Robust Sandwich Variance Estimator Research Articles

Trends and determinants of clustering for non-communicable disease risk factors in women of reproductive age in Nepal.

Understanding the clustering of two or more risk factors of non-communicable disease, such as smoking, overweight/obesity, and hypertension, among women of reproductive age could facilitate the design and implementation of strategies for prevention and control measures. This study examined the factors associated with smoking, overweight/obesity, and hypertension among Nepalese women of reproductive age (15-49 years). This study used the Nepal Demographic and Health Surveys (NDHS) 2016 (6,079 women for smoking and overweight/obesity, 6076 for hypertension) and 2022 (6,957 women for overweight/obesity and smoking status and 3,749 women for hypertension) for comparison of trends of NCD risk factors among women aged 15-49 years. Additionally, for each participant, risk factors score (range of 0 to 3) was created by summing individual risk factors. We assessed the determinants of risk factor clustering using multivariable Poisson regression models with robust sandwich variance estimator to calculate adjusted prevalence ratios using NDHS 2022. The national prevalence of overweight/obesity increased from 22.2% in 2016 to 29.2% in 2022 among women of reproductive age. In 2022, the prevalence for smoking, overweight/obesity, and hypertension were 3.8%, 29.2%, and 9.6%, respectively. More than one in four women (28.7%) had one NCD risk factor, while 6.5% had two such risk factors. Higher aged women (40-49 years) were more likely to have multiple NCD risk factors than those aged 15-29 years (APR: 3.19; 95% CI: 2.68-3.80). Those in the richest wealth quintile (APR: 1.52; 95% CI: 1.24-1.85), as well as married (APR: 3.02; 95% CI: 2.43-3.76) and widowed/divorced (APR: 2.85; 95% CI: 2.14-3.80) were more likely to have multiple NCD risk factors. Women from Koshi province (APR: 1.74; 95% CI: 1.41-2.15) had more NCD risk factors than those from the Sudurpaschim province. Working women also had a higher prevalence of NCD risk factors compared to non-working women (APR: 1.23; 95% CI: 1.06-1.43). Additionally, Hill Janajatis (APR: 1.44; 95% CI: 1.21-1.72) and Dalits (APR: 1.42; 95% CI: 1.15-1.75) women were more likely to have NCD risk factors compared to women of Brahmin hill origin. Clustering of two or more NCD risk factors was higher among women aged ≥30 years, those who are currently married or widowed/divorced/separated, working women, and individuals from the wealthiest socioeconomic groups. A higher burden of risk factors underscores the importance of targeted public health interventions, particularly among women from advantaged socio-economic groups, those of affluent regions, and in the workplace.

The Association between Residential Segregation and Access to Kidney Transplantation: Evidence from a Multistate Cohort Study.

Individuals currently living in neighborhoods historically influenced by racial segregation have reduced access to healthcare. Whether this is true for individuals with end-stage kidney disease (ESKD) seeking transplant is unknown. We identified Black or White adults (n = 42,401; 18-80 years) with ESKD initiating kidney replacement therapy (KRT) in three US States (Georgia, North Carolina, South Carolina) between January 2015 and December 2019, with follow-up through 2020, from the United States Renal Data System (USRDS). Residential segregation was defined using the racial Index of Concentration at the Extremes and classified into tertiles (predominantly Black, mixed, or predominantly White neighborhoods). Primary outcomes were referral within 12-months of KRT initiation (among patients initiating KRT) and evaluation within six-months of referral (among all referred patients), determined via linkage of USRDS to the Early-Steps to Transplant Access Registry. Secondary outcomes included waitlisting (among evaluated patients), and living or deceased donor transplant (among waitlisted patients). The association between residential segregation and each outcome was assessed using multivariable Cox models with robust sandwich variance estimators. In models adjusted for clinical factors, individuals living in predominantly Black or mixed (vs. predominantly White) neighborhoods were 8% (adjusted hazard ratio (aHR) 0.92 [0.88 - 0.96]) and 5% (aHR: 0.95 [0.91 - 0.99]) less likely to be referred for a kidney transplant, 18% (aHR: 0.82 [0.76 - 0.90]) and 9% (aHR: 0.91 [0.84 - 0.98]) less likely to be waitlisted among those who started evaluation, and 54% (aHR: 0.46 [0.36 - 0.58]) and 24% (aHR: 0.76 [0.63 - 0.93]) less likely to receive a living donor kidney transplant among those who were waitlisted, respectively. For other transplant steps, associations were non-significant. Individuals with ESKD living in historically and currently marginalized communities in the Southeast US have reduced access to important steps along the transplant care continuum.

