Structural nested models (SNMs) and the associated method of G-estimation were first proposed by James Robins over two decades ago as approaches to modeling and estimating the joint effects of a ...sequence of treatments or exposures. The models and estimation methods have since been extended to dealing with a broader series of problems, and have considerable advantages over the other methods developed for estimating such joint effects. Despite these advantages, the application of these methods in applied research has been relatively infrequent; we view this as unfortunate. To remedy this, we provide an overview of the models and estimation methods as developed, primarily by Robins, over the years. We provide insight into their advantages over other methods, and consider some possible reasons for failure of the methods to be more broadly adopted, as well as possible remedies. Finally, we consider several extensions of the standard models and estimation methods.
Four major frameworks have been developed for evaluating surrogate markers in randomized trials: one based on conditional independence of observable variables, another based on direct and indirect ...effects, a third based on a meta-analysis, and a fourth based on principal stratification. The first two of these fit into a paradigm we call the causal-effects (CE) paradigm, in which, for a good surrogate, the effect of treatment on the surrogate, combined with the effect of the surrogate on the clinical outcome, allow prediction of the effect of the treatment on the clinical outcome. The last two approaches fall into the causal-association (CA) paradigm, in which the effect of the treatment on the surrogate is associated with its effect on the clinical outcome. We consider the CE paradigm first, and consider identifying assumptions and some simple estimation procedures; we then consider the CA paradigm. We examine the relationships among these approaches and associated estimators. We perform a small simulation study to illustrate properties of the various estimators under different scenarios, and conclude with a discussion of the applicability of both paradigms.
Increased risk of mortality in patients with CKD has been attributed to inflammation. However, the association between kidney function, albuminuria, and biomarkers of inflammation has not been ...examined in a large cohort of CKD patients.
This study measured the plasma levels of IL-1β, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin in 3939 participants enrolled in the Chronic Renal Insufficiency Cohort study between June 2003 and September 2008. An inflammation score was established based on plasma levels of IL-1β, IL-6, TNF-α, hs-CRP, and fibrinogen. Estimated GFR (eGFR) and serum cystatin C were used as measures of kidney function. Albuminuria was quantitated by urine albumin to creatinine ratio (UACR).
Plasma levels of IL-1β, IL-1RA, IL-6, TNF-α, hs-CRP, and fibrinogen were higher among participants with lower levels of eGFR. Inflammation score was higher among those with lower eGFR and higher UACR. In regression analysis adjusted for multiple covariates, eGFR, cystatin C, and UACR were strongly associated with fibrinogen, serum albumin, IL-6, and TNF-α. Each unit increase in eGFR, cystatin C, and UACR was associated with a -1.2% (95% confidence interval, -1.4, -1), 64.9% (56.8, 73.3) and 0.6% (0.4, 0.8) change in IL-6, respectively (P<0.001).
Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria.
Recent theoretical studies have shown that conditioning on an instrumental variable (IV), a variable that is associated with exposure but not associated with outcome except through exposure, can ...increase both bias and variance of exposure effect estimates. Although these findings have obvious implications in cases of known IVs, their meaning remains unclear in the more common scenario where investigators are uncertain whether a measured covariate meets the criteria for an IV or rather a confounder. The authors present results from two simulation studies designed to provide insight into the problem of conditioning on potential IVs in routine epidemiologic practice. The simulations explored the effects of conditioning on IVs, near-IVs (predictors of exposure that are weakly associated with outcome), and confounders on the bias and variance of a binary exposure effect estimate. The results indicate that effect estimates which are conditional on a perfect IV or near-IV may have larger bias and variance than the unconditional estimate. However, in most scenarios considered, the increases in error due to conditioning were small compared with the total estimation error. In these cases, minimizing unmeasured confounding should be the priority when selecting variables for adjustment, even at the risk of conditioning on IVs.
Cystatin C is an endogenous glomerular filtration marker hence its serum level is affected by the glomerular filtration rate (GFR). To study what other factors might affect it blood level we ...performed a cross-sectional analysis of 3418 patients which included a pooled dataset of clinical trial participants and a clinical population with chronic kidney disease. The serum cystatin C and creatinine levels were related to clinical and biochemical parameters and errors-in-variables models were used to account for errors in GFR measurements. The GFR was measured as the urinary clearance of 125I-iothalamate and 51Cr-EDTA. Cystatin C was determined at a single laboratory while creatinine was standardized to reference methods and these were 2.1+/-1.1 mg/dL and 1.8+/-0.8 mg/L, respectively. After adjustment for GFR, cystatin C was 4.3% lower for every 20 years of age, 9.2% lower for female gender but only 1.9% lower in blacks. Diabetes was associated with 8.5% higher levels of cystatin C and 3.9% lower levels of creatinine. Higher C-reactive protein and white blood cell count and lower serum albumin were associated with higher levels of cystatin C and lower levels of creatinine. Adjustment for age, gender and race had a greater effect on the association of factors with creatinine than cystatin C. Hence, we found that cystatin C is affected by factors other than GFR which should be considered when the GFR is estimated using serum levels of cystatin C.
