glomerulopathy in Malawi.

BACKGROUND: Glomerulopathy is an increasingly identified complication in young patients with sickle cell disease (SCD). Hyperfiltration and albuminuria followed by declining glomerular filtration rates and eventual end-stage renal disease (ESRD) is assumed to be the typical progression of glomerular disease. There are only a few reported biomarkers to identify early-stage renal disease in SCD. PROCEDURES: We detail the renal profile of 101 children with SCD in Malawi and propose a novel urinary biomarker for the identification of early renal disease. RESULTS: Among children with sickle cell anemia, 24.8% had a urine albumin-creatinine ratio of 30 mg/g or above. In univariate analysis, only patients with higher urinary nephrin, a urinary marker of glomerular injury, had significantly greater odds of having albuminuria. In multivariable analysis, nephrin remained significantly associated with albuminuria. A nephrin-creatinine ratio (NCR) cut-point of 622 ng/mg, the 50th percentile, was associated with a 45.8 times greater odds of having albuminuria in children with nephrinuria above this value. Further analysis revealed this urinary NCR cut-point to have 96% sensitivity, 64% specificity, 47% positive predictive value, and 98% negative predictive value for the presence of albuminuria. CONCLUSIONS: These data suggest that a substantial number of children with SCD in Malawi have renal disease and could be at risk for worsening nephropathy and ESRD as they age. Our data suggest that urinary nephrin could be utilized as an early marker of glomerular disease in SCD.

Outcome-dependent sampling with interval-censored failure time data.

Epidemiologic studies and disease prevention trials often seek to relate an exposure variable to a failure time that suffers from interval-censoring. When the failure rate is low and the time intervals are wide, a large cohort is often required so as to yield reliable precision on the exposure-failure-time relationship. However, large cohort studies with simple random sampling could be prohibitive for investigators with a limited budget, especially when the exposure variables are expensive to obtain. Alternative cost-effective sampling designs and inference procedures are therefore desirable. We propose an outcome-dependent sampling (ODS) design with interval-censored failure time data, where we enrich the observed sample by selectively including certain more informative failure subjects. We develop a novel sieve semiparametric maximum empirical likelihood approach for fitting the proportional hazards model to data from the proposed interval-censoring ODS design. This approach employs the empirical likelihood and sieve methods to deal with the infinite-dimensional nuisance parameters, which greatly reduces the dimensionality of the estimation problem and eases the computation difficulty. The consistency and asymptotic normality of the resulting regression parameter estimator are established. The results from our extensive simulation study show that the proposed design and method works well for practical situations and is more efficient than the alternative designs and competing approaches. An example from the Atherosclerosis Risk in Communities (ARIC) study is provided for illustration.

Telephone Follow-Up for Older Adults Discharged to Home from the Emergency Department: A Pragmatic Randomized Controlled Trial.

BACKGROUND/OBJECTIVES: Telephone calls after discharge from the emergency department (ED) are increasingly used to reduce 30-day rates of return or readmission, but their effectiveness is not established. The objective was to determine whether a scripted telephone intervention by registered nurses from a hospital-based call center would decrease 30-day rates of return to the ED or hospital or of death. DESIGN: Randomized, controlled trial from 2013 to 2016. SETTING: Large, academic medical center in the southeast United States. PARTICIPANTS: Individuals aged 65 and older discharged from the ED were enrolled and randomized into intervention and control groups (N = 2,000). INTERVENTION: Intervention included a telephone call from a nurse using a scripted questionnaire to identify obstacles to elements of successful care transitions: medication acquisition, postdischarge instructions, and obtaining physician follow-up. Control subjects received a satisfaction survey only. MEASUREMENTS: Primary outcome was return to the ED, hospitalization, or death within 30 days of discharge from the ED. RESULTS: Rate of return to the ED or hospital or death within 30 days was 15.5% (95% confidence interval (CI) = 13.2-17.8%) in the intervention group and 15.2% (95% CI = 12.9-17.5%) in the control group (P = .86). Death was uncommon (intervention group, 0; control group, 5 (0.51%), 95% CI = 0.06-0.96%); 12.2% of intervention subjects (95% CI = 10.1-14.3%) and 12.5% of control subjects (95% CI = 10.4-14.6%) returned to the ED, and 9% of intervention subjects (95% CI = 7.2-10.8%) and 7.4% of control subjects (95% CI = 5.8-9.0%) were hospitalized within 30 days. CONCLUSION: A scripted telephone call from a trained nurse to an older adult after discharge from the ED did not reduce ED or hospital return rates or death within 30 days. Clinicaltrials.gov identifier: NCT01893931z.