Frailty and long-term survival among patients in Australian intensive care units with metastatic cancer (FRAIL-CANCER study): a retrospective registry-based cohort study

Recent advances in cancer therapeutics have improved outcomes, resulting in increasing candidacy of patients with metastatic cancer being admitted to intensive care units (ICUs). A large proportion of patients also have frailty, predisposing them to poor outcomes, yet the literature reporting on this is scarce. We aimed to assess the impact of frailty on survival in patients with metastatic cancer admitted to the ICU. In this retrospective registry-based cohort study, we used data from the Australia and New Zealand Intensive Care Society Adult Patient (age ≥16 years) database to identify patients with advanced (solid and haematological cancer) and a documented Clinical Frailty scale (CFS) admitted to 166 Australian ICUs. Patients without metastatic cancer were excluded. We analysed the effect of frailty (CFS 5-8) on long-term survival, and how this effect changed in specific subgroups (cancer subtypes, age [<65 years or ≥65 years], and those who survived hospitalisation). Because estimates tend to cluster within centres and vary between them, we used Cox proportional hazards regression models with robust sandwich variance estimators to assess the effect of frailty on survival time up to 4 years after ICU admission between groups. Between Jan 1, 2018, and March 31, 2022, 30 026 patients were eligible, and after exclusions 21 174 patients were included in the analysis; of these, 6806 (32·1%) had frailty, and 11 662 (55·1%) were male, 9489 (44·8%) were female, and 23 (0·1%) were intersex or self-reported indeterminate sex. The overall survival was lower for patients with frailty at 4 years compared with patients without frailty (29·5% vs 10·9%; p<0·0001). Frailty was associated with shorter 4-year survival times (adjusted hazard ratio 1·52 [95% CI 1·43-1·60]), and this effect was seen across all cancer subtypes. Frailty was associated with shorter survival times in patients younger than 65 years (1·66 [1·51-1·83]) and aged 65 years or older (1·40 [1·38-1·56]), but its effects were larger in patients younger than 65 years (pinteraction<0·0001). Frailty was also associated with shorter survival times in patients who survived hospitalisation (1·49 [1·40-1·59]). In patients with metastatic cancer admitted to the ICU, frailty was associated with poorer long-term survival. Patients with frailty might benefit from a goal-concordant time-limited trial in the ICU and will need suitable post-intensive care supportive management. None.

Bariatric Surgery and Suicide Risk in Patients With Obesity.

In a large multisite cohort of Veterans who underwent Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy, we compared the 5-year suicidal ideation and attempt rates with matched nonsurgical controls. Bariatric surgery has significant health benefits but has also been associated with adverse mental health outcomes. Five-year rates of suicidal ideation and suicide attempts of Veterans who underwent Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy from the fiscal year 2000-2016 to matched nonsurgical controls using sequential stratification using cumulative incidence functions (ideation cohort: n=38,199; attempt cohort: n=38,661 after excluding patients with past-year outcome events). Adjusted differences in suicidal ideation and suicide attempts were estimated using a Cox regression with a robust sandwich variance estimator. In the matched cohorts for suicidal ideation analyses, the mean age was 53.47 years and the majority were males (78.7%) and White (77.7%). Over 40% were treated for depression (41.8%), had a nonrecent depression diagnosis (40.9%), and 4.1% had past suicidal ideation or suicide attempts >1 year before index. Characteristics of the suicide attempt cohort were similar. Regression results found that risk of suicidal ideation was significantly higher for surgical patients (adjusted hazard ratio=1.21, 95% CI: 1.03-1.41), as was risk of suicide attempt (adjusted hazard ratio=1.62, 95% CI: 1.22-2.15). Bariatric surgery appears to be associated with a greater risk of suicidal ideation and attempts than nonsurgical treatment of patients with severe obesity, suggesting that patients need careful monitoring for suicidal ideation and additional psychological support after bariatric surgery.

