scholarly journals Use of Cox regression with treatment status as a time-dependent covariate to re-analyze survival benefit excludes immortal time bias effect in patients with glioblastoma who received prolonged adjuvant treatment with valganciclovir

2014 ◽  
Vol 135 (1) ◽  
pp. 248-249 ◽  
Author(s):  
Cecilia Söderberg-Naucler ◽  
Inti Peredo ◽  
Afsar Rahbar ◽  
Fredrik Hansson ◽  
Anders Nordlund ◽  
...  
Keyword(s):  
Adjuvant Treatment ◽  
Survival Benefit ◽  
Cox Regression ◽  
Time Dependent ◽  
Bias Effect ◽  
Treatment Status ◽  
Immortal Time Bias

scholarly journals Lack of Survival Advantage among Re-Resected Elderly Glioblastoma Patients: A SEER-Medicare Study

2020 ◽  
Author(s):  
Debra A Goldman ◽  
Anne S Reiner ◽  
Eli L Diamond ◽  
Lisa M DeAngelis ◽  
Viviane Tabar ◽  
...  
Keyword(s):  
Older Adults ◽  
Survival Benefit ◽  
Cox Regression ◽  
Geographic Region ◽  
Survival Advantage ◽  
Time Dependent ◽  
Poverty Level ◽  
Risk Of Death ◽  
Immortal Time Bias ◽  
Initial Resection

Abstract Background The survival benefit of re-resection for glioblastoma (GBM) remains controversial, owing to the immortal time bias inadequately considered in many studies where re-resection was treated as a fixed, rather than time-dependent factor. Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we assessed treatment patterns for older adults and evaluated the association between re-resection and overall survival (OS), accounting for timing of re-resection. Methods This retrospective cohort study included elderly patients (age≥66) in the SEER-Medicare linked database diagnosed with GBM between 2006 and 2015 who underwent initial resection. Time-dependent Cox regression was used to assess the association between re-resection and OS, controlling for age, gender, race, poverty level, geographic region, marital status, comorbidities, receipt of radiation+temozolomide, and surgical complications. Results Our analysis included 3,604 patients with median age 74 (range: 66-96); 54% were men and 94% were white. After initial resection, 44% received radiation+temozolomide and these patients had a lower hazard of death (HR: 0.28, 95%CI: 0.26-0.31, p<0.001). In total, 9.5% (n=343) underwent re-resection. In multivariable analyses, no survival benefit was seen for patients who underwent re-resection (HR: 1.12, 95%CI: 0.99-1.27, p=0.07). Conclusions Re-resection rates were low among elderly GBM patients and no survival advantage was observed for patients who underwent re-resection. However, patients who received standard of care at initial diagnosis had a lower risk of death. Older adults benefit from receiving radiation+temozolomide after initial resection, and future studies should assess the relationship between re-resection and OS taking time of re-resection into account.

scholarly journals Immortal Time Bias in Observational Studies of Time-to-Event Outcomes

2018 ◽  
Vol 25 (1) ◽  
pp. 107327481878935 ◽  
Author(s):  
Parul Agarwal ◽  
Erin Moshier ◽  
Meng Ru ◽  
Nisha Ohri ◽  
Ronald Ennis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Effect ◽  
Cox Regression ◽  
Analytical Techniques ◽  
Time Dependent ◽  
Simulation Studies ◽  
Significant Treatment ◽  
Immortal Time Bias ◽  
Postmastectomy Radiation Therapy ◽  
Landmark Model

The objectives of this study are to illustrate the effects of immortal time bias (ITB) using an oncology outcomes database and quantify through simulations the magnitude and direction of ITB when different analytical techniques are used. A cohort of 11 626 women who received neoadjuvant chemotherapy and underwent mastectomy with pathologically positive lymph nodes were accrued from the National Cancer Database (2004-2008). Standard Cox regression, time-dependent (TD), and landmark models were used to compare overall survival in patients who did or did not receive postmastectomy radiation therapy (PMRT). Simulation studies showing ways to reduce the effect of ITB indicate that TD exposures should be included as variables in hazard-based analyses. Standard Cox regression models comparing overall survival in patients who did and did not receive PMRT showed a significant treatment effect (hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.88-0.99). Time-dependent and landmark methods estimated no treatment effect with HR: 0.97, 95% CI: 0.92 to 1.03 and HR: 0.98, 95% CI, 0.92 to 1.04, respectively. In our simulation studies, the standard Cox regression model significantly overestimated treatment effects when no effect was present. Estimates of TD models were closest to the true treatment effect. Landmark model results were highly dependent on landmark timing. Appropriate statistical approaches that account for ITB are critical to minimize bias when examining relationships between receipt of PMRT and survival.