Inflammation and Progression of CKD: The CRIC Study Amdur, Richard L; Feldman, Harold I; Gupta, Jayanta ...
Clinical journal of the American Society of Nephrology,
09/2016, Letnik:
11, Številka:
9
Journal Article
Recenzirano
Odprti dostop
CKD is a global public health problem with significant mortality and morbidity.
We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, ...high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants.
Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant.
Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.
Abstract Background Observational studies are frequently used to estimate the comparative effectiveness of different colorectal cancer (CRC) screening methods due to the practical limitations and ...time needed to conduct large clinical trials. However, time-varying confounders, e.g. polyp detection in the last screening, can bias statistical results. Recently, generalized methods, or G-methods, have been used for the analysis of observational studies of CRC screening, given their ability to account for such time-varying confounders. Discretization, or the process of converting continuous functions into discrete counterparts, is required for G-methods when the treatment and outcomes are assessed at a continuous scale. Development This paper evaluates the interplay between time-varying confounding and discretization, which can induce bias in assessing screening effectiveness. We investigate this bias in evaluating the effect of different CRC screening methods that differ from each other in typical screening frequency. Application First, using theory, we establish the direction of the bias. Then, we use simulations of hypothetical settings to study the bias magnitude for varying levels of discretization, frequency of screening and length of the study period. We develop a method to assess possible bias due to coarsening in simulated situations. Conclusions The proposed method can inform future studies of screening effectiveness, especially for CRC, by determining the choice of interval lengths where data are discretized to minimize bias due to coarsening while balancing computational costs.
We discuss some causal estimands that are used to study racial discrimination in policing. A central challenge is that not all police–civilian encounters are recorded in administrative datasets and ...available to researchers. One possible solution is to consider the average causal effect of race conditional on the civilian already being detained by the police. We find that such an estimand can be quite different from the more familiar ones in causal inference and needs to be interpreted with caution. We propose using an estimand that is new for this context—the causal risk ratio, which has more transparent interpretation and requires weaker identification assumptions. We demonstrate this through a reanalysis of the NYPD Stop-and-Frisk dataset. Our reanalysis shows that the naive estimator that ignores the posttreatment selection in administrative records may severely underestimate the disparity in police violence between minorities and whites in these and similar data.
Background Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies. Study Design Cross-sectional study of ...1,433 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (ie, the GFR subcohort) to derive an internal GFR estimating equation using a split-sample approach. Setting & Participants Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black. Index Test CRIC GFR estimating equation. Reference Test or Outcome Urinary125 I-iothalamate clearance testing (measured GFR mGFR). Other Measurements Laboratory measures, including serum creatinine and cystatin C, and anthropometrics. Results In the validation data set, the model that included serum creatinine level, serum cystatin C level, age, sex, and race was the most parsimonious and similarly predictive of mGFR compared with a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, root mean square errors for the separate models were 0.207 versus 0.202, respectively. Performance of the CRIC GFR estimating equation was most accurate for the subgroups of younger participants, men, nonblacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m2 , those with higher 24-hour urine creatinine excretion, those with lower high-sensitivity C-reactive protein levels, and those with higher mGFRs. Limitations Urinary clearance of125 I-iothalamate is an imperfect measure of true GFR; cystatin C level is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors. Conclusions The CRIC GFR estimating equation predicts mGFR accurately in the CRIC cohort using serum creatinine and cystatin C levels, age, sex, and race. Its performance was best in younger and healthier participants.
Anemia is a common and early complication of nondialysis chronic kidney disease (CKD). One contributing factor is iron deficiency, which may be particularly problematic during erythropoietin ...replacement therapy. The aim of this study was to examine the prevalence of iron deficiency in nondialysis CKD.
The National Health and Nutritional Examination Survey (NHANES) data for NHANES III (1988 to 1994) and subsequent NHANES 2-yr datasets, 1999 to 2000, 2001 to 2002, and 2003 to 2004 were analyzed for individuals >18 yr old.
It was found that low levels of iron tests either serum ferritin < 100 ng/ml or transferrin saturation (TSAT) < 20% were present in most patients with reduced creatinine clearance (CrCl). The percentage of low iron tests was higher among women than men, present in 57.8 to 58.8% of men and 69.9 to 72.8% of women (P < 0.001). With declining levels of CrCl, in women, TSAT levels decreased, whereas, surprisingly, serum ferritin tended to progressively increase. The percentage of anemic subjects increased progressively with declining quartiles of TSAT but was unrelated to serum ferritin quartiles.
It was found that low levels of iron tests, following National Kidney Foundation/Kidney Disease Outcomes Quality Initiative guidelines (either serum ferritin < 100 ng/ml or TSAT < 20%) were present in most patients with reduced CrCl.
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