Separable effects for adherence.

Comparing different medications is complicated when adherence to these medications differs. We can overcome the adherence issue by assessing effectiveness under sustained use, as in usual causal 'per-protocol' estimands. However, when sustained use is challenging to satisfy in practice, the usefulness of these estimands can be limited. Here we propose a different class of estimands: separable effects for adherence. These estimands compare modified medications, holding fixed a component responsible for non-adherence. Under assumptions about treatment components' mechanisms of effect, a separable effects estimand can quantify the effectiveness of medication initiation strategies on an outcome of interest under the adherence mechanism of one of the medications. These assumptions are amenable to interrogation by subject-matter experts and can be evaluated using causal graphs. We describe an algorithm for constructing causal graphs for separable effects, illustrate how these graphs can be used to reason about assumptions required for identification, and provide semi-parametric weighted estimators.

Estimating the Effect of Bariatric Surgery on Cardiovascular Events Using Observational Data?

BACKGROUND: Observational studies have reported strongly protective effects of bariatric surgery on cardiovascular disease, but with oversimplified definitions of the intervention, eligibility criteria, and follow-up, which deviate from those in a randomized trial. We describe an attempt to estimate the effect of bariatric surgery on cardiovascular disease without introducing these sources of bias, which may not be entirely possible with existing observational data. METHODS: We propose two target trials among persons with diabetes: (1) bariatric operation (vs. no operation) among individuals who have undergone preoperative preparation (lifestyle modifications and screening) and (2) preoperative preparation and a bariatric operation (vs. neither preoperative nor operative component). We emulated both target trials using observational data of US veterans. RESULTS: Comparing bariatric surgery with no surgery (target trial #1; 8,087 individuals), the 7-year cardiovascular risk was 18.0% (95% CI = 6.9, 32.7) in the surgery group and 18.9% (95% CI = 17.7, 20.1) in the no-surgery group (risk difference -0.9, 95% CI = -12.0, 14.0). Comparing preoperative components plus surgery vs. neither (target trial #2; 10,065 individuals), the 7-year cardiovascular risk was 17.4% (95% CI = 13.6, 22.0) in the surgery group and 18.8% (95% CI = 17.8, 19.9) in the no-surgery group (risk difference -1.4, 95% CI = -5.1, 3.2). Body mass index and hemoglobin A1c were reduced with bariatric interventions in both emulations. CONCLUSIONS: Within limitations of available observational data, our estimates do not provide evidence that bariatric surgery reduces cardiovascular disease and support equipoise for a randomized trial of bariatric surgery for cardiovascular disease prevention.

The Prevalence of Sentinel Lymph Node Positivity and Implications for the Utility of Frozen Section Diagnosis Following Neoadjuvant Systemic Therapy in Patients with Clinically Node-Negative HER2-Positive or Triple-Negative Breast Cancer.

BACKGROUND: Axillary dissection is the standard of care for patients with positive sentinel lymph nodes (SLNs) following neoadjuvant systemic therapy. Frozen section can provide intraoperative information regarding the need for axillary dissection during the index operation. However, there are limited data on the utility of frozen section in patients with clinically node-negative (cN0) HER2-positive or triple-negative breast cancer. METHODS: We conducted a single-institution observational cohort study including patients with non-inflammatory, cN0, HER2-positive or triple-negative breast cancer treated with neoadjuvant systemic therapy between 2015 and 2019. We estimated the prevalence of SLN positivity and the diagnostic test characteristics of SLN frozen section. RESULTS: Overall, 662 patients were eligible for inclusion, and 44 patients had one or more positive SLNs (prevalence: 6.6%, 95% confidence interval [CI] 4.9-8.8). There were 490 (74.0%) patients who had intraoperative frozen section, and 19 (3.9%) tested positive among 33 (6.7%) with positive final pathology. Frozen section sensitivity was 57.6% (95% CI 39.2-74.5), specificity was 100% (95% CI 99.2-100), positive predictive value was 100% (95% CI 82.4-100), and negative predictive value was 97.0% (95% CI 95.1-98.4). The sensitivity of frozen section for detection of micrometastases or isolated tumor cells was 35.3% (95% CI 14.2-61.7). CONCLUSION: In patients with cN0 HER2-positive or triple-negative breast cancer who have been treated with neoadjuvant therapy, positive SLNs are uncommon and frozen section sensitivity is modest. Decisions to defer SLN evaluation to final pathology, which may be reasonable in many settings, can be informed, in part, by these findings.