Allogeneic stem cell transplantation (allo-SCT) in adult acute lymphoblastic leukemia (ALL)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17513-17513
Author(s):  
S. J. Wu ◽  
M. Yao ◽  
J. L. Tang ◽  
Y. C. Chen ◽  
A. L. Cheng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Benefit ◽  
Proportional Hazards Model ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Early Period ◽  
Population Based ◽  
Cox Proportional Hazards Model ◽  
Time Dependent ◽  
Immortal Time Bias

17513 Background: Although viewed as a potentially curable disease, the outcome of adult ALL is extremely poor. The role of allo-SCT, a possible curative modality, is of debate. Although the solid evidence is lacking, allo-SCT is viewed as a standard treatment in some institutions and some trials. The objective of the study is to clarify the effect of allo-SCT in the treatment of adult ALL patietns. Methods: From Jan. 1999 to Jun. 2006, we included 103 adult ALL patients whose age were between 15 and 55, the upper limit of age for allo-SCT in this institution. Their data, including clinical characteristics, cytogenetic results, treatment response and outcomes, were collected. To avoid the “immortal-time bias” in assessing the effect of transplant, the results from a time-independent and time-dependent Cox proportional hazards model were compared. We also conducted a population-based study to compare the outcomes of these patients with those diagnosed between Jan. 1986 and Dec.1993 in our institution. Results: There were 46 females and 57 males. The median age was 25.8, with 63 patients (61.2%) younger than 30. The median survival was 21.9 months and the 3-year overall survival was 34.2%. 48 patients(46.6%) received allo-SCT. The transplant conferred to marginally better survival in univariate analysis (p=0.049), but by time-dependent regression method, there was, after adjusting for other risk factors, no survival benefit for patients receiving transplant (HR 1.452, 95% CI 0.766∼2,751, p=0.253). The outcomes of these 103 patients were compared with another group of 69 patients diagnosed in the early period, among whom 13 patients(18.8%) received transplant. Although with higher proportion of patients undergoing allo- SCT, there was no advance in overall survival (p=0.157). Conclusions: In adult ALL, the outcome is still poor. Although there are new treatment protocols and modalities in chemotherapy and transplantation, these advances do not reflect to survival improvement. Transplantation provides limited survival benefit in population-based viewpoint. The candidates of allo-SCT should thus be carefully selected and allo-SCT should not be viewed as a standard in the treatment of adult ALL patients. No significant financial relationships to disclose.

scholarly journals Beta-Blocker Treatment in Ventilated COVID-19 patients – A Cox Regression with Time Dependent Covariate Analysis

2021 ◽  
Author(s):  
Dipesh Mistry ◽  
Anower Hossain ◽  
Jianxia Sun ◽  
Tonny Veenith ◽  
Ranjit Lall ◽  
...  
Keyword(s):  
Heart Rate ◽  
Critically Ill ◽  
Beta Blocker ◽  
Cox Regression ◽  
Prospective Trial ◽  
Time Dependent ◽  
Beta Blockade ◽  
Covariate Analysis ◽  
Risk Of Death ◽  
Immortal Time Bias

Abstract Background: Patients with co-morbidities are particularly vulnerable to severe COVID-19 disease. Critically ill patients with COVID-19 frequently experience severe tachycardias and avoidance of these is important in some co-morbidities, for instance cardiovascular disease. There is growing interest in beta blockade in critical illness as their use been associated with improved outcomes in a variety of conditions. We report the real-world use of heart rate management in patients during the first wave of the COVID-19 pandemic. As retrospective data are prone to an Immortal Time Bias, we created a Cohort Trial such as might be used for a future prospective trial and used Time Dependent Covariate Analysis for its analysis. Methods: Data for all PCR-proven COVID-19 patients ventilated in the Intensive Care Unit (ICU) were extracted from the hospital databases. To compensate for the risk of immortal time bias, we restricted analysis to 144 patients who achieved a heart rate (HR) of 90 beats per minute for more than 12 hours and were treated with norepinephrine. We recorded time from these ‘entry criteria’ to first beta blocker dose. Those patients who did not receive a beta blocker were given a nominal time to beta blocker beyond the censor day. Outcome was mortality censored at 28 days.Results: In the study group, 83/144 patients (57.6%) received a beta blocker. The median interval from entry criteria to beta blocker was 7.91 days (IQR 3.89, 13.15) and median duration of treatment was 7.00 days (IQR 4.00, 14.00). Twenty-four beta blocker patients (28.9%) died within 28 days compared with 29 (47.5%) who did not (adjusted OR 0.43; 95% CI 0.20-0.95, P=0.036). Cox Regression with time-dependent covariate analysis revealed there was an increased, but not significant, risk of death with beta blocker delay (Hazard Ratio 1.42 p=0.264). Mortality was also reduced for each day treated with beta blockade (adjusted Odds Ratio 0.76, 95% CI 0.64-0.91; P=0.002).Conclusions: In a retrospective analysis of critically ill ventilated patients with COVID-19 who developed a tachycardia >90 beats per minute and were treated with norepinephrine, beta blockade was associated with reduced mortality.

