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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2021)

This dissertation addresses positivity assumption violations in observational longitudinal studies with a large number of time-varying covariates by using the data adaptive parameter estimation techniques of Longitudinal Targeted Maximum Likelihood Estimation (LTMLE) and simulation-based analysis for causal inference in complex longitudinal data settings. The positivity assumption violation poses a problem of identifiability from observed data. It often goes undiagnosed and can threaten valid inference. We develop a new semiparametric bootstrap simulation tool, simreal, for longitudinal data structures designed to simulate data that ”matches” the original, real data in its characteristics. We introduce a variance estimator based approach for detecting positivity assumption violations in complex longitudinal data settings and a roadmap for implementing mitigation options using an extensive simreal simulation analysis. We also introduce a practical positivity violation detection test that can be readily conducted in the ltmle package and can be used to alert users to severe positivity violations causing unreliable statistical inference. Furthermore, in the case of severe positivity assumption violations, we introduce a set of longitudinal realistic rules defined so that if the estimated conditional probability of receiving a treatment, given past treatments and covariates, falls under some user-supplied probability threshold level α, the rule assigns an alternative, viable, and well supported choice. Causal effect models under realistic treatment rules are fully identifiable from the observed data. These results were applied to the longitudinal study of around 3000 hypotensive patients in intensive care units at the onset of septic shock. The goal was to improve the current protocol and determine the optimal time to start the vasopressor treatment. Our results show that introducing vasopressors in the third hour of the critical six hour time period reduces hospital mortality. This result is statistically significant.

    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2020)

    Introduction

    The benefits and risks of low-dose hydrocortisone in patients with septic shock have been investigated in numerous randomised controlled trials and trial-level meta-analyses. Yet, the routine use of this treatment remains controversial. To overcome the limitations of previous meta-analyses inherent to the use of aggregate data, we will perform an individual patient data meta-analysis (IPDMA) on the effect of hydrocortisone with or without fludrocortisone compared with placebo or usual care on 90-day mortality and other outcomes in patients with septic shock.

    Methods and analysis

    To assess the benefits and risks of hydrocortisone, with or without fludrocortisone for adults with septic shock, we will search major electronic databases from inception to September 2020 (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Latin American Caribbean Health Sciences Literature), complimented by a search for unpublished trials. The primary analysis will compare hydrocortisone with or without fludrocortisone to placebo or no treatment in adult patients with septic shock. Secondary analyses will compare hydrocortisone to placebo (or usual care), hydrocortisone plus fludrocortisone to placebo (or usual care), and hydrocortisone versus hydrocortisone plus fludrocortisone. The primary outcome will be all cause mortality at 90 days. We will conduct both one-stage IPDMA using mixed-effect models and machine learning with targeted maximum likelihood analyses. We will assess the risk of bias related to unshared data and related to the quality of individual trial.

    Ethics and dissemination

    This IPDMA will use existing data from completed randomised clinical trials and will comply with the ethical and regulatory requirements regarding data sharing for each of the component trials. The findings of this study will be submitted for publication in a peer-review journal with straightforward policy for open access.

    Prospero registration number

    CRD42017062198.
      Cover page: Effects of low-dose hydrocortisone and hydrocortisone plus fludrocortisone in adults with septic shock: a protocol for a systematic review and meta-analysis of individual participant dataCreative Commons 'BY-NC' version 4.0 license
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