Racial disparities in overall survival after the introduction of cyclin-dependent kinase 4/6 inhibitors for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have improved HR + /HER2- metastatic breast cancer (MBC) outcomes. However, it is still unclear whether the response to CDK4/6i is similar for all races. Therefore, we aimed to assess overall survival (OS) trends stratified by race in patients with HR + /HER2- MBC after the approval of CDK4/6i, as part of the standard of care, in 2015. We performed a population-based study using the SEER database. Patients with HR + /HER2- MBC were divided into two time-based cohorts: 1) pre-CDK4/6i era (diagnosed in 2011-2013) and 2) post-CDK4/6i era (diagnosed in 2015-2017). We used propensity score matching and identified 2,684 patients in each cohort that matched in several characteristics. Kaplan-Meier methods were used to estimate 2-year OS. Association between cohort and OS was evaluated using marginal Cox proportional hazards models with robust sandwich variance estimator. We conducted competing risk analysis to estimate the risk of breast cancer death in both cohorts. The 2-year OS rate was 65% for the post-CDK4/6i era and 62% for the pre-CDK4/6i era (stratified log-rank p = 0.025). The 2-year OS for non-Hispanic White (NHW) patients improved in the post-CDK4/6i era compared to the pre-CDK4/6i era (67% vs. 63%, p = 0.033). However, OS did not improve for non-Hispanic Black (NHB) (54% vs. 54%, p = 0.876) or Hispanic (67% vs. 65%, p = 0.617) groups. The risk of breast cancer death decreased in the post-CDK4/6i era as compared to the pre-CDK4/6i era (2-year risk of breast cancer death: 33% vs. 30%, p = 0.015); however, this effect was observed only in NHW (sHR 0.84, p = 0.005) women, but not in NHB (sHR 0.94, p = 0.630) or Hispanic (sHR 0.91, p = 0.550) women. Our study confirms that outcomes for HR + /HER2- MBC have improved after CDK4/6i were introduced in 2015. However, this effect is primarily driven by the improved OS in NHW patients, without significant improvement in OS in NHB or Hispanics.

Finite‐sample adjustments in variance estimators for clustered competing risks regression

The marginal Fine-Gray proportional subdistribution hazards model is a popular approach to directly study the association between covariates and the cumulative incidence function with clustered competing risks data, which often arise in multicenter randomized trials or multilevel observational studies. To account for the within-cluster correlations between failure times, the uncertainty of the regression parameters estimators is quantified by the robust sandwich variance estimator, which may have unsatisfactory performance with a limited number of clusters. To overcome this limitation, we propose four bias-corrected variance estimators to reduce the negative bias of the usual sandwich variance estimator, extending the bias-correction techniques from generalized estimating equations with noncensored exponential family outcomes to clustered competing risks outcomes. We further compare their finite-sample operating characteristics through simulations and two real data examples. In particular, we found the Mancl and DeRouen (MD) type sandwich variance estimator generally has the smallest bias. Furthermore, with a small number of clusters, the Wald -confidence interval with the MD sandwich variance estimator carries close to nominal coverage for the cluster-level effect parameter. The -confidence intervals based on the sandwich variance estimator with any one of the three types of multiplicative bias correction or the -confidence interval with the Morel, Bokossa and Neerchal (MBN) type sandwich variance estimator have close to nominal coverage for the individual-level effect parameter. Finally, we develop a user-friendly R package crrcbcv implementing the proposed sandwich variance estimators to assist practical applications.

Methods for population adjustment with limited access to individual patient data: A review and simulation study.

Population-adjusted indirect comparisons estimate treatment effects when access to individual patient data is limited and there are cross-trial differences in effect modifiers. Popular methods include matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC). There is limited formal evaluation of these methods and whether they can be used to accurately compare treatments. Thus, we undertake a comprehensive simulation study to compare standard unadjusted indirect comparisons, MAIC and STC across 162 scenarios. This simulation study assumes that the trials are investigating survival outcomes and measure continuous covariates, with the log hazard ratio as the measure of effect. MAIC yields unbiased treatment effect estimates under no failures of assumptions. The typical usage of STC produces bias because it targets a conditional treatment effect where the target estimand should be a marginal treatment effect. The incompatibility of estimates in the indirect comparison leads to bias as the measure of effect is non-collapsible. Standard indirect comparisons are systematically biased, particularly under stronger covariate imbalance and interaction effects. Standard errors and coverage rates are often valid in MAIC but the robust sandwich variance estimator underestimates variability where effective sample sizes are small. Interval estimates for the standard indirect comparison are too narrow and STC suffers from bias-induced undercoverage. MAIC provides the most accurate estimates and, with lower degrees of covariate overlap, its bias reduction outweighs the loss in precision under no failures of assumptions. An important future objective is the development of an alternative formulation to STC that targets a marginal treatment effect.

