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Rationale & Objective: In the PRO2TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO2TECT trials. Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial. Setting & Participants: A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD. Intervention: 1:1 randomization to receive vadadustat or darbepoetin alfa. Outcomes: The primary safety end point was the time to first MACE. Results: At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90 U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of ≥10 g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region, P = 0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups. Limitations: Several analyses are exploratory. Conclusions: In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group. Funding: Akebia Therapeutics, Inc. Trial Registration: ClinicalTrials.gov identifier: NCT02680574.
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Rationale & Objective: Prespecified analyses of the PRO2TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO2TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents. Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial. Setting and Participants: Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD. Intervention: Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa. Outcomes: The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis). Results: In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m2 and who may not have had access to dialysis. Limitations: Different regional treatment patterns of patients with NDD-CKD. Conclusions: The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.
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OBJECTIVE: Leptin (LEP) is an obesity-associated adipokine associated with tumor cell growth. We examined the relevance of genetic variants of LEP and leptin receptor (LEPR) to colorectal cancer (CRC) survival by using data from the Newfoundland Familial Colorectal Cancer Study. METHODS: A total of 532 patients newly diagnosed with CRC between 1997 and 2003 were followed up until April 2010. Data on their demographics and lifestyles were collected via questionnaires. Genotyping of blood samples was performed with the Illumina Human Omni-Quad Bead chip. Multivariable Cox models were used to assess the relationships of 35 tag single-nucleotide polymorphisms (SNPs) in LEP and LEPR with overall survival (OS), disease-free survival (DFS), and CRC-specific survival. RESULTS: At the gene level, LEP was associated with DFS (P = 0.017), and LEPR was associated with both DFS (P = 0.021) and CRC-specific survival (P = 0.013) in patients with CRC. In single-SNP analysis, LEP rs11763517, LEPR rs9436301, and LEPR rs7602 were associated with DFS after adjustment for multiple testing. The LEPR haplotypes G-C-T (rs7534511-rs9436301-rs1887285) and A-A-G (rs7602-rs970467-rs9436748) were associated with prolonged OS among patients with CRC overall (G-C-T: HR, 0.63; 95% CI, 0.43-0.93; A-A-G: HR, 0.59; 95% CI, 0.38-0.91) and those diagnosed with colon cancer (G-C-T: HR, 0.54; 95% CI, 0.34-0.86; A-A-G: HR, 0.49; 95% CI, 0.29-0.83). Similar results were observed for DFS. Moreover, significant interactions were found among LEPR rs7602 (A vs. G), LEPR rs1171278 (T vs. C), red meat intake, and BMI status: the associations between these variants and prolonged DFS were limited to patients with below-median red meat consumption and body mass index (BMI) < 25 kg/m2. CONCLUSIONS: Polymorphic variations in the LEP and LEPR genes were associated with survival of patients after CRC diagnosis. The LEP/LEPR-CRC survival association was modified by participants' red meat intake and BMI.
Subject(s)
Colorectal Neoplasms , Leptin , Humans , Leptin/genetics , Receptors, Leptin/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Colorectal Neoplasms/geneticsABSTRACT
BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36). RESULTS: Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS: In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.
Subject(s)
Anemia , Erythropoietin , Hematinics , Peritoneal Dialysis , Renal Insufficiency, Chronic , Humans , Darbepoetin alfa/therapeutic use , Renal Dialysis/adverse effects , Anemia/drug therapy , Anemia/etiology , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/therapy , Renal Insufficiency, Chronic/chemically induced , Peritoneal Dialysis/adverse effects , Hematinics/adverse effects , Hemoglobins/analysis , Erythropoietin/adverse effectsABSTRACT
INTRODUCTION: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production. METHODS: To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm. RESULTS: In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events. DISCUSSION/CONCLUSION: Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.
