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1.
Int J Epidemiol ; 53(4)2024 Jun 12.
Article in English | MEDLINE | ID: mdl-39002174

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.


Subject(s)
Bias , Colorectal Neoplasms , Early Detection of Cancer , Humans , Colorectal Neoplasms/diagnosis , Early Detection of Cancer/methods , Time Factors , Mass Screening/methods , Observational Studies as Topic/methods , Confounding Factors, Epidemiologic
2.
Ocul Immunol Inflamm ; 29(6): 1064-1071, 2021 Aug 18.
Article in English | MEDLINE | ID: mdl-31821051

ABSTRACT

Introduction: We evaluated visual acuity (VA) over 5 years in a subspecialty noninfectious uveitis population.Methods: Retrospective data from 5,530 noninfectious uveitis patients with anterior, intermediate, posterior or panuveitis were abstracted by expert reviewers. Mean VA was calculated using inverse probability of censoring weighting to account for losses to follow-up.Results: Patients were a median of 41 years old, 65% female, and 73% white. Initial mean VA was worse among panuveitis (20/84) than posterior (20/64), intermediate (20/47), and anterior (20/37) uveitides. On average, mean VA improved by 0.62, 0.51, 0.37, and 0.26 logMAR-equivalent lines over 2 years, respectively (each P < .001), then remained stable, except posterior uveitis mean VA worsened to initial levels.Conclusion: Mean VA of uveitic eyes improved and, typically, improvement was sustained under uveitis subspecialty care. Because VA tends to improve under tertiary care, mean VA change appears a better outcome for clinical studies than time-to-loss of VA.


Subject(s)
Uveitis/physiopathology , Visual Acuity/physiology , Adolescent , Adult , Aged , Female , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Retrospective Studies , Tertiary Healthcare , Time Factors , Uveitis/drug therapy , Young Adult
3.
Am J Ophthalmol ; 208: 68-75, 2019 12.
Article in English | MEDLINE | ID: mdl-31344346

ABSTRACT

PURPOSE: To compare mycophenolate mofetil (MMF) to methotrexate (MTX) as corticosteroid-sparing therapy for ocular inflammatory diseases. DESIGN: Retrospective analysis of cohort study data. METHODS: Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained via medical record review. The study included 352 patients who were taking single-agent immunosuppression with MTX or MMF at 4 tertiary uveitis clinics. Marginal structural models (MSM)-derived statistical weighting created a virtual population with covariates and censoring patterns balanced across alternative treatments. With this methodological approach, the results estimate what would have happened had none of the patients stopped their treatment. Survival analysis with stabilized MSM-derived weights simulated a clinical trial comparing MMF vs MTX for noninfectious inflammatory eye disorders. The primary outcome was complete control of inflammation on prednisone ≤10 mg/day, sustained for ≥30 days. RESULTS: The time to success was shorter (more favorable) for MMF than MTX (hazard ratio = 0.68, 95% confidence interval: 0.46-0.99). Adjusting for covariates, the proportion achieving success was higher at every point in time for MMF than MTX from 2 to 8 months, then converges at 9 months. The onset of corticosteroid-sparing success took more than 3 months for most patients in both groups. Outcomes of treatment (MMF vs MTX) were similar across all anatomic sites of inflammation. The incidence of stopping therapy for toxicity was similar in both groups. CONCLUSIONS: Our results suggest that, on average, MMF may be faster than MTX in achieving corticosteroid-sparing success in ocular inflammatory diseases.


Subject(s)
Immunosuppressive Agents/therapeutic use , Methotrexate/therapeutic use , Mycophenolic Acid/therapeutic use , Scleritis/drug therapy , Uveitis/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Glucocorticoids/therapeutic use , Humans , Infant , Inflammation/drug therapy , Male , Middle Aged , Prednisone/therapeutic use , Retrospective Studies , Scleritis/physiopathology , Uveitis/physiopathology , Visual Acuity/physiology
4.
Clin Trials ; 12(4): 309-16, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25948621

ABSTRACT

BACKGROUND: A surrogate marker is a variable commonly used in clinical trials to guide treatment decisions when the outcome of ultimate interest is not available. A good surrogate marker is one where the treatment effect on the surrogate is a strong predictor of the effect of treatment on the outcome. We review the situation when there is one treatment delivered at baseline, one surrogate measured at one later time point, and one ultimate outcome of interest and discuss new issues arising when variables are time-varying. METHODS: Most of the literature on surrogate markers has only considered simple settings with one treatment, one surrogate, and one outcome of interest at a fixed time point. However, more complicated time-varying settings are common in practice. In this article, we describe the unique challenges in two settings, time-varying treatments and time-varying surrogates, while relating the ideas back to the causal-effects and causal-association paradigms. CONCLUSION: In addition to discussing and extending popular notions of surrogacy to time-varying settings, we give examples illustrating that one can be misled by not taking into account time-varying information about the surrogate or treatment. We hope this article has provided some motivation for future work on estimation and inference in such settings.