Investigating the Impact of Early Valve Surgery on Survival in Staphylococcus aureus Infective Endocarditis Using a Marginal Structural Model Approach: Results of a Large, Prospectively Evaluated Cohort

2018 ◽  
Vol 69 (3) ◽  
pp. 487-494 ◽  
Author(s):  
Siegbert Rieg ◽  
Maja von Cube ◽  
Achim J Kaasch ◽  
Bastian Bonaventura ◽  
Wolfgang Bothe ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Clinical Trials ◽  
Survival Benefit ◽  
Structural Model ◽  
Cox Regression ◽  
Cox Model ◽  
Valve Surgery ◽  
Time Dependent ◽  
Marginal Structural Model ◽  
The Impact

Abstract Background The impact of valve surgery on outcomes of Staphylococcus aureus infective endocarditis (SAIE) remains controversial. We tested the hypothesis that early valve surgery (EVS) improves survival by using a novel approach that allows for inclusion of major confounders in a time-dependent way. Methods EVS was defined as valve surgery within 60 days. Univariable and multivariable Cox regression analyses were performed. To account for treatment selection bias, we additionally used a weighted Cox model (marginal structural model) that accounts for time-dynamic imbalances between treatment groups. To address survivor bias, EVS was included as a time-dependent variable. Follow-up of patients was 1 year. Results Two hundred and three patients were included in the analysis; 50 underwent EVS. All-cause mortality at day 30 was 26%. In the conventional multivariable Cox regression model, the effect of EVS on the death hazard was 0.85 (95% confidence interval [CI], .47–1.52). Using the weighted Cox model, the death hazard rate (HR) of EVS was 0.71 (95% CI, .34–1.49). In subgroup analyses, no survival benefit was observed in patients with septic shock (HR, 0.80 [CI, .26–2.46]), in NVIE (HR, 0.76 [CI, .33–1.71]) or PVIE (HR, 1.02 [CI, .29–3.54]), or in patients with EVS within 14 days (HR, 0.97 [CI, .46–2.07]). Conclusions Using both a conventional Cox regression model and a weighted Cox model, we did not find a survival benefit for patients who underwent EVS in our cohort. Until results of randomized controlled trials are available, EVS in SAIE should be based on individualized decisions of an experienced multidisciplinary team. Clinical Trials Registration German Clinical Trials registry (DRKS00005045).

The impact of statin therapy after surgical or endovascular treatment of cerebral aneurysms

2020 ◽  
Vol 133 (1) ◽  
pp. 182-189
Author(s):  
Tae-Jin Song ◽  
Seung-Hun Oh ◽  
Jinkwon Kim
Keyword(s):  
Statin Therapy ◽  
Coil Embolization ◽  
Primary Outcome ◽  
Cox Regression ◽  
Cerebral Aneurysms ◽  
Time Dependent ◽  
Lipid Lowering ◽  
Surgical Clipping ◽  
The Impact

OBJECTIVECerebral aneurysms represent the most common cause of spontaneous subarachnoid hemorrhage. Statins are lipid-lowering agents that may expert multiple pleiotropic vascular protective effects. The authors hypothesized that statin therapy after coil embolization or surgical clipping of cerebral aneurysms might improve clinical outcomes.METHODSThis was a retrospective cohort study using the National Health Insurance Service–National Sample Cohort Database in Korea. Patients who underwent coil embolization or surgical clipping for cerebral aneurysm between 2002 and 2013 were included. Based on prescription claims, the authors calculated the proportion of days covered (PDC) by statins during follow-up as a marker of statin therapy. The primary outcome was a composite of the development of stroke, myocardial infarction, and all-cause death. Multivariate time-dependent Cox regression analyses were performed.RESULTSA total of 1381 patients who underwent coil embolization (n = 542) or surgical clipping (n = 839) of cerebral aneurysms were included in this study. During the mean (± SD) follow-up period of 3.83 ± 3.35 years, 335 (24.3%) patients experienced the primary outcome. Adjustments were performed for sex, age (as a continuous variable), treatment modality, aneurysm rupture status (ruptured or unruptured aneurysm), hypertension, diabetes mellitus, household income level, and prior history of ischemic stroke or intracerebral hemorrhage as time-independent variables and statin therapy during follow-up as a time-dependent variable. Consistent statin therapy (PDC > 80%) was significantly associated with a lower risk of the primary outcome (adjusted hazard ratio 0.34, 95% CI 0.14–0.85).CONCLUSIONSConsistent statin therapy was significantly associated with better prognosis after coil embolization or surgical clipping of cerebral aneurysms.

scholarly journals Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab

2021 ◽  
Author(s):  
Andrew X. Zhu ◽  
Richard S. Finn ◽  
Yoon-Koo Kang ◽  
Chia-Jui Yen ◽  
Peter R. Galle ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Clinical Outcomes ◽  
Predictive Value ◽  
Survival Benefit ◽  
Radiographic Progression ◽  
Cox Regression ◽  
Selection Criterion ◽  
Alpha Fetoprotein ◽  
Advanced Hepatocellular Carcinoma ◽  
Clinical Trial Registration

Abstract Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2). Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed. Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001). Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab. Clinical Trial Registration ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).

