Doubly robust confidence sequences for sequential causal inference

This paper derives time-uniform confidence sequences (CS) for causal effects in experimental and observational settings. A confidence sequence for a target parameter $\psi$ is a sequence of confidence intervals $(C_t)_{t=1}^\infty$ such that every one of these intervals simultaneously captures $\psi$ with high probability. Such CSs provide valid statistical inference for $\psi$ at arbitrary stopping times, unlike classical fixed-time confidence intervals which require the sample size to be fixed in advance. Existing methods for constructing CSs focus on the nonasymptotic regime where certain assumptions (such as known bounds on the random variables) are imposed, while doubly robust estimators of causal effects rely on (asymptotic) semiparametric theory. We use sequential versions of central limit theorem arguments to construct large-sample CSs for causal estimands, with a particular focus on the average treatment effect (ATE) under nonparametric conditions. These CSs allow analysts to update inferences about the ATE in lieu of new data, and experiments can be continuously monitored, stopped, or continued for any data-dependent reason, all while controlling the type-I error. Finally, we describe how these CSs readily extend to other causal estimands and estimators, providing a new framework for sequential causal inference in a wide array of problems

Cerenkov Luminescence Imaging and Flexible Autoradiography for specimen margin assessment during breast-conserving cancer surgery

Background Among women with breast cancer who undergo breast-conserving surgery (BCS), 20-25% require further surgery due to close or involved margins. Improved techniques are needed to assess resection margins.PurposeThe study aims were to assess the feasibility of the combined techniques of Cerenkov Luminescence Imaging - Flexible AutoRadiography (CLI-FAR) to assess excision specimen margins in women undergoing BCS and to determine the diagnostic performance of intraoperative CLI-FAR imaging with postoperative histopathology as the reference standard..Materials and Methods Women undergoing BCS were recruited prospectively at a single centre over thirteen months. Patients were injected with 250MBq +/- 10MBq of 18F-fluorodeoxyglucose (18F-FDG), 145 minutes before surgery and the excised specimens were imaged intraoperatively. The surgically excised tumour was initially imaged using conventional x-ray, and margins suspected to be involved by tumor were then imaged using CLI-FAR. CLI-FAR imaging was performed using the LightPath system® (Lightpoint®), an in vitro diagnostic device designed to identify and locate positron-emitting radionuclides. Any suspicious margin underwent an immediate re-excision in the form of cavity shavings. Sensitivity, specificity, positive and negative predictive value whilst considering histopathological assessment as the golden standard were used to assess the performance of CLI-FAR.ResultsIn all, 54 specimens were imaged in 52 patients with a total of 104 margins reviewed using CLI-FAR. The results showed a specificity of 97.8% (89/91, 95% CI: 95.0%, 100.6%), sensitivity of 76.9% (10/13, 95% CI: 68.3%, 85.0%), PPV of 83.3% (10/12, 95% CI: 76.2%, 90.5%) and NPV of 96.7% (89/92, 95% CI: 93.3%, 100.2%). In all, 8 patients had 10 positive margins on CLI-FAR imaging and were treated accordingly. CLI-FAR imaging reduced the re-excision rate by (17.3/25) 69%. ConclusionCLI-FAR imaging is a promising technique for intraoperative margin assessment in women undergoing BCS for invasive breast cancer. <br/

Sex-related differences in oncologic outcomes, operative complications and health-related quality of life after curative-intent oesophageal cancer treatment: multicentre retrospective analysis

Background: Oesophageal cancer, in particular adenocarcinoma, has a strong male predominance. However, the impact of patient sex on operative and oncologic outcomes and recovery of health-related quality of life is poorly documented, and was the focus of this large multicentre cohort study. Methods: All consecutive patients who underwent oncological oesophagectomy from 2009 to 2015 in the 20 European iNvestigation of SUrveillance after Resection for Esophageal cancer study group centres were assessed. Clinicopathologic variables, therapeutic approach, postoperative complications, survival and health-related quality of life data were compared between male and female patients. Multivariable analyses adjusted for age, sex, tumour histology, treatment protocol and major complications. Specific subgroup analyses comparing adenocarcinoma versus squamous cell cancer for all key outcomes were performed. Results: Overall, 3974 patients were analysed, 3083 (77.6%) male and 891 (22.4%) female; adenocarcinoma was predominant in both groups, while squamous cell cancer was observed more commonly in female patients (39.8% versus 15.1%, P < 0.001). Multivariable analysis demonstrated improved outcomes in female patients for overall survival (HRmales 1.24, 95% c.i. 1.07 to 1.44) and disease-free survival (HRmales 1.22, 95% c.i. 1.05 to 1.43), which was caused by the adenocarcinoma subgroup, whereas this difference was not confirmed in squamous cell cancer. Male patients presented higher health-related quality of life functional scores but also a higher risk of financial problems, while female patients had lower overall summary scores and more persistent gastrointestinal symptoms. Conclusion: This study reveals uniquely that female sex is associated with more favourable long-term survival after curative treatment for oesophageal cancer, especially adenocarcinoma, although long-term overall and gastrointestinal health-related quality of life are poorer in women

ESCP Safe Anastomosis ProGramme in CoLorectal SurgEry (EAGLE): Study protocol for an international cluster randomised trial of a quality improvement intervention to reduce anastomotic leak following right colectomy

Aim: Cohort data suggest that anastomotic leak occurs after 8% of right colectomies causing significant morbidity and mortality. Patient selection, intra-operative factors, and technical variation all contribute to risk of leak. The EAGLE study will assess whether implementation of the European Society of Coloproctology (ESCP) Safe Anastomosis Intervention reduces anastomotic leak following right colectomy. Methods: An international, multi-centre, cluster randomised trial will be undertaken with hospitals as clusters. Hospitals will be recruited in a number of distinct phases, with each phase following the same research plan, in which clusters are randomised to one of three, staggered (dog-leg) schedules for implementation of the Safe Anastomosis Intervention. Results: Results from different phases will be meta-analysed. The intervention is a three-component behavioural change programme for surgeons, anaesthetists and operating room staff, supported by an online learning environment. All colorectal surgical units around the world will be eligible. Adults undergoing elective or emergency right colectomy or ileocaecal resection, by any approach and for any indication will be included. The primary outcome is 30-day anastomotic leak rate, defined as clinical or radiologically-detected leak or intra-abdominal or pelvic collection. Assuming hospitals provide data for an average of 10 patients per two month recruitment period, 333 clusters (4440 patients in total) will allow for detection of an absolute risk reduction of anastomotic leak from 8.1% to 5.6% (relative risk reduction 30%). This protocol adheres to Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT). Discussion: The protocol describes the methods for an evaluation of a hospital-level, education-based quality improvement intervention targeted to reduce the life-threatening surgical complication of anastomotic leak. Trial registration: ClinicalTrials.gov NCT04270721