Subject(s)
Biomarkers , Outcome Assessment, Health Care , Therapeutics , Clinical Trials as Topic , Humans , Mathematical Concepts , Regression Analysis , Time Factors
5.
PLoS One ; 10(4): e0124772, 2015.
Article in English | MEDLINE | ID: mdl-25909952

ABSTRACT

BACKGROUND: Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function. METHODS: Plasma levels of interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory. RESULTS: LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-α (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005). CONCLUSION: In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.


Subject(s)
Inflammation Mediators/blood , Myocardium/pathology , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/pathology , Adult , Aged , Biomarkers/blood , Cohort Studies , Echocardiography , Female , Humans , Hypertrophy, Left Ventricular/complications , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/physiopathology , Logistic Models , Male , Middle Aged , Prospective Studies , Renal Insufficiency, Chronic/complications , Risk Factors
6.
Stat Probab Lett ; 97: 185-191, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25554715

ABSTRACT

Efficient semiparametric estimation of longitudinal causal effects is often analytically or computationally intractable. We propose a novel restricted estimation approach for increasing efficiency, which can be used with other techniques, is straightforward to implement, and requires no additional modeling assumptions.

7.
Stat Med ; 33(26): 4577-89, 2014 Nov 20.
Article in English | MEDLINE | ID: mdl-25042626

ABSTRACT

Propensity scores are widely used to control for confounding when estimating the effect of a binary treatment in observational studies. They have been generalized to ordinal and continuous treatments in the recent literature. Following the definition of propensity function and its parameterizations (called the propensity parameter in this paper) proposed by Imai and van Dyk, we explore sufficient conditions for selecting propensity parameters to control for confounding for continuous treatments in the context of regression-based adjustment in linear models. Typically, investigators make parametric assumptions about the form of the dose-response function for a continuous treatment. Such assumptions often allow the analyst to use only a subset of the propensity parameters to control confounding. When the treatment is the only predictor in the structural, that is, causal model, it is sufficient to adjust only for the propensity parameters that characterize the expectation of the treatment variable or its functional form. When the structural model includes selected baseline covariates other than the treatment variable, those baseline covariates, in addition to the propensity parameters, must also be adjusted in the model. We demonstrate these points with an example estimating the dose-response relationship for the effect of erythropoietin on hematocrit level in patients with end-stage renal disease.


Subject(s)
Confounding Factors, Epidemiologic , Models, Statistical , Observational Studies as Topic/methods , Propensity Score , Aged , Computer Simulation , Dose-Response Relationship, Drug , Erythropoietin/therapeutic use , Hematocrit , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/therapy , Renal Dialysis
8.
Pediatrics ; 134(1): 37-44, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24935993

ABSTRACT

OBJECTIVES: ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). METHODS: Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. RESULTS: During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20-1.96) for clinical remission and 1.74 (95% CI, 1.33-2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4-11.1) for clinical remission and 5.0 (95% CI, 3.4-10.0) for corticosteroid-free remission. CONCLUSIONS: In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.


Subject(s)
Crohn Disease/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adolescent , Biomedical Research , Controlled Clinical Trials as Topic , Feasibility Studies , Female , Humans , Male , Pediatrics
9.
Nephrol Dial Transplant ; 29(4): 864-72, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24516231

ABSTRACT

BACKGROUND: Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD). METHODS: We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate. RESULTS: The mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m(2) in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. CONCLUSIONS: Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.