The Effect of Age on Increasing Susceptibility to Retinal Nerve Fiber Layer Loss in Glaucoma.

PurposeTo determine whether aging modifies the effect of intraocular pressure (IOP) on progressive glaucomatous retinal nerve fiber layer (RNFL) thinning over time.MethodsThis was a retrospective cohort study involving patients with glaucoma or suspected of having glaucoma who were followed over time from the Duke Glaucoma Registry. Rates of RNFL loss from spectral-domain optical coherence tomography (SD-OCT) were used to assess disease progression. Generalized estimating equations with robust sandwich variance estimators were used to investigate the effects of the interaction of age at baseline and mean IOP on rates of RNFL loss over time. Models were adjusted for gender, race, diagnosis, central corneal thickness, follow-up time, and baseline disease severity.ResultsThe study included 85,475 IOP measurements and 60,026 SD-OCT tests of 14,739 eyes of 7814 patients. Eyes had a mean follow-up time of 3.5 ± 1.9 years. The average rate of change in RNFL thickness was –0.70 µm/year (95% confidence interval, –0.72 to –0.67). There was a significant interaction between age and mean IOP and the rate of RNFL loss (P = 0.001), with older eyes having significantly faster rates of RNFL loss than younger ones for the same level of IOP. The effect of IOP on rates of change was greater in the inferior and superior regions of the optic disc.ConclusionsAge is a significant modifier of the relationship between IOP and glaucomatous loss in RNFL thickness over time. Older patients may be more susceptible to glaucomatous progression than younger patients at the same level of IOP.

Variance estimation in inverse probability weighted Cox models.

Inverse probability weighted Cox models can be used to estimate marginal hazard ratios under different point treatments in observational studies. To obtain variance estimates, the robust sandwich variance estimator is often recommended to account for the induced correlation among weighted observations. However, this estimator does not incorporate the uncertainty in estimating the weights and tends to overestimate the variance, leading to inefficient inference. Here we propose a new variance estimator that combines the estimation procedures for the hazard ratio and weights using stacked estimating equations, with additional adjustments for the sum of terms that are not independently and identically distributed in a Cox partial likelihood score equation. We prove analytically that the robust sandwich variance estimator is conservative and establish the asymptotic equivalence between the proposed variance estimator and one obtained through linearization by Hajage etal. in 2018. In addition, we extend our proposed variance estimator to accommodate clustered data. We compare the finite sample performance of the proposed method with alternative methods through simulation studies. We illustrate these different variance methods in both independent and clustered data settings, using a bariatric surgery dataset and a multiple readmission dataset, respectively. To facilitate implementation of the proposed method, we have developed an package ipwCoxCSV.

Statin therapy in acute cardioembolic stroke with no guidance-based indication.

It is uncertain whether patients with cardioembolic stroke and without a guidance-based indication for statin therapy should be administered a statin for prevention of subsequent vascular events. This study was performed to determine whether the statin therapy is beneficial in preventing major vascular events in this population. Using a prospective multicenter stroke registry database, we identified patients with acute cardioembolic stroke who were hospitalized between 2008 and 2015. Patients who had other established indications for statin therapy according to current guidelines were excluded. Major vascular event was defined as a composite of stroke recurrence, myocardial infarction, and vascular death. We performed frailty model analysis with the robust sandwich variance estimator using the stabilized inverse probability of treatment weighting method to estimate hazard ratios of statin therapy on outcomes. Of 6,124 patients with cardioembolic stroke, 2,888 (male 44.6%, mean age 75.3 years, 95% confidence interval [CI] 74.8-75.8) were eligible, and 1,863 (64.5%) were on statin therapy during hospitalization. After a median follow-up of 359 days, cumulative incidences of major vascular events were 9.3% in the statin users and 20.5% in the nonusers (p < 0.001 by log-rank test). The adjusted hazard ratios of statin therapy were 0.39 (95% CI 0.31-0.48) for major vascular events, 0.81 (95% CI 0.57-1.16) for stroke recurrence, 0.28 (95% CI 0.21-0.36) for vascular death, and 0.53 (95% CI 0.45-0.61) for all-cause death. Starting statin during the acute stage of ischemic stroke may reduce the risk of major vascular events, vascular death, and all-cause death in patients with cardioembolic stroke with no guidance-based indication for statin.

