Time-related Biases Research Articles

Timing of sodium-glucose cotransporter 2 inhibitor initiation and post-discharge outcomes in acute heart failure with diabetes: A population-based cohort study.

Results from randomized trials suggest benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitor initiation in clinically stable acute heart failure. We aim to examine the real-world effectiveness of early versus delayed post-discharge SGLT2 inhibitor initiation in people with acute heart failure and type 2 diabetes. Using linkable administrative databases in Ontario, Canada, individuals aged 66 years or older with type 2 diabetes who were discharged to the community from acute care hospitals for heart failure between 1 July 2016 and 31 March 2020 were included in this retrospective, population-based cohort study. The primary outcome was hospitalization for heart failure (HHF) or cardiovascular mortality as a composite. Follow-up started from discharge for maximum 1 year. We compared outcomes between post-discharge SGLT2 inhibitor initiation within 3 days, 4-90 days, or 91-180 days, versus delayed initiation for at least 180 days. The 'clone-censor-weight' approach with a target trial emulation framework was used to address time-related biases. There were 9641 eligible individuals. After cloning and artificial censoring, there were 38 564 clones, 12 439 person-years, and 7584 events. Compared to delayed initiation for at least 180 days, initiation within 3 days post-discharge was associated with a lower 1-year risk of HHF or cardiovascular mortality (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.45-0.83), while initiation 4-90 days (RR 0.83, 95% CI 0.72-0.93) or 91-180 days (RR 0.89, 95% CI 0.79-0.97) showed smaller risk reduction. Real-world evidence supports early SGLT2 inhibitor initiation to reduce HHF or cardiovascular mortality in acute heart failure and type 2 diabetes.

Identification process of time-related bias in pharmacoepidemiologic research based on a scoping review

Objective: To summarize the characteristics of pharmacoepidemiologic research involving diabetes patients, which were published in recent years, in terms of study design and analysis, and develop an identification process for time-related biases in pharmacoepidemiologic research. Methods: PubMed, Embase, CNKI and Wanfang were used for a systematical literature retrieval of relevant study papers published between January 1,2012 and September 26, 2022. Literature screening and data extraction were performed independently by two reviewers. Based on the mechanisms of different time-related biases and the characteristics of included study papers in terms of study design and analysis methods, an identification process for all types of time-related biases was developed. Results: A total of 281 study papers were included, of which 58 (20.64%) specifically mentioned certain time-related biases considered in the study. Based on the scoping review results, key points to identify time-related biases were summarized, involving data source, study design, control selection, comparator drugs, matching the duration of diabetes, identification of the washout period, identification of the induction/latency period, identification of the initiation of follow-up, identification of time window, statistical analysis methods, sensitivity analysis, and other design and analytical elements, in the identification process for time-related biases in pharmacoepidemiologic research. Conclusions: Time-related biases are common in pharmacoepidemiologic research and might significantly impact the study results. Based on scoping review results, this study further developed an identification process for time-related biases in pharmacoepidemiologic research, which will help researchers identify and avoid time-related biases and improve the reliability of related evidence in pharmacoepidemiologic research.

Too good to be true: Are GLP-1 receptor agonists the new metformin?

Recently, a health-care database study showed that persons with type 2 diabetes taking GLP-1 receptor agonists (GLP-1 RA) had a significantly lower risk of 10 out of 13 obesity-related cancers than patients taking insulin (Wang L, et al. JAMA Netw Open. 2024 7: e2421305). For some cancers, hazard ratios <0.5 were reported. This is reminiscent of studies published >10 years ago showing that people with type 2 diabetes taking metformin had a lower risk of many types of cancer than those not taking metformin. In some studies, also risk reductions of >50 % were reported.The strong effects observed in the metformin studies were explained by time-related biases, in particular, immortal time bias. In the current GLP-1 RA study, it was striking that the curves for the cumulative incidence of several cancers in GLP-1 RA and insulin users diverged immediately after therapy onset. This indicates that there is most likely a time-related bias: insulin is given at much later stages of type 2 diabetes than GLP-1 RA.The current study suggests that one should be sceptical about database results when spectacular risk reductions are reported. Time-related bias should always be considered as an alternative explanation.

Positive and negative controls in rheumatology research.

Observational research from large population databases may be affected by unmeasured confounding and time-related biases, such as immortal time bias. Modern causal inference practice applies propensity score-based methods, new-user designs, and other strategies to mitigate bias. The degree to which these methodologic approaches adequately address bias for any particular study may be difficult to measure. Recently, the incorporation of positive and negative controls has been identified as a means to assess for the impacts of residual confounding and/or time-related biases. The objective of this commentary is to describe the role of positive and negative controls in observational research. We offer recommendations for incorporating controls into critical appraisal and observational research projects.