Self-Reported Management of Inflammatory Breast Cancer Among the American Society of Breast Surgeons Membership: Consensus and Opportunities.

BACKGROUND: Inflammatory breast cancer (IBC) is rare and biologically aggressive. We sought to assess diagnostic and management strategies among the American Society of Breast Surgeons (ASBrS) membership. PATIENTS AND METHODS: An anonymous survey was distributed to ASBrS members from March to May 2023. The survey included questions about respondents' demographics and information related to stage III and IV IBC management. Agreement was defined as a shared response by >80% of respondents. In areas of disagreement, responses were stratified by years in practice, fellowship training, and annual IBC patient volume. RESULTS: The survey was administered to 2337 members with 399 (17.1%) completing all questions and defining the study cohort. Distribution of years in practice was 26.0% 0-10 years, 26.6% 11-20 years and 47.4% > 20 years. Overall, 51.2% reported surgical oncology or breast fellowship training, 69.2% maintain a breast-only practice, and 73.5% treat < 5 IBC cases/year. Agreement was identified in diagnostic imaging, trimodal therapy, and mastectomy with wide skin excision for stage III IBC. Lack of agreement was identified in surgical management of the axilla; respondents with < 10 years in practice or fellowship training were more likely to perform axillary dissection for cN0-N2 stage III IBC. Locoregional management of stage IV IBC was variable. CONCLUSIONS: Among ASBrS members, there is consensus in diagnostic evaluation, treatment sequencing and surgical approach to the breast in stage III IBC. Differences exist in surgical management of the cN0-2 axilla with uptake of de-escalation strategies. Clinical trials are needed to evaluate oncologic safety of de-escalation in this high-risk population.

Addressing the longitudinal components of surgical treatments.

Despite their pre- and postoperative components, surgical treatment strategies have typically been cast as point interventions in causal inference research. When longitudinal perioperative components affect outcomes of interest, leaving them unspecified or failing to measure adherence to them complicates the interpretation of effect estimates. Inspired by two recent landmark trials that assessed the risk of stroke or death after transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR), the PARTNER 3 trial and the Evolut Low Risk trial, we discuss possible ways that different postoperative therapies in treatment arms and incomplete adherence to those therapies can impact the interpretation of intention-to-treat effect estimates in surgical trials. We argue that surgical treatments are not necessarily point interventions, and make recommendations for improving the design and analysis of trials involving surgical interventions. Central to these recommendations is the need for investigators to specify and report adherence to longitudinal perioperative treatment components.

Colonoscopy Needs for Implementation of a Colorectal Cancer Screening Program in Ukraine.

BACKGROUND: In Ukraine, there is no established colorectal cancer screening program. We aimed to project the number of screening colonoscopies needed for implementation of various CRC screening strategies in Ukraine. METHODS: We modified a previously developed Markov microsimulation model to reflect the natural history of adenoma and CRC progression among average-risk 50-74-year-olds. We simulated colonoscopies needed for the following screening strategies: no screening, fecal occult blood test yearly, FOBT yearly with flexible sigmoidoscopy every 5 years, FS every 5 years, fecal immunohistochemistry test (FIT) yearly, or colonoscopy every 10 years. Assuming 80% screening adherence, we estimated colonoscopies required at 1 and 5 years depending on the implementation rate. In one-way sensitivity analyses, we varied implementation rate, screening adherence, sensitivity, and specificity. RESULTS: Assuming an 80% screening adherence and complete implementation (100%), besides a no screening strategy, the fewest screening colonoscopies are needed with an FOBT program, requiring on average 6,600 and 26,800 colonoscopies per 100,000 persons at 1 and 5 years post-implementation, respectively. The most screening colonoscopies are required with a colonoscopy program, requiring on average 76,600 and 101,000 colonoscopies per 100,000 persons at 1 and 5 years post-implementation, respectively. In sensitivity analyses, the biggest driver of number of colonoscopies needed was screening adherence. CONCLUSIONS: The number of colonoscopies needed and therefore the potential strain on the healthcare system vary substantially by screening test. These findings can provide valuable information for stakeholders on equipment needs when implementing a national screening program in Ukraine.