Using Cox regression to develop linear rank tests with zero-inflated clustered data.

Zero-inflated data arise in many fields of study. When comparing zero-inflated data between two groups with independent subjects, a two degree-of-freedom test has been developed, which is the sum of a 1 degree-of-freedom Pearson chi-square test for the 2×2 table of group vs dichotomized outcome (0,> 0) and a 1 degree-of-freedom Wilcoxon rank-sum test for the values of the outcome > 0. Here, we extend this 2 degree-of-freedom test to clustered data settings. We first propose using an estimating equations score statistic from a time-varying weighted Cox regression model under naive independence, with a robust sandwich variance estimator to account for clustering. Since our proposed test statistics can be put in the framework of a Cox model, to gain efficiency over naive independence, we apply a generalized estimating equations (GEE) Cox model with a non-independence 'working correlation' between observations in a cluster. The proposed methods are applied to a General Social Survey study of days with mental health problems in a month, in which 52.3% of subjects report they have no days with problems, a zero-inflated outcome. A simulation study is used to compare our proposed test statistics to previously proposed zero-inflated test statistics.

Robustness of ANCOVA in randomized trials with unequal randomization.

Randomized trials with continuous outcomes are often analyzed using analysis of covariance (ANCOVA), with adjustment for prognostic baseline covariates. The ANCOVA estimator of the treatment effect is consistent under arbitrary model misspecification. In an article recently published in the journal, Wang et al proved the model-based variance estimator for the treatment effect is also consistent under outcome model misspecification, assuming the probability of randomization to each treatment is 1/2. In this reader reaction, we derive explicit expressions which show that when randomization is unequal, the model-based variance estimator can be biased upwards or downwards. In contrast, robust sandwich variance estimators can provide asymptotically valid inferences under arbitrary misspecification, even when randomization probabilities are notequal.

The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response.

Dysfunction in a wide array of systems—including the immune, monoaminergic, and glutamatergic systems—is implicated in the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway. This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD (23F, ages 18–65) received a single ketamine infusion (0.5mg/kg) over 40 minutes. KYN pathway analytes—including plasma concentrations of indoleamine-2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)—were assessed at baseline (pre-infusion), 230 minutes, Day 1, and Day 3 post-ketamine. General linear models with restricted maximum likelihood estimation and robust sandwich variance estimators were implemented. A repeated effect of time was used to model the covariance of the residuals with an unstructured matrix. After controlling for age, sex, and body-mass index (BMI), post-ketamine IDO levels were significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA levels at Days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/KYN was observed at Day 1. In addition, baseline levels of pro-inflammatory cytokines and behavioral measures predicted KYN pathway changes post-ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.

Association Between Electronic Cigarette Use and Smoking Reduction in France

The electronic cigarette (EC) has become popular among smokers who wish to reduce their tobacco use levels or quit smoking, but its effectiveness as a cessation aid is uncertain. To examine the association of regular EC use with the number of cigarettes smoked per day, smoking cessation among current smokers, and smoking relapse among former smokers. The CONSTANCES (Consultants des Centres d'Examens de Santé) cohort study, based in France, began recruiting participants January 6, 2012, and is currently ongoing. Participants were enrolled in CONSTANCES through 2015, and included 5400 smokers (mean [SD] follow-up of 23.4 [9.3] months) and 2025 former smokers (mean [SD] follow-up of 22.1 [8.6] months) at baseline who quit smoking in 2010, the year in which ECs were introduced in France, or afterward. Analyses were performed from February 8, 2017, to October 15, 2018. The association between EC use and the number of cigarettes smoked during follow-up was studied using mixed regression models. The likelihood of smoking cessation was studied using Poisson regression models with robust sandwich variance estimators. The association between EC use and smoking relapse among former smokers was studied using Cox proportional hazards regression models. All statistical analyses were adjusted for sociodemographic characteristics, duration of follow-up, and smoking characteristics. Among the 5400 daily smokers (2906 women and 2494 men; mean [SD] age, 44.9 [12.4] years), regular EC use was associated with a significantly higher decrease in the number of cigarettes smoked per day compared with daily smokers who did not use ECs (-4.4 [95% CI, -4.8 to -3.9] vs -2.7 [95% CI, -3.1 to -2.4]), as well as a higher adjusted relative risk of smoking cessation (1.67; 95% CI, 1.51-1.84]). At the same time, among the 2025 former smokers (1004 women and 1021 men; mean [SD] age, 43.6 [12.1] years), EC use was associated with an increase in the rate of smoking relapse among former smokers (adjusted hazard ratio, 1.70; 95% CI, 1.25-2.30). This study's findings suggest that, among adult smokers, EC use appears to be associated with a decrease in smoking level and an increase in smoking cessation attempts but also with an increase in the level of smoking relapse in the general population after approximately 2 years of follow-up.

