Assessing the transportability of radiomic models for lung cancer diagnosis: commercial vs. open-source feature extractors.

Background: Radiomics has shown promise in improving malignancy risk stratification of indeterminate pulmonary nodules (IPNs) with many platforms available, but with no head-to-head comparisons. This study aimed to evaluate transportability of radiomic models across platforms by comparing performances of a commercial radiomic feature extractor (HealthMyne) with an open-source extractor (PyRadiomics) on diagnosis of lung cancer in IPNs. Methods: A commercial radiomic feature extractor was used to segment IPNs from computed tomography (CT) scans, and a previously validated radiomic model based on commercial features was used as baseline (ComRad). Using same segmentation masks, PyRadiomics, an open-source feature extractor was used to build three open-source radiomic models (OpenRad) using different methods: de novo open-source model derived using least absolute shrinkage and selection operator (LASSO) for feature selection, selecting open-source features matched to ComRad features based upon Imaging Biomarker Standardization Initiative (IBSI) nomenclature, and selecting open-source features most highly correlated to ComRad features. Radiomic models were trained on an internal cohort (n=161) and externally validated on 3 cohorts (n=278). We added Mayo clinical risk score to OpenRad and ComRad models, creating integrated clinical radiomic (ClinRad) models. All models were compared using area under the curve (AUC) and evaluated for clinical improvement using bias-corrected clinical net reclassification indices (cNRIs). Results: ComRad AUC was 0.76 [95% confidence interval (CI): 0.71-0.82], and OpenRad AUC was 0.75 (95% CI: 0.69-0.81) for LASSO model, 0.74 (95% CI: 0.68-0.79) for Spearman's correlation, and 0.71 (95% CI: 0.65-0.77) for IBSI. Mayo scores were added to OpenRad LASSO model, which performed best, forming open-source ClinRad model with AUC of 0.80 (95% CI: 0.74-0.86), identical to commercial ClinRad's AUC. Both ClinRad models showed clinical improvement compared to Mayo alone, with commercial ClinRad achieving cNRI of 0.09 (95% CI: 0.02-0.15) for benign and 0.07 (95% CI: 0.00-0.13) for malignant, and open-source ClinRad achieving cNRI of 0.09 (95% CI: 0.02-0.15) for benign and 0.06 (95% CI: 0.00-0.12) for malignant. Conclusions: Transportability of radiomic models across platforms directly does not conserve performance, but radiomic platforms can provide equivalent results when building de novo models allowing for flexibility in feature selection to maximize prediction accuracy.

Nurse and Social Worker Palliative Telecare Team and Quality of Life in Patients With COPD, Heart Failure, or Interstitial Lung Disease: The ADAPT Randomized Clinical Trial.