Subject(s)
DNA Methylation/genetics , Epigenesis, Genetic , Glomerular Filtration Rate , Renal Insufficiency, Chronic/genetics , Adult , Aged , Disease Progression , Epithelial-Mesenchymal Transition , Female , Humans , Male , Middle Aged , Prognosis , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/physiopathology , Young Adult
10.
Am J Kidney Dis ; 63(2): 236-43, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24182662

ABSTRACT

BACKGROUND: Various indicators of progression of chronic kidney disease (CKD) have been used as outcomes in clinical research studies. The effect of using varying measures on the association of risk factors with CKD progression has not been well characterized. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: The Chronic Renal Insufficiency Cohort (CRIC) Study (N=3,939) enrolled men and women with mild to moderate CKD, 48% of whom had diabetes and 42% were self-reported black race. PREDICTORS: Age, race, sex, diabetes, baseline estimated glomerular filtration rate (eGFR), proteinuria, and other established CKD risk factors. OUTCOMES: Death, end-stage renal disease (ESRD), and eGFR events, including: (1) eGFR halving, (2) eGFR<15mL/min/1.73m(2), (3) eGFR halving and <15mL/min/1.73m(2), (4) eGFR decrease of 20mL/min/1.73m(2), (5) eGFR halving or decrease of 20mL/min/1.73m(2), and (6) eGFR decrease of 25% and change in CKD stage. RESULTS: Mean entry eGFR was 44.9mL/min/1.73m(2). Annual rates of death, ESRD, and eGFR halving were 2.5%, 4.0%, and 6.1%, respectively, during an average follow-up of 5.4 years. Associations between risk factors and ESRD and eGFR events were similar across different definitions. However, these associations were substantially different from those with death. HRs for ESRD, eGFR halving, and death in the highest compared to the lowest proteinuria category were 11.83 (95% CI, 8.40-16.65), 11.19 (95% CI, 8.53-14.68), and 1.47 (95% CI, 1.10-1.96), respectively. LIMITATIONS: Participants may not be representative of the entire CKD population. CONCLUSIONS: Using ESRD or eGFR events, but not death, in the definition of kidney disease outcomes is appropriate in follow-up studies to identify risk factors for CKD progression.


Subject(s)
Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/physiopathology , Adult , Aged , Cohort Studies , Female , Follow-Up Studies , Glomerular Filtration Rate/physiology , Humans , Male , Middle Aged , Prospective Studies , Renal Insufficiency, Chronic/epidemiology , Risk Factors , Treatment Outcome , Young Adult
11.
Stat Med ; 33(20): 3421-33, 2014 Sep 10.
Article in English | MEDLINE | ID: mdl-23255088

ABSTRACT

Tom Ten Have made many contributions to causal inference and biostatistics before his untimely death. This paper reviews Tom's contributions and discusses potential related future research directions. We focus on Tom's contributions to longitudinal/repeated measures categorical data analysis and particularly his contributions to causal inference. Tom's work on causal inference was primarily in the areas of estimating the effect of receiving treatment in randomized trials with nonadherence and mediation analysis. A related area to mediation analysis he was working on at the time of his death was posttreatment effect modification with applications to designing adaptive treatment strategies.


Subject(s)
Biostatistics/methods , Causality , Randomized Controlled Trials as Topic/methods , Humans , Longitudinal Studies , Patient Compliance , Regression Analysis , Research
12.
Biometrics ; 69(3): 572-5, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24073863
13.
J Rheumatol ; 40(8): 1394-403, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23818712

ABSTRACT

OBJECTIVE: To evaluate the outcome of tumor necrosis factor-α inhibition (anti-TNF) for pediatric uveitis. METHODS: We retrospectively assessed children (age ≤ 18 yrs) with noninfectious uveitis receiving anti-TNF at 5 uveitis centers and 1 pediatric rheumatology center. Incident treatment success was defined as minimal or no uveitis activity at ≥ 2 consecutive ophthalmological examinations ≥ 28 days apart while taking no oral and ≤ 2 eyedrops/day of corticosteroids. Eligible children had active uveitis and/or were taking higher corticosteroid doses. RESULTS: Among 56 eligible children followed over 33.73 person-years, 52% had juvenile idiopathic arthritis (JIA) and 75% had anterior uveitis (AU). The Kaplan-Meier estimated proportion achieving treatment success within 12 months was 75% (95% CI 62%-87%). Complete absence of inflammatory signs with discontinuation of all corticosteroids was observed in an estimated 64% by 12 months (95% CI 51%-76%). Diagnoses of JIA or AU were associated with greater likelihood of success, as was the oligoarticular subtype among JIA cases. In a multivariable model, compared to those with JIA-associated AU, those with neither or with JIA or AU alone had a 75%-80% lower rate of achieving quiescence under anti-TNF, independent of the number of immunomodulators previously or concomitantly prescribed. Uveitis reactivated within 12 months of achieving quiescence in 14% of those continuing anti-TNF (95% CI 6%-31%). The incidence of discontinuation for adverse effects was 8%/year (95% CI 1%-43%). CONCLUSION: Treatment with anti-TNF was successful and sustained in a majority of children with noninfectious uveitis, and treatment-limiting toxicity was infrequent. JIA-associated AU may be especially responsive to anti-TNF.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/therapeutic use , Immunoglobulin G/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Uveitis, Anterior/drug therapy , Uveitis/drug therapy , Adalimumab , Adolescent , Arthritis, Juvenile/drug therapy , Arthritis, Juvenile/epidemiology , Child , Child, Preschool , Cohort Studies , Comorbidity , Etanercept , Female , Humans , Infant , Infliximab , Kaplan-Meier Estimate , Male , Retrospective Studies , Time Factors , Treatment Outcome , Uveitis/epidemiology , Uveitis, Anterior/epidemiology
15.
Pharmacoepidemiol Drug Saf ; 22(6): 593-606, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23637097

