Synthesis Of Multiple Types Of Survival Data Within A Weibull Proportional Hazards Meta-Analysis: Treatment Outcomes In Patients With Double Hit Lymphoma (DHL)

Abstract Background The United States’ opioid epidemic has led to an increase in people who inject drugs (PWID) and opioid-associated infections, including infectious endocarditis (IE). Cardiac surgery is often indicated in IE to improve outcomes but is controversial in PWID due to the concerns about continued injection drug use leading to risk for reinfection and decreased survival. In response, we assessed the long-term survival after cardiac valve surgery in PWID compared with people who do not inject drugs (non-PWID) in the published literature. Methods We performed a systematic review and meta-analysis (MA) of studies that reported survival data after surgery for IE in PWID. We searched PUBMED up to April 2018. We extracted Kaplan–Meier (KM) curves from included studies. From the KM curves, we used an algorithm to estimate individual participant data (eIPD). In a one-step approach, we ran a Cox proportional hazards (CPH) model analysis of the eIPD with study random effects. In a two-step approach, we fitted CPH models by individual study; then, we ran a mixed-effects MA model of the log hazard ratios (HR) and standard errors. Results We identified 11 retrospective studies. Of these, six reported comparisons of PWID vs. non-PWID, and five reported results for PWID only. Based on eIPD, we included 407 PWID and 1,877 non-PWID. Mean age for PWID was 36.7 years (95% CI 34.4–39.1) and for non-PWID was 52.0 years (95% CI 45.3–59.4). There were 144 deaths (35.3%) in PWID and 559 (29.8%) deaths in non-PWID. We present by study and by group KM curves of eIPD (Figures 1 and 2). In one-step MA (included all 11 studies), the HR for PWID was 1.13 (95% CI 0.92–1.39). In two-step MA (included six comparison studies), heterogeneity was high (I2 = 72%); and there was no significant between-group difference (HR 1.29, 95% CI 0.80–2.07) (Figure 3). Conclusion Survival time post-surgery of PWID was similar to that of non-PWID. These estimates are concerning, as PWID on average are much younger than non-PWID with IE. Future studies should explore interventions to improve outcomes in PWID after surgery, including treatment of addiction during and after the index hospitalization and provision of naloxone at the time of discharge. Disclosures All authors: No reported disclosures.

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Multi-state network meta-analysis of cause-specific survival data

10.1101/2020.11.13.20231332 ◽

2020 ◽

Author(s):

Jeroen P. Jansen ◽

Devin Incerti ◽

Thomas Trikalinos

Keyword(s):

Survival Data ◽

Treatment Effects ◽

Proportional Hazards ◽

Treatment Effectiveness ◽

Meta Analysis ◽

Progression Free Survival ◽

Evidence Base ◽

Free Survival ◽

Parametric Survival ◽

Cause Specific Survival

AbstractMultiple randomized controlled trials, each comparing a subset of competing interventions, can be synthesized by means of a network meta-analysis to estimate relative treatment effects between all interventions in the evidence base. Often there is an interest in estimating the relative treatment effects regarding time-to-event outcomes. Cancer treatment effectiveness is frequently quantified by analyzing overall survival (OS) and progression-free survival (PFS). In this paper we introduce a method for the joint network meta-analysis of PFS and OS that is based on a time-inhomogeneous tri-state (stable, progression, and death) Markov model where time-varying transition rates and relative treatment effects are modeled with known parametric survival functions or fractional polynomials. The data needed to run these analyses can be extracted directly from published survival curves. We demonstrate use by applying the methodology to a network of trials for the treatment of non-small-cell lung cancer. The proposed approach allows the joint synthesis of OS and PFS, relaxes the proportional hazards assumption, extends to a network of more than two treatments, and simplifies the parameterization of decision and cost-effectiveness analyses.

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Efficacy and Safety of Bevacizumab for Vestibular Schwannoma in Neurofibromatosis Type 2: A Systematic Review and Meta-analysis of Treatment Outcomes

10.1055/s-0040-1702498 ◽

2020 ◽

Author(s):

Victor Lu ◽

Ravindran Krishnan ◽

Christopher Graffeo ◽

Avital Perry ◽

Jamie Van Gompel ◽

...