Strengthening Health Services Research Using Target Trial Emulation: An Application to Volume-Outcomes Studies.

The number of operations that surgeons have previously performed is associated with their patients' outcomes. However, this association may not be causal, because previous studies have often been cross-sectional and their analyses have not considered time-varying confounding or positivity violations. In this paper, using the example of surgeons who perform coronary artery bypass grafting, we describe (hypothetical) target trials for estimation of the causal effect of the surgeons' operative volumes on patient mortality. We then demonstrate how to emulate these target trials using data from US Medicare claims and provide effect estimates. Our target trial emulations suggest that interventions on physicians' volume of coronary artery bypass grafting operations have little effect on patient mortality. The target trial framework highlights key assumptions and draws attention to areas of bias in previous observational analyses that deviated from their implicit target trials. The principles of the presented methodology may be adapted to other scenarios of substantive interest in health services research.

Association and interplay of surgeon and hospital volume with mortality after open abdominal aortic aneurysm repair in the modern era.

OBJECTIVE: Operative volume has been used as a marker of quality. Research from previous decades has suggested minimum open abdominal aortic aneurysm (AAA) repair volume requirements for surgeons of 9 to 13 open AAA repairs annually and for hospitals of 18 open AAA repairs annually to purportedly achieve acceptable results. Given concerns regarding the decreased frequency of open repairs in the endovascular era, we examined the association of surgeon and hospital volume with the 30- and 90-day mortality in the Vascular Quality Initiative (VQI) registry. METHODS: Patients who had undergone elective open AAA repair from 2013 to 2018 were identified in the VQI registry. We performed a cross-sectional evaluation of the association between the average hospital and surgeon volume and 30-day postoperative mortality using a hierarchical Bayesian model. Cross-level interactions were permitted, and random surgeon- and hospital-level intercepts were used to account for clustering. The mortality results were adjusted by standardizing to the observed distribution of relevant covariates in the overall cohort. The outcomes were compared to the Society for Vascular Surgery guidelines recommended criteria of <5% perioperative mortality. RESULTS: A total of 3078 patients had undergone elective open AAA repair by 520 surgeons at 128 hospitals. The 30- and 90-day risks of postoperative mortality were 4.1% (n = 126) and 5.4% (n = 166), respectively. The mean surgeon volume and hospital volume both correlated inversely with the 30-day mortality. Averaged across all patients and hospitals, we found a 96% probability that surgeons who performed an average of four or more repairs per year achieved <5% 30-day mortality. Substantial interplay was present between surgeon volume and hospital volume. For example, at lower volume hospitals performing an average of five repairs annually, <5% 30-day mortality would be expected 69% of the time for surgeons performing an average of three operations annually. In contrast, at higher volume hospitals performing an average of 40 repairs annually, a <5% 30-day mortality would be expected 96% of the time for surgeons performing an average of three operations annually. As hospital volume increased, a diminishing difference occurred in 30-day mortality between lower and higher volume surgeons. Likewise, as surgeon volume increased, a diminishing difference was found in 30-day mortality between the lower and higher volume hospitals. CONCLUSIONS: Surgeons and hospitals in the VQI registry achieved mortality outcomes of <5% (Society for Vascular Surgery guidelines), with an average surgeon volume that was substantially lower compared with previous reports. Furthermore, when considering the development of minimal surgeon volume guidelines, it is important to contextualize the outcomes within the hospital volumes.

Estimating the effect of increasing utilization of living donor liver transplantation using observational data.