ABSTRACT

PURPOSE: Erythropoietin (EPO) improves measures of quality of life and reduces transfusions. Clinical trials have reported higher mortality associated with higher hemoglobin targets in varied clinical settings, making difficult the selection of erythropoiesis stimulation strategies in end-stage kidney disease. Observational studies distinguishing an effect of EPO from underlying conditions are challenging, but promise insights relevant to real-world settings. METHODS: Using data from the United States Renal Data System, we performed a retrospective cohort study of hemodialysis patients treated between 2000 and 2004. 409 364 Medicare insured patients receiving hemodialysis therapy as of January 2000 or who began dialysis after January 2000 and survived >6 months were studied. We examined the association of EPO dose in any given month with death over subsequent follow-up. RESULTS: Within each hematocrit group (<30%, 30%­< 33%, 33%­< 36%, 36%­< 39% and >39%), the hazard ratios comparing the 80th percentile to the median EPO dose were 0.88 (95% CI: [0.87­0.90]), 0.94 ([0.93­0.94]), 0.98 ([0.98­0.99]), 1.06 ([1.05­1.06]) and 1.08 ([1.07­1.09]), respectively. Within the highest hematocrit group, the association of a high EPO dose with elevated mortality was attenuated over time. Among patients with malignancy or indications of EPO resistance, the association of higher EPO dose with lower mortality was attenuated when hematocrit was low, while its association with higher mortality was stronger when hematocrit was high. CONCLUSIONS: These analyses demonstrate a complex relationship between EPO dosing and mortality, suggesting a possible beneficial effect among severely anemic hemodialysis patients, but possible harm when administered to individuals with higher hematocrit levels.


Subject(s)
Erythropoietin/therapeutic use , Renal Dialysis , Renal Insufficiency/mortality , Dose-Response Relationship, Drug , Erythropoietin/administration & dosage , Erythropoietin/adverse effects , Female , Hematocrit , Humans , Male , Medical Record Linkage , Mortality/trends , Proportional Hazards Models , Renal Insufficiency/blood , Renal Insufficiency/therapy , United States
16.
Am J Nephrol ; 36(4): 342-7, 2012.
Article in English | MEDLINE | ID: mdl-23107930

ABSTRACT

BACKGROUND: Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease (CKD) population. We examined the discriminative ability of noninvasive measures of atherosclerosis, including carotid intima-media thickness (cIMT), carotid plaque, coronary artery calcification (CAC) and ascending and descending thoracic aorta calcification (TCAC), and Framingham risk score (FRS) to predict self-reported prevalent CVD. METHODS AND RESULTS: Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort (CRIC) study and also had all of the above measures within an 18-month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n = 220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate ≥60, 45-59, 30-44, and <30 ml/min/1.73 m(2) was 21, 41, 28, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (C-statistic 0.70, 95% CI: 0.62-0.78; C-statistic 0.68, 95% CI: 0.60-0.75, and C-statistic 0.64, CI: 0.56-0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self-reported prevalent CVD (C-statistic 0.58). CONCLUSIONS: There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD.


