Automatic covariate selection in logistic models for chest pain diagnosis: A new approach

A newly established method for optimizing logistic models via a minorization-majorization procedure is applied to the problem of diagnosing acute coronary syndromes (ACS). The method provides a principled approach to the selection of covariates which would otherwise require the use of a suboptimal method owing to the size of the covariate set. A strategy for building models is proposed and two models optimized for performance and for simplicity are derived via ten-fold cross-validation. These models confirm that a relatively small set of covariates including clinical and electrocardiographic features can be used successfully in this task. The performance of the models is comparable with previously published models using less principled selection methods. The models prove to be portable when tested on data gathered from three other sites. Whilst diagnostic accuracy and calibration diminishes slightly for these new settings, it remains satisfactory overall. The prospect of building predictive models that are as simple as possible for a required level of performance is valuable if data-driven decision aids are to gain wide acceptance in the clinical situation owing to the need to minimize the time taken to gather and enter data at the bedside

Predicting Other Cause Mortality Risk for Older Men with Localized Prostate Cancer: A Dissertation

Background: Overtreatment of localized prostate cancer (PCa) is a concern as many men die of other causes prior to experiencing a treatment benefit. This dissertation characterizes the need for assessing other cause mortality (OCM) risk in older men with PCa and informs efforts to identify patients most likely to benefit from definitive PCa treatment. Methods: Using the linked Surveillance Epidemiology and End Results-Medicare Health Outcomes Survey database, 2,931 men (mean age=75) newly diagnosed with clinical stage T1a-T3a PCa from 1998-2009 were identified. Survival analysis methods were used to compare observed 10-year OCM by primary treatment type. Age and health factors predictive of primary treatment type were assessed with multinomial logistic regression. Predicted mortality estimates from Social Security life tables (recommended for life expectancy evaluation) and two OCM risk estimation tools were compared to observed rates. An improved OCM prediction model was developed fitting Fine and Gray competing risks models for 10-year OCM with age, sociodemographic, comorbidity, activities of daily living, and patient-reported health data as predictors. The tools’ ability to discriminate between patients who died and those who did not was evaluated with Harrell’s c-index (range 0.5-1), which also guided new model selection. Results: Fifty-four percent of older men with localized PCa underwent radiotherapy while 13% underwent prostatectomy. Twenty-three percent of those treated with radiotherapy and 12% of those undergoing prostatectomy experienced OCM within 10 years of treatment and thus were considered overtreated. Health factors indicative of a shorter life expectancy (increased comorbidity, worse physical health, smoking) had little to no association with radiotherapy assignment but were significantly related to reductions in the likelihood of undergoing prostatectomy. Social Security life tables overestimated mortality risk and discriminated poorly between men who died and those who did not over 10 years (c-index=0.59). Existing OCM risk estimation tools were less likely to overestimate OCM rates and had limited but improved discrimination (c-index=0.64). A risk model developed with self-reported age, Charlson comorbidity index score, overall health (excellent-good/fair/poor), smoking, and marital status predictors had improved discrimination (c-index=0.70). Conclusions: Overtreatment of older men with PCa is primarily attributable to radiotherapy and may be reduced by pretreatment assessment of mortality-related health factors. This dissertation provides a prognostic model which utilizes a set of five self-reported characteristics that better identify patients likely to die of OCM within 10 years of diagnosis than age and comorbidity-based assessments alone

Electrocardiographic patch devices and contemporary wireless cardiac monitoring.

Cardiac electrophysiologic derangements often coexist with disorders of the circulatory system. Capturing and diagnosing arrhythmias and conduction system disease may lead to a change in diagnosis, clinical management and patient outcomes. Standard 12-lead electrocardiogram (ECG), Holter monitors and event recorders have served as useful diagnostic tools over the last few decades. However, their shortcomings are only recently being addressed by emerging technologies. With advances in device miniaturization and wireless technologies, and changing consumer expectations, wearable “on-body” ECG patch devices have evolved to meet contemporary needs. These devices are unobtrusive and easy to use, leading to increased device wear time and diagnostic yield. While becoming the standard for detecting arrhythmias and conduction system disorders in the outpatient setting where continuous ECG monitoring in the short to medium term (days to weeks) is indicated, these cardiac devices and related digital mobile health technologies are reshaping the clinician-patient interface with important implications for future healthcare delivery

Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial.

BackgroundAdjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC.MethodsWe did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805.FindingsBetween June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment.InterpretationAddition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC.FundingNational Cancer Institute of the National Institutes of Health

Expediting the confirmation of acute myocardial infarction with point of care troponin and heart fatty acid binding protein testing to facilitate early intervention in emergency department

Cardiac troponin is the reference standard biomarker for the diagnosis of acute myocardial infarction (AMI). In the appropriate clinical context, the detection of a rise and/or fall of cardiac troponin is highly sensitive and specific for this diagnosis. However, troponin testing has two key limitations. First, as levels in serum or plasma can take several hours to rise, the diagnostic sensitivity of troponin testing is insufficient to allow acute coronary syndromes to be safely ‘ruled out’ and serial testing remains necessary. Second, because of the need to detect a rise and/or fall of troponin, serial testing is essential to differentiate chronic troponin elevations from those related to AMI. As a result, international guidance currently recommends serial testing over 6-12 hours. Recent evidence suggests that, with contemporary sensitive troponin assays, AMI can often be ‘ruled out’ and/or ‘ruled in’ with serial testing over as little as 1 to 3 hours However, as the turnaround time of laboratory-based testing is typically 1-2 hours, these results may still be unavailable at the time key decisions about initial treatment and patient disposition are made in the Emergency Department (ED). Point of care troponin (POCT) testing at the patient’s bedside has a shorter turnaround time than laboratory-based assays and eliminates the need to transport the sample to a central laboratory. When patient pathways are appropriately designed to accommodate point of care testing, key management decisions may be expedited, potentially reducing ED length of stay. If the accuracy and safety of rapid diagnostic strategies using point of care troponin testing over 3 hours can be demonstrated, there are tremendous potential benefits for ED throughput, healthcare resource use and for patients (both in terms of receiving appropriate reassurance with avoidance of hospital admission and receiving appropriate early treatment for acute coronary syndromes). In this study, we will evaluate several promising strategies that may enable clinicians to make accurate diagnoses based on information available in the ED and a single blood test for cardiac markers at the POC. During the study period of February 2015 to March 2017 there were 1,613 patients enrolled. Of this cohort, some patients were excluded for missing i-Stat on arrival, and the patients who did not have an ECG recorded were excluded. This left 733 patients in the final group for analysis consisting of 457 men (62.3%) and 276 women (37.7%). The mean age was 58 years (standard deviation 16). In a pragmatic study we determined the interobserver reliability of Heart-type fatty acid–binding protein (h-FABP) the absolute agreement between investigators was 93.0% with a kappa of 0.81 (95% CI 0.6–1.0), indicating near perfect agreement. In total there were three (7.0%) disagreements. The diagnostic accuracy of POC h-FABP lateral flow immunoassay (True Rapid, FABPulous BV) device for diagnosing or excluding AMI using a single test at the time of patient presentation to the ED and three hours later has been evaluated, the sensitivity and NPV to rule out AMI were 48.24% (95%CI: 37.26% to 59.34%) and 92.48 % (95%CI: 90.91% to 93.80%) respectively. While Specificity and PPV were 89.27 % (95%CI: 86.53%to 91.62%) and 38.68% (95%CI: 31.45% to 46.44%) respectively. However, this strategy would allow 85 % of patients to be discharged (rule out percentage). The diagnostic accuracy of a contemporary POC cTn assay used on arrival and 3 hours later in patients with suspected ACS, at the conventional 99th percentile and novel LoD cut-offs was also evaluated. Finally, we were validated the T-MACS with a contemporary POC cTn assay (i-Stat, Abbott Point of Care, New Jersey) in order to investigate the clinical diagnostic accuracy of i-Stat device to rule out AMI in EDs. By setting the cut off levels of POC at 10ng/ml and functional sensitivity at 10% CV, the T-MACS rule has successfully ‘ruled out’ > 41.8% of patients with suspected cardiac chest pain following a single blood test, with a sensitivity of 97.4% (90.8 - 99.7%) and NPV of 99.3% (97.1 – 99.8%), in a very short turnaround time of 5-10 minutes. On the other hand T-MACS has risk stratified the patients who were at high risk to have AMI with a specificity of 93.56% (91.27% to 95.40%) and a PPV of 50.00% (42.08% to 57.92%). To our knowledge, this is the first successful validation of a single test ‘rule out strategy’ using a POC cTn assay. With a 5-10 minute turnaround time, this assay could help to unburden crowded EDs by enabling almost immediate reassurance and discharge for >40% of patients with suspected cardiac chest pain