There has been a recent increase in enthusiasm for expansion of living donor liver transplantation (LDLT) programmes. Using all adults initially placed on the waiting list in the United States, we estimated the risk of overall mortality under national strategies which differed in their utilization of LDLT. We used a generalization of inverse probability weighting which can estimate the effect of interventions in the setting of finite resources. From 2005 to 2015, 93 812 eligible individuals were added to the waitlist: 51 322 received deceased donor grafts while 1970 underwent LDLT. Individuals who underwent LDLT had more favourable prognostic factors, including lower mean MELD score at transplant (14.6 vs. 20.5). The 1-year, 5-year and 10-year cumulative incidence of death under the current level of LDLT utilization were 18.0% (95% CI: 17.8, 18.3%), 41.2% (95% CI: 40.8, 41.5%) and 57.4% (95% CI: 56.9, 57.9%) compared to 17.9% (95% CI: 17.7, 18.2%), 40.6% (95% CI: 40.2, 40.9%) and 56.4% (95% CI: 55.8, 56.9%) under a strategy which doubles LDLT utilization. Expansion of LDLT utilization would have a measurable, modest effect on the risk of mortality for the entire cohort of individuals who begin on the transplant waiting list.

Opioid Prescription Patterns for Children Following Laparoscopic Appendectomy.

OBJECTIVE: To describe variability in and consequences of opioid prescriptions following pediatric laparoscopic appendectomy. SUMMARY BACKGROUND DATA: Postoperative opioid prescribing patterns may contribute to persistent opioid use in both adults and children. METHODS: We included children <18 years enrolled as dependents in the Military Health System Data Repository who underwent uncomplicated laparoscopic appendectomy (2006-2014). For the primary outcome of days of opioids prescribed, we evaluated associations with discharging service, standardized to the distribution of baseline covariates. Secondary outcomes included refill, Emergency Department (ED) visit for constipation, and ED visit for pain. RESULTS: Among 6732 children, 68% were prescribed opioids (range = 1-65 d, median = 4 d, IQR = 3-5 d). Patients discharged by general surgery services were prescribed 1.23 (95% CI = 1.06-1.42) excess days of opioids, compared with those discharged by pediatric surgery services. Risk of ED visit for constipation (n = 61, 1%) was increased with opioid prescription [1-3 d, risk ratio (RR) = 2.46, 95% CI = 1.31-5.78; 4-6 d, RR = 1.89, 95% CI = 0.83-4.67; 7-14 d, RR = 3.75, 95% CI = 1.38-9.44; >14 d, RR = 6.27, 95% CI = 1.23-19.68], compared with no opioid prescription. There was similar or increased risk of ED visit for pain (n = 319, 5%) with opioid prescription [1-3 d, RR = 1.00, 95% confidence interval (CI) = 0.74-1.32; 4-6 d, RR = 1.31, 95% CI = 0.99-1.73; 7-14 d, RR = 1.52, 95% CI = 1.00-2.18], compared with no opioid prescription. Likewise, need for refill (n = 157, 3%) was not associated with initial days of opioid prescribed (reference 1-3 d; 4-6 d, RR = 0.96, 95% CI = 0.68-1.35; 7-14 d, RR = 0.91, 95% CI = 0.49-1.46; and >14 d, RR = 1.22, 95% CI = 0.59-2.07). CONCLUSIONS: There was substantial variation in opioid prescribing patterns. Opioid prescription duration increased risk of ED visits for constipation, but not for pain or refill.

A Graphical Description of Partial Exchangeability.

Partial exchangeability is sufficient for the identification of some causal effects of interest. Here we review the use of common graphical tools and the sufficient component cause model in the context of partial exchangeability. We illustrate the utility of single world intervention graphs (SWIGs) in depicting partial exchangeability and provide an illustrative example of when partial exchangeability might hold in the absence of complete exchangeability.

Adjusting for adherence in randomized trials when adherence is measured as a continuous variable: An application to the Lipid Research Clinics Coronary Primary Prevention Trial.

BACKGROUND: Clinicians and patients may be more interested in per-protocol effect estimates than intention-to-treat effect estimates from randomized trials. However, per-protocol effect estimates may be biased due to insufficient adjustment for prognostic factors that predict adherence. Adjustment for this bias is possible when appropriate methods, such as inverse probability weighting, are used. But, when adherence is measured as a continuous variable, constructing these weights can be challenging. METHODS: In the placebo arm of the Lipid Research Clinics Coronary Primary Prevention Trial, we estimated the 7-year cumulative incidence of coronary heart disease under 100% adherence and 0% adherence to placebo. We used dose-response discrete-hazards models with inverse probability weighting to adjust for pre- and post-randomization covariates. We considered several continuous distributions for constructing the inverse probability weights. RESULTS: The risk difference estimate for 100% adherence compared with 0% adherence ranged from -7.7 to -6.1 percentage points without adjustment for baseline and post-baseline covariates, and ranged from -1.8 to 2.2 percentage points with adjustment using inverse probability weights, depending on the dose-response model and inverse probability weight distribution used. CONCLUSIONS: Methods which appropriately adjust for time-varying post-randomization variables can explain away much of the bias in the "effect" of adherence to placebo. When considering continuous adherence, investigators should consider several models as estimates may be sensitive to the model chosen.