Exposure to polybrominated biphenyl and stochastic epigenetic mutations: application of a novel epigenetic approach to environmental exposure in the Michigan polybrominated biphenyl registry

ABSTRACTEndocrine-disrupting compounds are associated with altered epigenetic regulation and adverse health outcomes, although inconsistent results suggest that people have varied responses to the same exposure. Interpersonal variation in response to environmental exposures is not identified using standard, population-based methods. However, methods that capture an individual’s response, such as analyzing stochastic epigenetic mutations (SEMs), may capture currently missed effects of environmental exposure. To test whether polybrominated biphenyl (PBB) was associated with SEMs, DNA methylation was measured using Illumina’s MethylationEPIC array in PBB-exposed individuals, and SEMs were identified. Association was tested using a linear regression with robust sandwich variance estimators, controlling for age, sex, lipids, and cell types. The number of SEMs was variable (range: 119–18,309), and positively associated with age (p = 1.23e-17), but not with sex (p = 0.97). PBBs and SEMs were only positively associated in people who were older when they were exposed (p = 0.02 vs. p = 0.91). Many subjects had SEMs enriched in biological pathways, particularly in pathways involved with xenobiotic metabolism and endocrine function. Higher number of SEMs was also associated with higher age acceleration (intrinsic: p = 1.70e-3; extrinsic: p = 3.59e-11), indicating that SEMs may be associated with age-related health problems. Finding an association between environmental contaminants and higher SEMs may provide insight into individual differences in response to environmental contaminants, as well as into the biological mechanism behind SEM formation. Furthermore, these results suggest that people may be particularly vulnerable to epigenetic dysregulation from environmental exposures as they age.