Keyword(s):

Systematic Review ◽

Treatment Outcomes ◽

Vestibular Schwannoma ◽

Meta Analysis ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Efficacy And Safety

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Association of the Omega-3 Index with Incident Prostate Cancer with Updated Meta-Analysis: The Cooper Center Longitudinal Study

Nutrients ◽

10.3390/nu13020384 ◽

2021 ◽

Vol 13 (2) ◽

pp. 384

Author(s):

Stephen W. Farrell ◽

Laura F. DeFina ◽

Nathan L. Tintle ◽

David Leonard ◽

Kenneth H. Cooper ◽

...

Keyword(s):

Prostate Cancer ◽

Proportional Hazards ◽

Meta Analysis ◽

Continuous Variable ◽

Omega 3 ◽

Proportional Hazards Regression ◽

Time To Diagnosis ◽

Docosahexaenoic Acids ◽

Long Chain

Background: The association between long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) and prostate cancer (PC) remains unclear. Methods: We compared incident PC rates as a function of the Omega-3 Index [O3I, erythrocyte eicosapentaenoic and docosahexaenoic acids (EPA + DHA)] in 5607 men (40–80 years of age) seen at the Cooper Clinic who were free of PC at baseline. The average follow-up was 5.1 ± 2.8 years until censoring or reporting a new PC diagnosis. Proportional hazards regression was used to model the linear association between baseline O3I and the age-adjusted time to diagnosis. A meta-analysis of n-3 PUFA biomarker-based studies and incident PC was updated with the present findings. Results: A total of 116 cases of incident PC were identified. When O3I was examined as a continuous variable, the age-adjusted hazard ratio (HR) (95% CI) was 0.98 (0.89, 1.07; p = 0.25) for each 1% increment in the O3I. The updated meta-analysis with 10 biomarker-based studies found no significant relationship between EPA or DHA levels and risk for PC. Conclusions: We find no evidence in this study nor in a meta-analysis of similar studies that consuming n-3 PUFA-rich fish or using fish oil supplements affects the risk of PC.

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Diabetes among tuberculosis patients and its impact on tuberculosis treatment in South Asia: a systematic review and meta-analysis

Scientific Reports ◽

10.1038/s41598-021-81057-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sanju Gautam ◽

Nipun Shrestha ◽

Sweta Mahato ◽

Tuan P. A. Nguyen ◽

Shiva Raj Mishra ◽

...

Keyword(s):

Systematic Review ◽

Sri Lanka ◽

Treatment Failure ◽

South Asia ◽

Treatment Outcomes ◽

Meta Analysis ◽

Tb Treatment ◽

Effect Model ◽

Pooled Prevalence ◽

The Impact

AbstractThe escalating burden of diabetes is increasing the risk of contracting tuberculosis (TB) and has a pervasive impact on TB treatment outcomes. Therefore, we conducted this systematic review and meta-analysis to examine the burden of diabetes among TB patients and assess its impact on TB treatment in South Asia (Afghanistan, Bangladesh, Bhutan, Maldives, Nepal, India, Pakistan, and Sri Lanka). PubMed, Excerpta Medica Database (EMBASE), and CINAHL databases were systematically searched for observational (cross-sectional, case–control and cohort) studies that reported prevalence of diabetes in TB patients and published between 1 January 1980 and 30 July 2020. A random-effect model for computing the pooled prevalence of diabetes and a fixed-effect model for assessing its impact on TB treatment were used. The review was registered with PROSPERO number CRD42020167896. Of the 3463 identified studies, a total of 74 studies (47 studies from India, 10 from Pakistan, four from Nepal and two from both Bangladesh and Sri-Lanka) were included in this systematic review: 65 studies for the prevalence of diabetes among TB patients and nine studies for the impact of diabetes on TB treatment outcomes. The pooled prevalence of diabetes in TB patients was 21% (95% CI 18.0, 23.0; I2 98.3%), varying from 11% in Bangladesh to 24% in Sri-Lanka. The prevalence was higher in studies having a sample size less than 300 (23%, 95% CI 18.0, 27.0), studies conducted in adults (21%, 95% CI 18.0, 23.0) and countries with high TB burden (21%, 95% CI 19.0, 24.0). Publication bias was detected based on the graphic asymmetry of the funnel plot and Egger’s test (p < 0.001). Compared with non-diabetic TB patients, patients with TB and diabetes were associated with higher odds of mortality (Odds Ratio (OR) 1.7; 95% CI 1.2, 2.51; I2 19.4%) and treatment failure (OR 1.7; 95% CI 1.1, 2.4; I2 49.6%), but not associated with Multi-drug resistant TB (OR 1.0; 95% CI 0.6, 1.7; I2 40.7%). This study found a high burden of diabetes among TB patients in South Asia. Patients with TB-diabetes were at higher risk of treatment failure and mortality compared to TB alone. Screening for diabetes among TB patients along with planning and implementation of preventive and curative strategies for both TB and diabetes are urgently needed.