The meaning of confounding adjustment in the presence of multiple versions of treatment: an application to organ transplantation.

Causal inference for treatments with many versions requires a careful specification of the versions of treatment. Specifically, the existence of multiple relevant versions of treatment has implications for the selection of confounders. To illustrate this, we estimate the effect of organ transplantation using grafts from donors who died due to anoxic drug overdose, on recipient graft survival in the US. We describe how explicitly outlining the target trial (i.e. the hypothetical randomized trial which would answer the causal question of interest) to be emulated by an observational study analysis helps conceptualize treatment versions, guides selection of appropriate adjustment variables, and helps clarify the settings in which causal effects of compound treatments will be of value to decision-makers.

Long-term oncological outcomes following emergency resection of colon cancer.

PURPOSE: The relationship between emergency colon cancer resection and long-term oncological outcomes is not well understood. Our objective was to characterize the impact of emergency resection for colon cancer on disease-free and overall patient survival. METHODS: Data on patients undergoing resection for colon cancer from 2006 to 2015 were collected from a prospectively maintained clinical and administrative database. The median follow-up time was 4.4 years. Cox proportional hazards models were used to estimate the hazard ratios for recurrence and death for patients treated with surgery for an emergent presentation. Differences in initiation of, and timeliness of, adjuvant chemotherapy between emergently and electively treated patients were also examined. RESULTS: Of the 1180 patients who underwent resection for stages I, II, or III colon cancer, 158 (13%) had emergent surgery. After adjustment for patient, tumor, and treatment characteristics, the HR for recurrence was 1.64 (95% CI 1.12-2.40) and for death was 1.47 (95% CI 1.10-1.97). After adjustment for tumor characteristics, patients who underwent emergency resection were similarly likely to receive adjuvant chemotherapy (OR 1.1; 95% CI 0.70-1.76). The time from surgery to initiation of adjuvant chemotherapy was also similar between the groups. CONCLUSIONS: Emergency surgery for localized or regional colon cancer is associated with a greater risk of recurrence and death. This association does not appear to be due to differences in adjuvant treatment. A focus on screening and colon cancer awareness in order to reduce emergency presentations is warranted.

Do Moderate Surgical Treatment Delays Influence Survival in Colon Cancer?

BACKGROUND: Studies examining treatment delay and survival after surgical treatment of colon cancer have varied in quality and outcome, with little evidence available regarding the safety of longer surgical treatment wait times. OBJECTIVE: Our study examined the effect of surgical treatment wait times on survival for patients with stage I to III colon cancer. DESIGN: A subset cohort analysis was performed using data from a prospectively maintained database. SETTINGS: The study was conducted at a tertiary referral center. PATIENTS: Data on all of the patients undergoing elective surgery for stage I to III colon cancer from 2006 to 2015 were collected from a prospectively maintained clinical and administrative database. MAIN OUTCOME MEASURES: We examined the impact of prolonged wait time to surgery on disease-free and overall survival. Patients were divided into 2 groups based on a treatment wait time of ≤30 or >30 days and were compared using a Cox proportional hazards model. A subgroup analysis was performed using alternative treatment delay cutoffs of 60 and 90 days. RESULTS: There were 908 patients with stage I to III colon cancer treated over the study period, with a median treatment wait time of 38 days (interquartile range, 21-61 days); 368 patients were treated within 30 days, and 540 were treated beyond 30 days from diagnosis. In adjusted multivariate analysis, a treatment delay of >30 days was not associated with decreased disease-free survival (HR = 0.89 (95% CI, 0.61-1.3); p = 0.52) or overall survival (HR = 0.82 (95% CI, 0.63-1.1); p = 0.16). Likewise, subgroup analysis using alternative treatment delay cutoffs of 60 and 90 days did not demonstrate an adverse effect on survival. LIMITATIONS: This study was limited by retrospective analysis. CONCLUSIONS: Despite longer median treatment wait times from diagnosis to surgery, with the majority of patients exceeding 30 days and many experiencing delays of 2 to 3 months, no adverse impact on survival was observed. Patients who require additional consultations or investigations preoperatively may safely have their surgery moderately delayed to minimize their perioperative risk without any evidence that this will compromise treatment outcomes. See Video Abstract at http://links.lww.com/DCR/A397.