Subject(s)
Calcinosis/mortality , Carotid Intima-Media Thickness/statistics & numerical data , Carotid Stenosis/mortality , Coronary Artery Disease/mortality , Renal Insufficiency, Chronic/mortality , Adult , Aged , Calcinosis/diagnostic imaging , Carotid Stenosis/diagnostic imaging , Coronary Artery Disease/diagnostic imaging , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Morbidity , Prevalence , Risk Assessment/methods , Risk Factors , Tomography, X-Ray Computed , Young Adult
17.
Am J Nephrol ; 36(5): 397-404, 2012.
Article in English | MEDLINE | ID: mdl-23076013

ABSTRACT

BACKGROUND: While higher blood pressure is known to increase proteinuria, whether increased dietary sodium as estimated from 24-hour urinary excretion correlates with increased proteinuria in patients with chronic kidney disease (CKD) is not well studied. METHODS: We measured 24-hour urinary sodium, potassium and protein excretion in 3,680 participants in the Chronic Renal Insufficiency Cohort study, to determine the relationship between urinary sodium and potassium and urinary protein excretion in patients with CKD. We stratified our data based on the presence or absence of diabetes given the absence of any data on this relationship and evidence that diabetics had greater urinary protein excretion at nearly every level of urinary sodium excretion. Multiple linear regressions were used with a stepwise inclusion of covariates such as systolic blood pressure, demographics, hemoglobin A1c and type of antihypertensive medications to evaluate the relationship between urinary electrolyte excretion and proteinuria. RESULTS: Our data demonstrated that urinary sodium (+1 SD above the mean), as a univariate variable, explained 12% of the variation in proteinuria (ß = 0.29, p < 0.0001), with rising urinary sodium excretion associated with increasing proteinuria. The significance of that relationship was only partially attenuated with adjustment for demographic and clinical factors and the addition of 24-hour urinary potassium to the model (ß = 0.13, R(2) = 0.35, p < 0.0001). CONCLUSIONS: An understanding of the relationship between these clinical factors and dietary sodium may allow a more tailored approach for dietary salt restriction in patients with CKD.


Subject(s)
Proteinuria/urine , Sodium/urine , Female , Humans , Male , Middle Aged , Proteinuria/complications , Regression Analysis , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/urine
18.
Clin J Am Soc Nephrol ; 7(12): 1938-46, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23024164

ABSTRACT

BACKGROUND AND OBJECTIVES: 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study measured the plasma levels of IL-1ß, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-α, TGF-ß, 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-1ß, 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). RESULTS: Plasma levels of IL-1ß, 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). CONCLUSIONS: Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria.


Subject(s)
Albuminuria/urine , Cytokines/blood , Inflammation/blood , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/physiopathology , Aged , Albuminuria/complications , Biomarkers/blood , C-Reactive Protein/metabolism , Cohort Studies , Confidence Intervals , Creatinine/urine , Cystatin C/blood , Female , Fibrinogen/metabolism , Glomerular Filtration Rate , Humans , Inflammation/complications , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Multivariate Analysis , Renal Insufficiency, Chronic/complications , Serum Albumin/metabolism , Statistics, Nonparametric , Transforming Growth Factor beta/blood , Tumor Necrosis Factor-alpha/blood
19.
Am J Kidney Dis ; 60(2): 250-61, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22658574

ABSTRACT

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: Urinary (125)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/m(2), 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 of (125)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.


Subject(s)
Glomerular Filtration Rate , Renal Insufficiency, Chronic/physiopathology , Adult , Aged , C-Reactive Protein/analysis , Creatinine/blood , Creatinine/urine , Cross-Sectional Studies , Cystatin C/blood , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Renal Insufficiency, Chronic/diagnosis
20.
Pharmacoepidemiol Drug Saf ; 21(3): 241-5, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22509500

ABSTRACT

We review the concept of time-dependent confounding by using the example in paper "Comparative effectiveness of individual angiotensin receptor blockers on risk of mortality in patients with chronic heart failure" by Desai et al. and illustrate how to adjust for it by using inverse probability of treatment weighting through a simulated example. We discuss a few subtle issues that arise in specification of the model for treatment required to fit marginal structural models (MSMs) and in specification of the structural model for the outcome. We discuss the differences between the effects estimated in MSMs and intention-to-treat effects estimated in randomized trials, followed by an outline of some limitations of MSMs.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Benzimidazoles/therapeutic use , Biphenyl Compounds/therapeutic use , Heart Failure , Losartan/therapeutic use , Tetrazoles/therapeutic use , Valine/analogs & derivatives , Female , Humans , Irbesartan , Male , Valine/therapeutic use , Valsartan
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