PF790 RELATIONSHIP BETWEEN LIVER IRON CONCENTRATION MEASURED BY MRI T2∗ AND SERUM FERRITIN IN HEMOGLOBIN H DISEASE

Background:Patients with non‐transfusion dependent thalassemia (NTDT) are at risk of developing liver iron overload. T2∗‐weighted magnetic resonance imaging (MRI T2∗) is an accurate and reproducible method to determine liver iron concentration (LIC) but it is not always readily available especially in resources limited setting. Serum ferritin (SF) level remains important in the quantification of body iron. Past studies demonstrated (1) a positive correlation between LIC and SF in β‐thalassemia intermedia (TI) and transfusion dependent thalassemia (TDT), and (2) lower SF values in TI patients than in TDT patients with comparable LICs because of preferential iron accumulation in the liver in TI.Aims:The relationship between LIC measured by MRI T2∗ and SF in hemoglobin H (HbH) disease, the most common type of NTDT in Southern China, was determined in this study.Methods:Data was obtained from 82 patients with HbH disease (male 34%, mean age 51 ± 15 years) identified in a cross‐sectional single‐center study performed during Jan 2017 to Jun 2018 to evaluate the complication profile of Southern Chinese adults with NTDT. Data collection included review of medical charts, blood samples tested for steady‐state SF, and MRI T2∗ (SIEMENS 1.5T Aera) to determine LIC. SF and LIC data from 27 TDT patients (male 52%, mean age 32 ± 8 years) managed in the center during the same period were collected for comparison. Nonparametric analysis of covariance (ANCOVA) was used to evaluate for any difference in the LIC‐SF relationship in patients with HbH disease and TDT. The LIC‐SF relationship was subsequently studied by regression analysis. Transformation of variables was adopted to handle nonlinearity of residuals. Robust regression with robust sandwich variance estimator was used to address the problem of outliers, influential observations and heteroscedasticity.Results:Among patients with HbH disease, 63 (77%) and 19 (23%) were of deletional vs. non‐deletional type respectively, 45 (55%) received blood transfusion before, 10 (12%) had history of iron chelation therapy, 8 (10%) were splenectomized, 3 (4%) and 2 (2%) were hepatitis B and C virus carriers respectively. All TDT patients received blood transfusions every 3–4 weeks and iron chelation. Median SF was 394 (range 19–2,159) μg/L and median LIC was 3.14 (range 0.23–14.24) mg Fe/g dry weight (dw) in HbH disease patients. Median SF was 1,325 (range 79–5,409) μg/L and median LIC was 3.94 (range 1.12–9.27) mg Fe/g dw in TDT patients. ANCOVA showed that the relationship between LIC and SF was different in HbH disease and TDT (p &lt; 0.001) and thus regression analysis was performed separately in the two groups of patients. The models best predicted LIC when SF was raised to the power of 0.5 and 0.3 in HbH disease and TDT respectively. LIC was positively correlated with SF0.5 in HbH disease (p &lt; 0.001) and SF0.3 in TDT (p &lt; 0.001). The estimated regression equation for HbH disease was LIC = 0.21 × SF0.5 – 0.81 (R2 = 0.52; 95% CI for the slope: 0.17–0.25), and for TDT was LIC = 0.97 × SF0.3 – 3.81 (R2 = 0.57; 95% CI for the slope: 0.73–1.20) (Figure 1).Summary/Conclusion:The study demonstrated a positive correlation between LIC and SF. Patients with HbH disease had lower SF values than in TDT patients when their LICs were comparable. SF had moderate predictive ability of LIC in both HbH disease and TDT, suggesting that it is an acceptable marker to estimate liver iron deposition. However, result has to be interpreted cautiously because the relationship between LIC and SF alters with the type of thalassemia syndrome and SF could also be affected by other factors.image

Chronic hepatitis C virus infection and subsequent HIV viral load among women with HIV initiating antiretroviral therapy.

One in four persons living with HIV is coinfected with hepatitis C virus (HCV). Biological and behavioral mechanisms may increase HIV viral load among coinfected persons. Therefore, we estimated the longitudinal effect of chronic HCV on HIV suppression after ART initiation among women with HIV (WWH). HIV RNA was measured every 6 months among 441 WWH in the Women's Interagency HIV Study who initiated ART from 2000 to 2015. Log-binomial regression models were used to compare the proportion of study visits with detectable HIV RNA between women with and without chronic HCV. Robust sandwich variance estimators accounted for within-person correlation induced by repeated HIV RNA measurements during follow-up. We controlled for confounding and selection bias (because of loss to follow-up and death) using inverse probability-of-exposure-and-censoring weights. One hundred and fourteen women (25%) had chronic HCV before ART initiation. Overall, the proportion of visits with detectable HIV RNA was similar among women with and without chronic HCV [relative risk (RR) 1.19 (95% CI 0.72, 1.95)]. Six months after ART initiation, the proportion of visits with detectable HIV RNA among women with chronic HCV was 1.88 (95% CI 1.41-2.51) times that among women without HCV, at 2 years, the ratio was 1.60 (95% CI 1.17-2.19), and by 6 years there was no difference (1.03; 95% CI 0.60-1.79). Chronic HCV may negatively impact early HIV viral response to ART. These findings reaffirm the need to test persons with HIV for HCV infection, and increase engagement in HIV care and access to HCV treatment among persons with HIV/HCV coinfection.

Testing for gene-environment interaction under exposure misspecification.

Complex interplay between genetic and environmental factors characterizes the etiology of many diseases. Modeling gene-environment (GxE) interactions is often challenged by the unknown functional form of the environment term in the true data-generating mechanism. We study the impact of misspecification of the environmental exposure effect on inference for the GxE interaction term in linear and logistic regression models. We first examine the asymptotic bias of the GxE interaction regression coefficient, allowing for confounders as well as arbitrary misspecification of the exposure and confounder effects. For linear regression, we show that under gene-environment independence and some confounder-dependent conditions, when the environment effect is misspecified, the regression coefficient of the GxE interaction can be unbiased. However, inference on the GxE interaction is still often incorrect. In logistic regression, we show that the regression coefficient is generally biased if the genetic factor is associated with the outcome directly or indirectly. Further, we show that the standard robust sandwich variance estimator for the GxE interaction does not perform well in practical GxE studies, and we provide an alternative testing procedure that has better finite sample properties.