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The effect of organizational arrangements on people with type 2 diabetes and foot ulcers in Scotland

European Journal of Public Health ◽

10.1093/eurpub/ckaa166.048 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

B Meza-Torres ◽

S Cunningham ◽

G Leese ◽

S de Lusignan ◽

F Carinci

Keyword(s):

Type 2 Diabetes ◽

Proportional Hazards ◽

Meta Analysis ◽

Foot Ulcers ◽

Case Mix ◽

Hazard Ratios ◽

Standard Set ◽

National Databases ◽

Diabetes Register

Abstract Background A recent meta-analysis showed that specific organizational arrangements may decrease the risk of lower extremity amputations among subjects with type 2 diabetes (T2D) affected by foot ulcers (DFU). We aim to translate these results into algorithms to extract cohorts from routine data from the Scottish Diabetes Register (SCI-Diabetes). We used models to estimate the actual effectiveness of different practices and discuss transferability of the approach to other contexts e.g. the English database of general practitioners. Methods A multidisciplinary team mapped the Scottish database to the outputs of meta-analysis, adopting the standard set for diabetes of the International Consortium for Health Outcomes Measurement. Algorithms extracted a standardized retrospective cohort for 2016-2019. Records up to 5 years before first entry into the cohort were used for case-mix. Proportional hazards were used for multivariate modelling. Results were expressed in terms of hazard ratios with 95% confidence intervals. Results In 2016-2019, a total of 275,386 adults with T2D were registered in SCI-diabetes. Among them, 1,843 (0.66%) had an amputation, of which 777(42%) had a previous DFU diagnosis. We applied the criteria derived from meta-analysis and the definitions of the diabetes standard set to calculate columns included in the case-mix for predictive modelling. The refinement of multivariate models is still in progress and all adjusted hazard ratios will be included in the revised version of this abstract to be presented at the Conference. Conclusions Epidemiological evidence on diabetes care can be directly translated into algorithms for extracting dynamic cohorts from high quality diabetes registers. Results can be generalised to different types of national databases, adjusting for the heterogeneous dataset structures. Key messages Sets of criteria and definitions adopted for the conduction of meta-analyses can be translated into algorithms to extract cohorts and test models of real-world evidence from routine national databases. The Scottish Diabetes Register was successfully used to confirm the effectiveness of organizational arrangements in diabetes in normal practice.

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How I treat double-hit lymphoma

Blood ◽

10.1182/blood-2017-04-737320 ◽

2017 ◽

Vol 130 (5) ◽

pp. 590-596 ◽

Cited By ~ 50

Author(s):