Subject(s)
Anemia , Erythropoietin , Hematinics , Renal Insufficiency, Chronic , Humans , Darbepoetin alfa/adverse effects , Quality of Life , Anemia/drug therapy , Anemia/etiology , Erythropoietin/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Hematinics/adverse effects , Renal Dialysis/adverse effects , Hemoglobins/analysisABSTRACT
BACKGROUND: Paradoxically epidemiological data illustrate a negative relationship between dietary folate intake and colorectal cancer (CRC) risk. The occurrence and progression of CRC may be influenced by variants in some key enzyme coding genes in the folate metabolic pathway. We investigated the correlation between genetic variants in methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) and CRC survival. METHODS: This study used data collected from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients diagnosed with CRC for the first time from 1999 to 2003 were enrolled, and their mortality were tracked until April 2010. DNA samples were genotyped by Illumina's integrated quantum 1 million chip. Cox models were established to assess 33 tag single-nucleotide polymorphisms in MTRR and MTHFR in relation to overall survival (OS), disease-free survival (DFS) and CRC-specific survival. RESULTS: The MTRR and MTHFR genes were associated with DFS and CRC-specific survival in CRC patients at the gene level. After multiple comparison adjustment, MTRR rs1801394 A (vs. G) allele was associated with increased DFS (p = 0.024), while MTHRT rs3737966 (G vs. A), rs4846049 (T vs. G), rs1476413 (A vs. G), rs1801131 (C vs. A), rs12121543 (A vs. C), rs1801133 (C vs. T), rs4846052 (T vs. C), rs2066471 (A vs. G) and rs7533315 (T vs. C) were related to worse CRC-specific survival. Additionally, significant interactions were seen among pre-diagnostic alcohol consumption with MTRR rs1801394, rs3776467, rs326124, rs162040, and rs3776455, with superior OS associated with those protective variant alleles limited to patients with alcohol consumption under the median. The MTHFR rs3737966 (G vs. A) allele seemed to be detrimental to CRC survival only among subjects with fruit intake below the median. CONCLUSIONS: Polymorphic variants in MTRR and MTHFR genes that code for key enzymes for folate metabolism may be associated with survival in patients with CRC. The gene-CRC outcome association seems modulated by alcohol drinking and fruit intake.
Subject(s)
Colorectal Neoplasms , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Ferredoxin-NADP Reductase/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Single Nucleotide , Genotype , Folic Acid/metabolism , Case-Control Studies , Genetic Predisposition to Disease , 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/geneticsABSTRACT
We examined dietary fiber intake for its relevance to Colorectal cancer (CRC) survival in a cohort of CRC patients and a meta-analysis including results from four prospective cohort studies. We analyzed 504 CRC patients enrolled in the Newfoundland Familial Colorectal Cancer Study (NFCCS) who were newly diagnosed with CRC between 1999 and 2003. Follow-up for deaths was through April 2010. All participants completed a self-administered food frequency questionnaire to evaluate their dietary intakes one year before diagnosis. Multivariable Cox proportional hazard models were used to explore the associations of dietary fiber intake with all-cause mortality and CRC-specific mortality. In the meta-analysis, we identified prospective cohort studies published between January 1991 and December 2021 by searching PubMed, EMBASE, and Cochrane Library. Fixed-effects or random-effects models were used to combine the study-specific hazard ratio (HR) from our original analysis and three other cohorts. In the NFCCS, we found that CRC patients with the second quartile of dietary fiber intake had a 42% lower risk of all-cause mortality (HR: 0.58, 95% CI: 0.35-0.98) and 58% lower risk of CRC-specific mortality (HR: 0.42, 95% CI: 0.21-0.87) compared with those with the lowest quartile. In the meta-analysis, a similar inverse association between dietary fiber and total mortality was detected among CRC patients; each 10 g/day increase in dietary fiber intake was associated with a 16% decreased risk of total mortality. The dose-response meta-analysis showed a linear relationship between dietary fiber intake and all-cause mortality, with no sign of a plateau. For CRC-specific mortality, intriguingly, the benefit associated with increasing dietary fiber intake achieved its maximum at approximately 22 g/day, and no further reduction in CRC-specific mortality was observed beyond this intake level. Our results suggest that high dietary fiber intake may be associated with prolonged survival among CRC patients. Our findings add to the sparse literature on the role of dietary fiber in CRC survival.
ABSTRACT
Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.
Subject(s)
Anemia , Erythropoietin , Hematinics , Renal Insufficiency, Chronic , Anemia/drug therapy , Anemia/etiology , Clinical Trials, Phase III as Topic , Darbepoetin alfa/therapeutic use , Erythropoiesis , Erythropoietin/therapeutic use , Ferritins , Glycine/analogs & derivatives , Hematinics/therapeutic use , Hemoglobins/metabolism , Hepcidins , Humans , Iron/therapeutic use , Picolinic Acids , Randomized Controlled Trials as Topic , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Transferrins/therapeutic useABSTRACT
BACKGROUND: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants. METHODS: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve. RESULTS: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores. CONCLUSIONS: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.