Treatment Time or Convection Volume in HDF: What Drives the Reduced Mortality Risk?

2015 ◽  
Vol 40 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Camiel L.M. de Roij van Zuijdewijn ◽  
Menso J. Nubé ◽  
Piet M. ter Wee ◽  
Peter J. Blankestijn ◽  
Renée Lévesque ◽  
...  
Keyword(s):  
Confidence Intervals ◽  
Mortality Risk ◽  
Survival Benefit ◽  
Regression Models ◽  
Cox Regression ◽  
Treatment Time ◽  
High Volume ◽  
P Values ◽  
Hazard Ratios

Background/Aims: Treatment time is associated with survival in hemodialysis (HD) patients and with convection volume in hemodiafiltration (HDF) patients. High-volume HDF is associated with improved survival. Therefore, we investigated whether this survival benefit is explained by treatment time. Methods: Participants were subdivided into four groups: HD and tertiles of convection volume in HDF. Three Cox regression models were fitted to calculate hazard ratios (HRs) for mortality of HDF subgroups versus HD: (1) crude, (2) adjusted for confounders, (3) model 2 plus mean treatment time. As the only difference between the latter models is treatment time, any change in HRs is due to this variable. Results: 114/700 analyzed individuals were treated with high-volume HDF. HRs of high-volume HDF are 0.61, 0.62 and 0.64 in the three models, respectively (p values <0.05). Confidence intervals of models 2 and 3 overlap. Conclusion: The survival benefit of high-volume HDF over HD is independent of treatment time.

scholarly journals Neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients

2015 ◽  
Vol 45 (6) ◽  
pp. 1642-1652 ◽  
Author(s):  
Nelson Lee ◽  
Yee-Sin Leo ◽  
Bin Cao ◽  
Paul K.S. Chan ◽  
W.M. Kyaw ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Cox Regression ◽  
Management Strategies ◽  
Patient Characteristics ◽  
Primary Outcome Measure ◽  
Time Dependent ◽  
High Morbidity ◽  
Neuraminidase Inhibitors ◽  
Systemic Corticosteroids ◽  
Time Dependent Analysis

We aimed to study factors influencing outcomes of adults hospitalised for seasonal and pandemic influenza. Individual-patient data from three Asian cohorts (Hong Kong, Singapore and Beijing; N=2649) were analysed. Adults hospitalised for laboratory-confirmed influenza (prospectively diagnosed) during 2008–2011 were studied. The primary outcome measure was 30-day survival. Multivariate Cox regression models (time-fixed and time-dependent) were used.Patients had high morbidity (respiratory/nonrespiratory complications in 68.4%, respiratory failure in 48.6%, pneumonia in 40.8% and bacterial superinfections in 10.8%) and mortality (5.9% at 30 days and 6.9% at 60 days). 75.2% received neuraminidase inhibitors (NAI) (73.8% received oseltamivir and 1.4% received peramivir/zanamivir; 44.5% of patients received NAI ≤2 days and 65.5% ≤5 days after onset of illness); 23.1% received systemic corticosteroids. There were fewer deaths among NAI-treated patients (5.3% versus 7.6%; p=0.032). NAI treatment was independently associated with survival (adjusted hazard ratio (HR) 0.28, 95% CI 0.19–0.43), adjusted for treatment-propensity score and patient characteristics. Superinfections increased (adjusted HR 2.18, 95% CI 1.52–3.11) and chronic statin use decreased (adjusted HR 0.44, 95% CI 0.23–0.84) death risks. Best survival was shown when treatment started within ≤2 days (adjusted HR 0.20, 95% CI 0.12–0.32), but there was benefit with treatment within 3–5 days (adjusted HR 0.35, 95% CI 0.21–0.58). Time-dependent analysis showed consistent results of NAI treatment (adjusted HR 0.39, 95% CI 0.27–0.57). Corticosteroids increased superinfection (9.7% versus 2.7%) and deaths when controlled for indications (adjusted HR 1.73, 95% CI 1.14–2.62). Early NAI treatment was associated with shorter length of stay in a subanalysis.NAI treatment may improve survival of hospitalised influenza patients; benefit is greatest from, but not limited to, treatment started within 2 days of illness. Superinfections and corticosteroids increase mortality. Antiviral and non-antiviral management strategies should be considered.

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