Bariatric surgery and all-cause mortality: A methodological review of studies using a non-surgical comparator.

Non-randomized studies on bariatric surgery have reported large reductions in mortality within 6-12 months after surgery compared with non-surgical patients. It is unclear whether these findings are the result of bias. We searched PubMed to identify all non-randomized studies investigating the effect of bariatric surgery on all-cause mortality compared with non-surgical patients. We assessed these studies for potential confounding and time-related biases. We conducted bias analyses to quantify the effect of these biases. We identified 21 cohort studies that met our inclusion criteria. Among those, 11 were affected by immortal time bias resulting from the misclassification or exclusion of relevant follow-up time. Five studies were subject to potential confounding bias because of a lack of adjustment for body mass index (BMI). All studies used an inadequate comparator group that lacked indications for bariatric surgery. Bias analyses to correct for potential confounding from BMI shifted the effect estimates towards the null [reported hazard ratio (HR): 0.78 vs. bias-adjusted HR: 0.92]. Bias analyses to correct for the presence of immortal time also shifted the effect estimates towards the null (adjustment for 2-year wait time: reported HR: 0.57 vs. bias-adjusted HR: 0.81). Several important sources of bias were identified in non-randomized studies of the effectiveness of bariatric surgery versus non-surgical comparators on mortality. Future studies should ensure that confounding by BMI is accounted for, considering the choice of the comparator group, and that the design or analysis avoids immortal time bias from the misclassification or exclusion.

Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study

ObjectiveTo investigate whether use of glucagon-like peptide 1 (GLP1) receptor agonists is associated with increased risk of thyroid cancer.DesignScandinavian cohort study.SettingDenmark, Norway, and Sweden, 2007-21.ParticipantsPatients who started GLP1 receptor agonist...

Effectiveness of Aspirin on Major COPD Outcomes: A Prevalent New-User Design Observational Study

Observational studies that have reported an association between aspirin use in chronic obstructive pulmonary disease (COPD) with reductions in mortality and COPD exacerbations were shown to be affected by time-related biases. We assessed this association using a prevalent new-user study design that avoids these biases. We used the United Kingdom’s Clinical Practice Research Datalink (CPRD) to form a cohort of patients with COPD. Aspirin initiators were matched on time and propensity score with nonusers during 2002–2018. The outcomes were all-cause mortality and COPD exacerbation within a one-year follow-up. Hazard ratios (HR) and 95% confidence interval (CI) of each outcome associated with aspirin use compared to nonuse were estimated using an as-treated approach. The study cohort included 10,287 initiators of aspirin and 10,287 matched nonusers. The cumulative incidence of all-cause mortality at one year was 11.5% for aspirin users and 9.2% for nonusers. The HR of all-cause mortality associated with aspirin initiation was 1.22 (95% CI: 1.08–1.37), while for severe exacerbation it was 1.21 (95% CI 1.08–1.37), compared with nonuse. The HR of a first moderate or severe exacerbation with aspirin use was 0.90 (95% CI 0.85–0.95). These estimates did not vary by platelet count. This large population-based study, designed to emulate a trial, found aspirin use in patients with COPD associated with a higher risk of all-cause mortality and severe exacerbation, but a lower risk of moderate or severe exacerbation. Further research is warranted to assess this reduction in moderate or severe exacerbations, particularly in patients with cardiovascular risk factors.

Neural mechanisms of sequential dependence in time perception: the impact of prior task and memory processing.

Our perception and decision-making are susceptible to prior context. Such sequential dependence has been extensively studied in the visual domain, but less is known about its impact on time perception. Moreover, there are ongoing debates about whether these sequential biases occur at the perceptual stage or during subsequent post-perceptual processing. Using functional magnetic resonance imaging, we investigated neural mechanisms underlying temporal sequential dependence and the role of action in time judgments across trials. Participants performed a timing task where they had to remember the duration of green coherent motion and were cued to either actively reproduce its duration or simply view it passively. We found that sequential biases in time perception were only evident when the preceding task involved active duration reproduction. Merely encoding a prior duration without reproduction failed to induce such biases. Neurally, we observed activation in networks associated with timing, such as striato-thalamo-cortical circuits, and performance monitoring networks, particularly when a "Response" trial was anticipated. Importantly, the hippocampus showed sensitivity to these sequential biases, and its activation negatively correlated with the individual's sequential bias following active reproduction trials. These findings highlight the significant role of memory networks in shaping time-related sequential biases at the post-perceptual stages.