Systemic Metronidazole May Not Reduce Posthemorrhoidectomy Pain: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Hemorrhoidectomy is associated with significant postoperative pain. Oral metronidazole has been recommended as an adjunct to improve posthemorrhoidectomy analgesia. OBJECTIVE: This study aimed to evaluate the impact of oral metronidazole on patient-reported pain following hemorrhoidectomy. DATA SOURCES: We conducted a systematic search in the MEDLINE, EMBASE, ISI Web of Science, and Cochrane Central Register of Controlled Trials databases. STUDY SELECTION: Randomized controlled trials examining adults who underwent surgical hemorrhoidectomy were included. Participants in an active intervention group received oral metronidazole postoperatively, and those in a control group received placebo or usual care. Postoperative pain was assessed for at least 3 days postoperatively. INTERVENTION: A random-effects model was used. MAIN OUTCOMES MEASURES: The primary outcome was pain during the first 2 postoperative weeks, measured on a visual analogue scale. The secondary outcome was time to return to normal activities. RESULTS: Patients who received oral metronidazole had significantly lower reported pain scores on postoperative day 1 (standardized mean difference, -0.87 ± 0.44; 95% CI, -1.73 to -0.015; p = 0.046; n = 4) and day 4 (standardized mean difference, -1.43 ± 0.71; 95% CI, -2.83 to -0.037; p = 0.044; n = 3). Metronidazole use was associated with a significantly shorter time to return to normal activities (standardized mean difference, -0.76 ± 0.34; 95% CI, -1.43 to -0.088, p = 0.027). The improvements disappeared in a sensitivity analysis excluding the largest trial with a high risk of bias, and no significance was observed during the remaining postoperative days. LIMITATIONS: The meta-analysis was limited by lack of double blinding, absence of a placebo, and unclear or high risk of bias in a proportion of the included trials. CONCLUSIONS: Although a favorable adverse effect profile supports consideration of oral metronidazole to reduce posthemorrhoidectomy pain, pooled analysis reveals inconsistent results with no pain reduction on most postoperative days. The current recommendation for routine prescription of oral metronidazole should be reevaluated in the absence of additional well-designed trials.

Patient Survival After Simultaneous ALPPS and Colorectal Resection.

BACKGROUND: Liver resection combined with colorectal surgery (CRS) is the only curative option in many patients presenting with synchronous colorectal cancer and liver metastases (CRLM). Simultaneous resection has been shown to offer benefits in patients with low hepatic tumor load; however, in the setting of in situ colorectal tumor with extensive CRLM and a small predicted future liver remnant (FLR), the use of simultaneous ALPPS and CRS is controversial, lacking outcome data. METHODS: Thirty-one cases of simultaneous ALPPS and CRS prospectively entered into the International ALPPS Registry were examined. Univariate analysis was used to identify factors associated with 90-day mortality after stage-2. RESULTS: Thirty patients (97%) completed both stages. CRS was performed during stage-1 in 22 patients (73%). Seven patients (23%) had severe complications (Clavien-Dindo ≥ IIIb) following stage-2 ALPPS. The 90-day mortality rate was 15%. Patients who had a severe complication after stage-1 were significantly more likely to have 90-day mortality following stage-2 (p = 0.002). MELD score > 10 on postoperative day-5 after stage-1 was also significantly associated with 90-day mortality (p = 0.011). Disease-free survival and overall survival were 36% and 76% at 1 year, respectively. CONCLUSIONS: In light of the high mortality and poor long-term survival identified in this series, the adoption of ALPPS with CRS cannot be recommended without further data. Patients who suffer severe complications or have an elevated MELD score after stage-1 are at higher risk of mortality following stage-2.