Subject(s)
Colorectal Neoplasms , Early Detection of Cancer , Aged , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Female , Genetic Predisposition to Disease , Humans , Male , Mass Screening , Middle Aged , Risk Assessment , Risk FactorsABSTRACT
OBJECTIVE: The use of antipsychotics to treat seniors in long-term care facilities (LTCFs) has raised concern because of health consequences (i.e., increased risk of falls, stroke, death) in this vulnerable population. This study measured geographic patterns of antipsychotic utilization among seniors living in LTCFs in Newfoundland and Labrador (NL) and assessed potential inappropriateness. METHOD: We analyzed prescription records among adults 66 years and older with provincial prescription drug coverage admitted to LTCFs in NL between April 1, 2011, and March 31, 2014. Patterns of use were analyzed across the 4 regional health authorities (RHAs) in NL and LTCFs. Logistic, Poisson and linear regression models were used to test variations in prevalence, rate and volume of antipsychotic utilization. To assess potential inappropriateness of antipsychotic use, we analyzed data from Resident Assessment Instrument-Minimum Data Set (RAI-MDS) 2.0 forms from NL LTCFs between January 1, 2016, and December 31, 2018. Pearson chi-squared analysis was performed at the RHA and LTCF levels to determine changes in percentage of total prescriptions or antipsychotic prescriptions without psychosis. RESULTS: Between 2011 and 2014, 2843 seniors were admitted to LTCFs across NL; of these, 1323 residents were prescribed 1 or more antipsychotics. Within the 3-year period, the percentage of antipsychotic use across facilities ranged from 35% to 78%. Using data from 27,260 RAI-MDS 2.0 assessments between 2016 and 2018, 71% (6995/9851) of antipsychotic prescriptions were potentially inappropriate. DISCUSSION: There is substantial variation across NL regions concerning the utilization of antipsychotics for senior in LTCFs. Facility size and management styles may be reasons for this. CONCLUSION: With nearly three-quarters of antipsychotic prescriptions shown to be potentially inappropriate, systematic interventions to assess indications for antipsychotic use are warranted. Can Pharm J (Ott) 2021;154:xx-xx.
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Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite. Methods: Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite. Results: Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P = .04). Conclusion: In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.
Subject(s)
Colonic Neoplasms/etiology , Rectal Neoplasms/etiology , Adult , Age of Onset , Aged , Alcoholism/complications , Alcoholism/epidemiology , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Case-Control Studies , Cattle , Colonic Neoplasms/epidemiology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/etiology , Confidence Intervals , Dietary Fiber/administration & dosage , Educational Status , Humans , Incidence , Logistic Models , Meat , Middle Aged , Odds Ratio , Rectal Neoplasms/epidemiology , Risk FactorsABSTRACT
Clinical epidemiology is the science of human disease investigation with a focus on diagnosis, prognosis, and treatment. The generation of a reasonable question requires definition of patients, interventions, controls, and outcomes. The goal of research design is to minimize error, ensure adequate samples, measure input and output variables appropriately, consider external and internal validities, limit bias, and address clinical as well as statistical relevance. The hierarchy of evidence for clinical decision-making places randomized controlled trials (RCT) or systematic review of good-quality RCTs at the top of the evidence pyramid. Prognostic and etiologic questions are best addressed with longitudinal cohort studies.
Subject(s)
Evidence-Based Medicine/methods , Research Design , Biomedical Research/methods , Clinical Decision-Making , Epidemiologic Studies , Humans , Longitudinal Studies , Prognosis , Randomized Controlled Trials as Topic , Systematic Reviews as TopicABSTRACT
Clinical epidemiological research entails assessing the burden and etiology of disease, the diagnosis and prognosis of disease, the efficacy of preventive measures or treatments, the analysis of the risks and benefits of diagnostic and therapeutic maneuvers, and the evaluation of health care services. In all areas, the main focus is to describe the relationship between exposure and outcome and to determine one of the following: prevalence, incidence, cause, prognosis, or effect of treatment. The accuracy of these conclusions is determined by the validity of the study. Validity is determined by addressing potential biases and possible confounders that may be responsible for the observed association. Therefore, it is important to understand the types of bias that exist and also to be able to assess their impact on the magnitude and direction of the observed effect. The following chapter reviews the epidemiological concepts of selection bias, information bias, intervention bias, and confounding and discusses ways in which these sources of bias can be minimized.
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Bias , Confounding Factors, Epidemiologic , Humans , Incidence , Prevalence , Research Design , Selection BiasABSTRACT
Statistical models are used to study the relationship between exposure and disease while accounting for the potential role of other factors' impact upon outcomes. This adjustment is useful to obtain unbiased estimates of true effects or to predict future outcomes. Statistical models include a systematic and an error component. The systematic component explains the variability of the response variable as a function of the predictors and is summarized in the effect estimates (model coefficients). The error element of the model represents the variability in the data unexplained by the model and is used to build measures of precisions around the point estimates (Confidence Intervals).
