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OBJECTIVES:The optimal approach for resuscitation in septic shock remains unclear despite multiple randomized controlled trials (RCTs). Our objective was to investigate whether previously uncharacterized variation across individuals in their response to resuscitation strategies may contribute to conflicting average treatment effects in prior RCTs. DESIGN:We randomly split study sites from the Australian Resuscitation of Sepsis Evaluation (ARISE) and Protocolized Care for Early Septic Shock (ProCESS) trials into derivation and validation cohorts. We trained machine learning models to predict individual absolute risk differences (iARDs) in 90-day mortality in derivation cohorts and tested for heterogeneity of treatment effect (HTE) in validation cohorts and swapped these cohorts in sensitivity analyses. We fit the best-performing model in a combined dataset to explore roles of patient characteristics and individual components of early goal-directed therapy (EGDT) to determine treatment responses. SETTING:Eighty-one sites in Australia, New Zealand, Hong Kong, Finland, Republic of Ireland, and the United States. PATIENTS:Adult patients presenting to the emergency department with severe sepsis or septic shock. INTERVENTIONS:EGDT vs. usual care. MEASUREMENTS AND MAIN RESULTS:A local-linear random forest model performed best in predicting iARDs. In the validation cohort, HTE was confirmed, evidenced by an interaction between iARD prediction and treatment (p< 0.001). When patients were grouped based on predicted iARDs, treatment response increased from the lowest to the highest quintiles (absolute risk difference [95% CI], –8% [–19% to 4%] and relative risk reduction, 1.34 [0.89–2.01] in quintile 1 suggesting harm from EGDT, and 12% [1–23%] and 0.64 [0.42–0.96] in quintile 5 suggesting benefit). Sensitivity analyses showed similar findings. Pre-intervention albumin contributed the most to HTE. Analyses of individual EGDT components were inconclusive. CONCLUSIONS:Treatment response to EGDT varied across patients in two multicenter RCTs with large benefits for some patients while others were harmed. Patient characteristics, including albumin, were most important in identifying HTE.
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Technical note: Optimal allocation of limited proton therapy resources using model‐based patient selection
Abstract PurposeWe consider the following scenario: A radiotherapy clinic has a limited number of proton therapy slots available each day to treat cancer patients of a given tumor site. The clinic's goal is to minimize the expected number of complications in the cohort of all patients of that tumor site treated at the clinic, and thereby maximize the benefit of its limited proton resources. MethodsTo address this problem, we extend the normal tissue complication probability (NTCP) model–based approach to proton therapy patient selection to the situation of limited resources at a given institution. We assume that, on each day, a newly diagnosed patient is scheduled for treatment at the clinic with some probability and with some benefit from protons over photons, which is drawn from a probability distribution. When a new patient is scheduled for treatment, a decision for protons or photons must be made, and a patient may wait only for a limited amount of time for a proton slot becoming available. The goal is to determine the thresholds for selecting a patient for proton therapy, which optimally balance the competing goals of making use of all available slots while not blocking slots with patients with low benefit. This problem can be formulated as a Markov decision process (MDP) and the optimal thresholds can be determined via a value‐policy iteration method. ResultsThe optimal thresholds depend on the number of available proton slots, the average number of patients under treatment, and the distribution of values. In addition, the optimal thresholds depend on the current utilization of the facility. For example, if one proton slot is available and a second frees up shortly, the optimal threshold is lower compared to a situation where all but one slot remain blocked for longer. ConclusionsMDP methodology can be used to augment current NTCP model–based patient selection methods to the situation that, on any given day, the number of proton slots is limited. The optimal threshold then depends on the current utilization of the proton facility. Although, the optimal policy yields only a small nominal benefit over a constant threshold, it is more robust against variations in patient load.
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- Award ID(s):
- 1847865
- PAR ID:
- 10370350
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Medical Physics
- Volume:
- 49
- Issue:
- 8
- ISSN:
- 0094-2405
- Page Range / eLocation ID:
- p. 4980-4987
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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