Jonathan W. Friedberg

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Involvement ◽

B Cell Lymphoma ◽

World Health ◽

Large B Cell Lymphoma ◽

Double Hit Lymphoma ◽

Increased Risk ◽

Double Hit ◽

Large B Cell

Abstract The 2016 revision of the World Health Organization (WHO) classification for lymphoma has included a new category of lymphoma, separate from diffuse large B-cell lymphoma, termed high-grade B-cell lymphoma with translocations involving myc and bcl-2 or bcl-6. These lymphomas, which occur in <10% of cases of diffuse large B-cell lymphoma, have been referred to as double-hit lymphomas (or triple-hit lymphomas if all 3 rearrangements are present). It is important to differentiate these lymphomas from the larger group of double-expressor lymphomas, which have increased expression of MYC and BCL-2 and/or BCL-6 by immunohistochemistry, by using variable cutoff percentages to define positivity. Patients with double-hit lymphomas have a poor prognosis when treated with standard chemoimmunotherapy and have increased risk of central nervous system involvement and progression. Double-hit lymphomas may arise as a consequence of the transformation of the underlying indolent lymphoma. There are no published prospective trials in double-hit lymphoma, however retrospective studies strongly suggest that aggressive induction regimens may confer a superior outcome. In this article, I review my approach to the evaluation and treatment of double-hit lymphoma, with an eye toward future clinical trials incorporating rational targeted agents into the therapeutic armamentarium.

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1388. Dose Discrimination for ASN100: Bridging from Rabbit Survival Data to Predicted Activity in Humans Using a Minimal Physiologically Based Pharmacokinetic (mPBPK) Model

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1219 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S426-S426

Author(s):

Christopher M Rubino ◽

Lukas Stulik ◽

Harald Rouha ◽

Zehra Visram ◽

Adriana Badarau ◽

...

Keyword(s):

Survival Data ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Model ◽

Virulent Strain ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Simulated Patients ◽

Research Support ◽

Mpbpk Model

Abstract Background ASN100 is a combination of two co-administered fully human monoclonal antibodies (mAbs), ASN-1 and ASN-2, that together neutralize the six cytotoxins critical to S. aureus pneumonia pathogenesis. ASN100 is in development for prevention of S. aureus pneumonia in mechanically ventilated patients. A pharmacometric approach to dose discrimination in humans was taken in order to bridge from dose-ranging, survival studies in rabbits to anticipated human exposures using a mPBPK model derived from data from rabbits (infected and noninfected) and noninfected humans [IDWeek 2017, Poster 1849]. Survival in rabbits was assumed to be indicative of a protective effect through ASN100 neutralization of S. aureus toxins. Methods Data from studies in rabbits (placebo through 20 mg/kg single doses of ASN100, four strains representing MRSA and MSSA isolates with different toxin profiles) were pooled with data from a PK and efficacy study in infected rabbits (placebo and 40 mg/kg ASN100) [IDWeek 2017, Poster 1844]. A Cox proportional hazards model was used to relate survival to both strain and mAb exposure. Monte Carlo simulation was then applied to generate ASN100 exposures for simulated patients given a range of ASN100 doses and infection with each strain (n = 500 per scenario) using a mPBPK model. Using the Cox model, the probability of full protection from toxins (i.e., predicted survival) was estimated for each simulated patient. Results Cox models showed that survival in rabbits is dependent on both strain and ASN100 exposure in lung epithelial lining fluid (ELF). At human doses simulated (360–10,000 mg of ASN100), full or substantial protection is expected for all four strains tested. For the most virulent strain tested in the rabbit pneumonia study (a PVL-negative MSSA, Figure 1), the clinical dose of 3,600 mg of ASN100 provides substantially higher predicted effect relative to lower doses, while doses above 3,600 mg are not predicted to provide significant additional protection. Conclusion A pharmacometric approach allowed for the translation of rabbit survival data to infected patients as well as discrimination of potential clinical doses. These results support the ASN100 dose of 3,600 mg currently being evaluated in a Phase 2 S. aureus pneumonia prevention trial. Disclosures C. M. Rubino, Arsanis, Inc.: Research Contractor, Research support. L. Stulik, Arsanis Biosciences GmbH: Employee, Salary. H. Rouha, 3Arsanis Biosciences GmbH: Employee, Salary. Z. Visram, Arsanis Biosciences GmbH: Employee, Salary. A. Badarau, Arsanis Biosciences GmbH: Employee, Salary. S. A. Van Wart, Arsanis, Inc.: Research Contractor, Research support. P. G. Ambrose, Arsanis, Inc.: Research Contractor, Research support. M. M. Goodwin, Arsanis, Inc.: Employee, Salary. E. Nagy, Arsanis Biosciences GmbH: Employee, Salary.

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