Importance: Many patients with chronic obstructive pulmonary disease (COPD), heart failure (HF), and interstitial lung disease (ILD) endure poor quality of life despite conventional therapy. Palliative care approaches may benefit this population prior to end of life. Objective: Determine the effect of a nurse and social worker palliative telecare team on quality of life in outpatients with COPD, HF, or ILD compared with usual care. Design, Setting, and Participants: Single-blind, 2-group, multisite randomized clinical trial with accrual between October 27, 2016, and April 2, 2020, in 2 Veterans Administration health care systems (Colorado and Washington), and including community-based outpatient clinics. Outpatients with COPD, HF, or ILD at high risk of hospitalization or death who reported poor quality of life participated. Intervention: The intervention involved 6 phone calls with a nurse to help with symptom management and 6 phone calls with a social worker to provide psychosocial care. The nurse and social worker met weekly with a study primary care and palliative care physician and as needed, a pulmonologist, and cardiologist. Usual care included an educational handout developed for the study that outlined self-care for COPD, ILD, or HF. Patients in both groups received care at the discretion of their clinicians, which could include care from nurses and social workers, and specialists in cardiology, pulmonology, palliative care, and mental health. Main Outcomes and Measures: The primary outcome was difference in change in quality of life from baseline to 6 months between the intervention and usual care groups (FACT-G score range, 0-100, with higher scores indicating better quality of life, clinically meaningful change ≥4 points). Secondary quality-of-life outcomes at 6 months included disease-specific health status (Clinical COPD Questionnaire; Kansas City Cardiomyopathy Questionnaire-12), depression (Patient Health Questionnaire-8) and anxiety (Generalized Anxiety Disorder-7) symptoms. Results: Among 306 randomized patients (mean [SD] age, 68.9 [7.7] years; 276 male [90.2%], 30 female [9.8%]; 245 White [80.1%]), 177 (57.8%) had COPD, 67 (21.9%) HF, 49 (16%) both COPD and HF, and 13 (4.2%) ILD. Baseline FACT-G scores were similar (intervention, 52.9; usual care, 52.7). FACT-G completion was 76% (intervention, 117 of 154; usual care, 116 of 152) at 6 months for both groups. Mean (SD) length of intervention was 115.1 (33.4) days and included a mean of 10.4 (3.3) intervention calls per patient. In the intervention group, 112 of 154 (73%) patients received the intervention as randomized. At 6 months, mean FACT-G score improved 6.0 points in the intervention group and 1.4 points in the usual care group (difference, 4.6 points [95% CI, 1.8-7.4]; P = .001; standardized mean difference, 0.41). The intervention also improved COPD health status (standardized mean difference, 0.44; P = .04), HF health status (standardized mean difference, 0.41; P = .01), depression (standardized mean difference, -0.50; P < .001), and anxiety (standardized mean difference, -0.51; P < .001) at 6 months. Conclusions and Relevance: For adults with COPD, HF, or ILD who were at high risk of death and had poor quality of life, a nurse and social worker palliative telecare team produced clinically meaningful improvements in quality of life at 6 months compared with usual care. Trial Registration: ClinicalTrials.gov Identifier: NCT02713347.

Assessing the clinical utility of biomarkers using the intervention probability curve (IPC).

BACKGROUND: Assessing the clinical utility of biomarkers is a critical step before clinical implementation. The reclassification of patients across clinically relevant subgroups is considered one of the best methods to estimate clinical utility. However, there are important limitations with this methodology. We recently proposed the intervention probability curve (IPC) which models the likelihood that a provider will choose an intervention as a continuous function of the probability, or risk, of disease. OBJECTIVE: To assess the potential impact of a new biomarker for lung cancer using the IPC. METHODS: The IPC derived from the National Lung Screening Trial was used to assess the potential clinical utility of a biomarker for suspected lung cancer. The summary statistics of the change in likelihood of intervention over the population can be interpreted as the expected clinical impact of the added biomarker. RESULTS: The IPC analysis of the novel biomarker estimated that 8% of the benign nodules could avoid an invasive procedure while the cancer nodules would largely remain unchanged (0.1%). We showed the benefits of this approach compared to traditional reclassification methods based on thresholds. CONCLUSIONS: The IPC methodology can be a valuable tool for assessing biomarkers prior to clinical implementation.

Differences in VA and Non-VA Pulmonary Nodules: All Evaluations Are not Created Equal.