Statins and Mortality in COPD: A Methodological Review of Observational Studies

Randomized controlled trials and observational studies have reported conflicting results on the potential beneficial effects of statins on mortality in patients with chronic obstructive pulmonary disease (COPD). We performed a systematic search of the literature to review all observational studies reporting relative risks of death with statin use in COPD, focusing on potential sources of bias. We identified 15 observational studies, out of 2835, of which 12 were affected by time-related and other biases and the remaining 3 by confounding bias. All 15 studies were also subject to confounding bias due to lack of adjustment for important COPD-related factors. The risk of death associated with statin use was reduced across all 15 studies (pooled relative risk (PRR) 0.66; 95% CI: 0.59-0.74). The reduction was observed in 7 studies with immortal time bias (PRR 0.62; 95%: 0.53-0.72), two with collider-stratification bias (PRR 0.60; 95% CI: 0.45-0.80), one with time-window bias (RR 0.61; 95% CI: 0.38-0.98), one with immeasurable time bias (RR 0.50; 95% CI: 0.40-0.62), and one with exposure misclassification (RR 0.86; 95% CI: 0.72-1.03). The three studies that avoided these biases were, however, affected by confounding bias resulting in a PRR of 0.77 (95% CI: 0.61-0.98). In conclusion, the observational studies investigating statin use and mortality in COPD are affected by major biases, many of which can result in spurious protective effects. Well-designed observational studies that carefully emulate randomized trials are needed to resolve this uncertainty regarding the potential beneficial benefits of statins on mortality in patients with COPD.

Effectiveness of Specific Health Check-ups in Japan for the primary prevention of obesity-related diseases: a protocol for a target trial emulation

IntroductionConcerns about public health threats have shifted towards obesity-related, non-communicable diseases in both developed and developing countries. Since 2008, Japan has adopted a nationwide universal screening programme called Specific Health...

Opportunistic Imaging: Counterpoint-Overdiagnosis and Unclear Benefit to Individual Patients, New Inefficiencies in Medical Care and Costs, and Time-Related Biases.

This article does not include an abstract. Please see the accompanying Point by Miriam A. Bredella. Please see the Author Video associated with this article.

Metformin and Cancer: Solutions to a Real-World Evidence Failure.

The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.

Risk of spontaneous abortion after periconceptional medication use: Time to tackle the methodological challenges.

Risk of spontaneous abortion after periconceptional medication use: Time to tackle the methodological challenges.

A New Source of Heterogeneity in Comparative and Translational Clinical Trials: The "Border-Time" Bias.

The use of target-oriented drugs is profoundly changing the anti-cancer treatments. This new and expanding therapeutic context relies on the translation of biomarkers expression (laboratory testing) into clinical practice (treatment). Progression-free survival is a primary or co-primary endpoint in the large part of comparative clinical trials about biologic anti-cancer agents. Here, we describe the "border time" bias represented by specific time points and intervals that are an underestimated source of methodologic heterogeneity and can contribute to wrong evaluation of time-to-outcome. These issues are concentrated at the beginning (head: pre-screening and screening activities) and at the end (tail: modalities of disease reassessment) of the anti-cancer treatment and can represent a time-related bias. Reporting, and ideally shortening, the time spent in pre-screening and screening activities with synthetic and innovative methodological tools as well as more harmonized rules about timing of disease reassessment can contribute to reduce, or even prevent, this bias in clinical studies.

Trimodality Therapy vs Definitive Chemoradiation in Older Adults With Locally Advanced Esophageal Cancer.

The comparative effectiveness of trimodality therapy vs definitive chemoradiation for treating locally advanced esophageal cancer in older adults is uncertain. Existing trials lack generalizability to older adults, a population with heightened frailty. We sought to emulate a hypothetical trial comparing these treatments using real-world data. A cohort of adults aged 66-79 years diagnosed with locally advanced esophageal cancer between 2004 and 2017 was identified in the Surveillance Epidemiology and End Results-Medicare database. The clone-censor-weight method was leveraged to eliminate time-related biases when comparing outcomes between treatments. Outcomes included overall mortality, esophageal cancer-specific mortality, functional adverse events, and healthy days at home. A total of 1240 individuals with adenocarcinomas and 661 with squamous cell carcinomas were identified. For adenocarcinomas, the standardized 5-year risk of mortality was 73.4% for trimodality therapy and 83.8% for definitive chemoradiation (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.82 to 0.95). Trimodality therapy was associated with mortality risk reduction for squamous cell carcinomas (RR = 0.87, 95% CI = 0.70 to 1.01). The 1-year incidence of functional adverse events was higher in the trimodality group (adenocarcinomas RR = 1.40, 95% CI = 1.22 to 1.65; squamous cell carcinomas RR = 1.21, 95% CI = 1.00 to 1.49). Over 5 years, trimodality therapy was associated with 160 (95% CI = 67 to 229) and 177 (95% CI = 51 to 313) additional home days in individuals with adenocarcinomas and squamous cell carcinomas, respectively. Compared with definitive chemoradiation, trimodality therapy was associated with reduced mortality but increased risk of function-related adverse events. Discussing these tradeoffs may help optimize care plans.

Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases.

Background:When studying drug effects using observational data, time-related biases may exist and result in spurious associations. Numerous observational studies have investigated metformin and dementia risk, but have reported inconsistent findings, some of which might be caused by unaddressed time-related biases. Immortal time bias biases the results toward a “protective” effect, whereas time-lag and time-window biases can lead to either a “detrimental” or “protective” effect.Objective:To conduct a systematic review examining time-related biases in the literature on metformin and dementia.Methods:The electronic databases PubMed, Web of Science, and ProQuest were searched for the terms “Metformin” AND (“dementia” OR “Alzheimer’s Disease” OR “cognitive impairment"). These databases were searched from inception through 09/24/2021. Only English language articles and human research were eligible.Results:Seventeen studies were identified: thirteen cohort studies, two case-control studies, and two nested case-control studies. Eleven (64.7%) studies reported a reduced risk of dementia associated with metformin use; two (11.8%) suggested metformin increased dementia risk, while four (23.5%) concluded no significant associations. Eight (61.5%) of thirteen cohort studies had immortal time bias or did not clearly address it. Fifteen (88.2%) of seventeen reviewed studies had time-lag bias or did not clearly address it. Two (50.0%) of four case-control studies did not explicitly address time-window bias. The studies that addressed most biases concluded no associations between metformin and dementia risk.Conclusion:None of the reviewed studies clearly addressed relevant time-related biases, illustrating time-related biases are common in observational studies investigating the impact of anti-diabetic medications on dementia risk.

Metformin use is not associated with colorectal cancer incidence in type-2 diabetes patients: evidence from methods that avoid immortal time bias.

Immortal time bias (ITB) continues to distort many observational studies on metformin use and cancer risk. Our objective was to employ three statistical methods proven to avoid ITB and compare their results to that of a naïve time-fixed analysis in order to provide further evidence of metformin's association, or none thereof, with colorectal cancer (CRC) incidence. A total of 41,533 Korean subjects with newly diagnosed type-2 diabetes in 2005-2015 were selected from a prospectively maintained cohort (median follow-up of 6.3years). Time-to-CRC incidence was regressed upon metformin use (yes/no, average prescription days/year) using time-dependent Cox, landmark, nested case-control, and time-fixed Cox analyses. Other CRC risk factors were included to adjust for possible confounding. Neither metformin ever-use nor average metformin prescription days/year was associated with incident CRC hazard in time-dependent Cox, landmark, and nested case-control analyses with HR (95% CI) of 0.88 (0.68-1.13), 0.86 (0.65-1.12), and 1.10 (0.86-1.40) for metformin ever-use, and 0.97 (0.90-1.04), 0.95 (0.88-1.04), and 1.02 (0.95-1.10) for average metformin prescription days/year, respectively. In contrast, time-fixed Cox regression showed a falsely exaggerated protective effect of metformin on CRC incidence. The association between metformin use and subsequent CRC incidence was statistically nonsignificant after accounting for time-related biases such as ITB. Previous studies that avoided these biases and meta-analyses of RCTs on metformin and cancer incidence were in agreement with our results. A definitive, large-scale RCT is needed to clarify this topic, and future observational studies should be explicit in avoiding ITB and other time-related biases.

Timing of adjuvant chemotherapy initiation and mortality among colon cancer patients at a safety-net health system