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Longitudinal Studies , Models, Statistical , Humans , Multivariate Analysis , Regression AnalysisABSTRACT
In longitudinal studies, the relationship between exposure and disease can be measured once or multiple times while participants are monitored over time. Traditional regression techniques are used to model outcome data when each epidemiological unit is observed once. These models include generalized linear models for quantitative continuous, discrete, or qualitative outcome responses, and models for time-to-event data. When data come from the same subjects or group of subjects, observations are not independent and the underlying correlation needs to be addressed in the analysis. In these circumstances, extended models are necessary to handle complexities related to clustered data, and repeated measurements of time-varying predictors and/or outcomes.
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Longitudinal Studies , Survival Analysis , Adult , Age Factors , Female , Humans , Linear Models , Male , Middle Aged , Models, Statistical , Regression Analysis , Research Design , Young AdultABSTRACT
Today's clinical practice relies on the application of well-designed clinical research, the gold standard test of an intervention being the randomized controlled trial. Principles of the randomized control trial include emphasis on the principal research question, randomization, blinding; definitions of outcome measures, of inclusion and exclusion criteria, and of co-morbid and confounding factors; enrolling an adequate sample size; planning data management and analysis; preventing challenges to trial integrity such as drop-out, drop-in, and bias. The application of pre-trial planning is stressed to ensure the proper application of epidemiological principles resulting in clinical studies that are feasible and generalizable. In addition, funding strategies and trial team composition are discussed.
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Randomized Controlled Trials as Topic/methods , Research Design , Bias , Humans , Models, Theoretical , Outcome Assessment, Health Care , Sample SizeABSTRACT
When analyzing the results of a trial, the primary outcome variable must be kept in clear focus. In the analysis plan, consideration must be given to comparing the characteristics of the subjects, taking account of differences in these characteristics, intention-to-treat analysis, interim analyses and stopping rules, mortality comparisons, composite outcomes, research design including run-in periods, factorial, stratified and crossover designs, number needed to treat, power issues, multivariate modeling, subgroup analysis, competing risks, and hypothesis-generating analyses.
Subject(s)
Randomized Controlled Trials as Topic/methods , Cross-Over Studies , Humans , Intention to Treat Analysis , Multivariate Analysis , Research DesignABSTRACT
Quality-of-life (QoL) outcomes are important elements of randomized controlled trials. The instruments for measurement of QoL vary but usually multiple comparisons are possible, a concern that can be offset by prespecifying the outcomes of interest. Missing data may threaten the validity of QoL assessments in trials. Therefore, familiarity with the strategies used to account for missing data is necessary. Measures that incorporate both survival and QoL are helpful for treatment decisions. The definition of minimal clinically important differences in QoL scores is important and often derived using inadequate methods.
Subject(s)
Quality of Life , Randomized Controlled Trials as Topic/methods , Research Design , Health Status , Humans , Male , Patient Reported Outcome Measures , Surveys and QuestionnairesABSTRACT
The intention-to-treat analysis is the gold standard for evaluating the efficacy in a randomized controlled trial. However, when non-adherence to randomized treatments is high the actual treatment effect may be underestimated. The impact of drop-out from the intervention group or drop-in to the control group may be controlled by trial design, increasing the sample size, effective study execution, and a pre-specified analytical plan to take contamination into account.These analyses may include censoring at the time of co-interventions associated with stopping treatment, lag censoring which allows an additional period after discontinuation of study treatment to account for residual treatment effects, inverse probability of censoring weights (IPCW), accelerated failure time models, and contamination adjusted intent-to-treat analysis . These methods are particularly useful in assessing the "prescribed efficacy" of the study treatment, which can aid clinical decision-making .
Subject(s)
Randomized Controlled Trials as Topic/standards , Treatment Outcome , Data Interpretation, Statistical , Humans , Intention to Treat Analysis , Patient Compliance , Probability , Research Design , Sample SizeABSTRACT
The quantity of health spending does not equate directly to the quality of healthcare. Social spending and nonmedical determinants of health impact on health outcomes. The value of health spending in the United States is limited by the high cost of goods and labor, and administrative costs, high use of low-level care, and lack of basic healthcare coverage in a substantial minority of the population. There are additional reasons for differences in the value of health spending as revealed by a comparison of Canada and Australia, where similar spending per capita results in better health system performance in Australia than in Canada. Within Canada, there are large differences between provinces in the value of health spending. Overutilization of health resources occurs when an intervention is not indicated, or of low value, or is provided at the wrong time. The Choosing Wisely Initiative is a solution for overutilization of low-value care. Recognition of the reality that effective treatments are often applied inconsistently and inappropriately has spurred the development of a science concerned with improvement of quality of care.