The Association of Ursodeoxycholic Acid Use With Colorectal Cancer Risk: A Nationwide Cohort Study.

Data from preclinical studies suggest that ursodeoxycholic acid (UDCA) has a chemopreventive effect on colorectal cancer (CRC) development, but no large observational study has examined this possibility.The aim of this study was to investigate the association of UDCA use with CRC risk in a nationwide population-based cohort.This nationwide population-based cohort study used data from the Taiwan National Health Insurance Research Database for the period from 2000 through 2010. This study included data from 7119 Taiwanese adults who received ≥28 cumulative defined daily doses (cDDDs) of UDCA and 14,238 patients who did not receive UDCA (<28 cDDDs). UDCA nonusers were matched 1:2 for age, sex, enrollment date, and presence of chronic liver disease, viral hepatitis, cholelithiasis, and alcoholic liver disease. The 2 cohorts were followed until December 31, 2010 or occurrence of CRC. Cox proportional hazards regression with robust Sandwich variance estimator, which can cooperate with matching design, was used to examine the association between UDCA use and CRC risk.During 109,312 person-years of follow-up (median, 5 years), 121 patients had newly diagnosed CRC: 28 UDCA users (76.7 per 100,000 person-years) and 93 nonusers (127.7 per 100,000 person-years) (log-rank test, P = 0.0169). After multivariate adjustment for age, UDCA use was associated with a reduced risk of CRC (hazard ratio, 0.60; 95% confidence interval [CI], 0.39–0.92). The adjusted hazard ratios were 0.55 (95% CI, 0.35–0.89), 0.89 (95% CI, 0.36–2.20), and 0.63 (95% CI, 0.16–2.53) for patients with 28 to 180, 181 to 365, and >365 cDDDs, respectively, relative to nonusers.UDCA use was associated with reduced risk of CRC in a cohort mainly comprising patients with chronic liver diseases. However, further studies are needed to determine the optimal dosage of UDCA.

Genetic Variation in the Human SORBS1 Gene is Associated With Blood Pressure Regulation and Age at Onset of Hypertension: A SAPPHIRe Cohort Study.

Essential hypertension is a complex disease involving multiple genetic and environmental factors. A human gene containing a sorbin homology domain and 3 SH3 domains in the C-terminal region, termed SORBS1, plays a significant role in insulin signaling. We previously found a significant association between the T228A polymorphism and insulin resistance, obesity, and type 2 diabetes. It has been hypothesized that a set of genes responsible for insulin resistance may be closely linked with genes susceptible to the development of hypertension. Identification of insulin resistance-related genetic factors may, therefore, enhance our understanding of essential hypertension. This study aimed to examine whether common SORBS1 genetic variations are associated with blood pressure and age at onset of hypertension in an ethnic Chinese cohort.We genotyped 9 common tagged single nucleotide polymorphisms of the SORBS1 gene in 1136 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance family study. Blood pressure was measured upon enrolment. The associations of the SORBS1 single nucleotide polymorphisms with blood pressure and the presence of hypertension were analyzed with a generalized estimating equation model. We used the false-discovery rate measure Q value with a cutoff <0.1 to adjust for multiple comparisons. In the Cox regression analysis for hypertension-free survival, a robust sandwich variance estimator was used to deal with the within-family correlations with age at onset of hypertension. Gender, body mass index, and antihypertension medication were adjustment covariates in the Cox regression analysis.In this study, genetic variants of rs2281939 and rs2274490 were significantly associated with both systolic and diastolic blood pressure. A genetic variant of rs2274490 was also significantly associated with the presence of hypertension. Furthermore, genetic variants of rs2281939 and rs2274490 were associated with age at onset of hypertension after adjustment for gender, body mass index, and antihypertension medication.In conclusion, we provide evidence for an association between common SORBS1 genetic variations and blood pressure, presence of hypertension, and age at onset of hypertension. The biological mechanism of genetic variation associated with blood pressure regulation needs further investigation.