BackgroundPrior studies reported survival benefits from early initiation of adjuvant chemotherapy for stage III colon cancer, but this evidence was derived from studies that may be sensitive to time-related biases. Therefore, we aimed to estimate the effect of initiating adjuvant chemotherapy ≤8 or ≤ 12 weeks on overall and disease-free survival among stage III colon cancer patients using a study design that helps address time-related biases.MethodsWe used institutional registry data from JPS Oncology and Infusion Center, a Comprehensive Community Cancer Program. Eligible patients were adults aged < 80 years, diagnosed with first primary stage III colon cancer between 2011 and 2017, and received surgical resection with curative intent. We emulated a target trial with sequential eligibility. We subsequently pooled the trials and estimated risk ratios (RRs) along with 95% confidence limits (CL) for all-cause mortality and recurrence or death at 5-years between initiators and non-initiators of adjuvant chemotherapy ≤8 or ≤ 12 weeks using pseudo-observations and a marginal structural model with stabilized inverse probability of treatment weights.ResultsOur study population comprised 222 (for assessing initiation ≤8 weeks) and 310 (for assessing initiation ≤12 weeks) observations, of whom the majority were racial/ethnic minorities (64–65%), or uninsured with or without enrollment in our hospital-based medical assistance program (68–71%). Initiation of adjuvant chemotherapy ≤8 weeks of surgical resection did not improve overall survival (RR for all-cause mortality = 1.04, 95% CL: 0.57, 1.92) or disease-free survival (RR for recurrence or death = 1.07, 95% CL: 0.61, 1.88). The results were similar for initiation of adjuvant chemotherapy ≤12 weeks of surgical resection.ConclusionsOur results suggest that the overall and disease-free survival benefits of initiating adjuvant chemotherapy ≤8 or ≤ 12 weeks of surgical resection may be overestimated in prior studies, which may be attributable to time-related biases. Nevertheless, our estimates were imprecise and differences in population characteristics are an alternate explanation. Additional studies that address time-related biases are needed to clarify our findings.

Angiotensin-converting enzyme inhibitors and risk of age-related macular degeneration in individuals with hypertension.

AimsSeveral observational studies have examined the potential protective effect of angiotensin‐converting enzyme inhibitor (ACE‐I) use on the risk of age‐related macular degeneration (AMD) and have reported contradictory results owing to confounding and time‐related biases. We aimed to assess the risk of AMD in a base cohort of patients aged 40 years and above with hypertension among new users of ACE‐I compared to an active comparator cohort of new users of calcium channel blockers (CCB) using data obtained from IQVIA Medical Research Data, a primary care database in the UK.MethodsIn this study, 53 832 and 43 106 new users of ACE‐I and CCB were included between 1995 and 2019, respectively. In an on‐treatment analysis, patients were followed up from the time of index drug initiation to the date of AMD diagnosis, loss to follow‐up, discontinuation or switch to the comparator drug. A comprehensive range of covariates were used to estimate propensity scores to weight and match new users of ACE‐I and CCB. Standardized mortality ratio weighted Cox proportional hazards model was used to estimate hazard ratios of developing AMD.ResultsDuring a median follow‐up of 2 years (interquartile range 1–5 years), the incidence rate of AMD was 2.4 (95% confidence interval 2.2–2.6) and 2.2 (2.0–2.4) per 1000 person‐years among the weighted new users of ACE‐I and CCB, respectively. There was no association of ACE‐I use on the risk of AMD compared to CCB use in either the propensity score weighted or matched, on‐treatment analysis (adjusted hazard ratio: 1.07 [95% confidence interval 0.90–1.27] and 0.87 [0.71–1.07], respectively).ConclusionWe found no evidence that the use of ACE‐I is associated with risk of AMD in patients with hypertension.

Effect of Immortal Time Bias Controlled Metformin for Cancer Development in Diabetic Patients

Background: This study aimed to determine the effectiveness of metformin as first line oral hypoglycemic agent in diabetes patients in inhibiting cancer incidence, on the basis of the sample cohort supplied by the National Health Insurance Service, and to ascertain the effects of time-related bias on the results.Methods: A t-test was performed to compare the time taken for cancer development between the compliant and non-compliant metformin users and the non-metformin users. Survival analyses for cancer patients, regarding the period time until cancer incidence, were performed according to metformin use through three models: model 1 adjusted for age and sex; model 2 further adjusted for body mass index, cholesterol, and smoking status;and model 3 further adjusted for hypertension.Results: The odds ratio for cancer development was 1.11 times higher for the non-metformin users (6,997) than for the metformin compliant users (16,132), which was significant at the 0.1 significance level. The age, sex, body mass index, cholesterol, smoking status, and hypertension-adjusted hazard ratio was 0.86.Conclusions: This study has confirmed that metformin is effective in delaying cancer development for patients at risk of cancer rather than in inhibiting cancer incidence itself, by strict application of metformin exposure, with which immortal time biases are controlled. It is therefore necessary to manage compliance with an agent, as well as to prescribe metformin for patients at high risk of cancer, giving consideration to the risk factors for cancer development (old age, being male) instead of focusing on metformin prescription, with the objective of inhibiting cancer development.