BACKGROUND: Indeterminate pulmonary nodules present a common challenge for clinicians who must recommend surveillance or intervention based on an assessed risk of malignancy. PATIENTS AND METHODS: In this cohort study, patients presenting for indeterminate pulmonary nodule evaluation were enrolled at sites participating in the Colorado SPORE in Lung Cancer. They were followed prospectively and included for analysis if they had a definitive malignant diagnosis, benign diagnosis, or radiographic resolution or stability of their nodule for > 2 years. RESULTS: Patients evaluated at the Veterans Affairs (VA) and non-VA sites were equally as likely to have a malignant diagnosis (48%). The VA cohort represented a higher-risk group than the non-VA cohort regarding smoking history and chronic obstructive pulmonary disease (COPD). There were more squamous cell carcinoma diagnoses among VA malignant nodules (25% vs. 10%) and a later stage at diagnosis among VA patients. Discrimination and calibration of risk calculators produced estimates that were wide-ranging and different when comparing between risk score calculators as well as between VA/non-VA cohorts. Application of current American College of Chest Physicians guidelines to our groups could have resulted in inappropriate resection of 12% of benign nodules. CONCLUSION: Comparison of VA with non-VA patients shows important differences in underlying risk, histology of malignant nodules, and stage at diagnosis. This study highlights the challenge in applying risk calculators to a clinical setting, as the model discrimination and calibration were variable between calculators and between our higher-risk VA and lower-risk non-VA groups. MICROABSTRACT: Risk stratification and management of indeterminate pulmonary nodules (IPNs) is a common clinical problem. In this prospective cohort study of 282 patients with IPNs from Veterans Affairs (VA) and non-VA sites, we found differences in patient and nodule characteristics, histology and diagnostic stage, and risk calculator performance. Our findings highlight challenges and shortcomings of current IPN management guidelines and tools.

Association of Residual Ischemic Disease With Clinical Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: Anatomical scoring systems have been used to assess completeness of revascularization but are challenging to apply to large real-world datasets. OBJECTIVES: The aim of this study was to assess the prevalence of complete revascularization and its association with longitudinal clinical outcomes in the U.S. Department of Veterans Affairs (VA) health care system using an automatically computed anatomic complexity score. METHODS: Patients undergoing percutaneous coronary intervention (PCI) between October 1, 2007, and September 30, 2020, were identified, and the burden of prerevascularization and postrevascularization ischemic disease was quantified using the VA SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score. The association between residual VA SYNTAX score and long-term major adverse cardiovascular events (MACE; death, myocardial infarction, repeat revascularization, and stroke) was assessed. RESULTS: A total of 57,476 veterans underwent PCI during the study period. After adjustment, the highest tertile of residual VA SYNTAX score was associated with increased hazard of MACE (HR: 2.06; 95% CI: 1.98-2.15) and death (HR: 1.50; 95% CI: 1.41-1.59) at 3 years compared to complete revascularization (residual VA SYNTAX score = 0). Hazard of 1- and 3-year MACE increased as a function of residual disease, regardless of baseline disease severity or initial presentation with acute or chronic coronary syndrome. CONCLUSIONS: Residual ischemic disease was strongly associated with long-term clinical outcomes in a contemporary national cohort of PCI patients. Automatically computed anatomic complexity scores can be used to assess the longitudinal risk for residual ischemic disease after PCI and may be implemented to improve interventional quality.

The Effect of Intrathoracic Lesion Location on Initial Tyrosine Kinase Inhibitor Response in Advanced Oncogene-Addicted Non-Small Cell Lung Cancer: A Comparison Between RECIST 1.1 and a Novel Method of Response Assessment (MAX).

INTRODUCTION: Different subtypes of non-small cell lung cancer (NSCLC) are associated with different patterns of metastatic spread. Anatomic location of lesions in the chest may influence patterns of cancer growth and the shrinkage to therapy. Consequently, lesion location could affect apparent response rates per RECIST. We sought to explore this and develop, as needed, treatment response assessments less affected by the location. METHODS: Cases of advanced oncogene-addicted NSCLC (EGFR, ALK, and ROS1) with pre- and on-therapy imaging during initial targeted therapy were identified. Lesions located in the lung parenchyma, pleural space or intra-thoracic lymph nodes were identified and analyzed separately from each other by RECIST 1.1 (unidimensional measurements) and by a novel MAX methodology (bidimensional measurements) which takes the axis with the greatest absolute percentage change on therapy in each location as the representative measurement. RESULTS: Three hundred three patients with 446 unidimensional measured lesions were included for RECIST analysis. Two hundred forty nine patients with 386 bidimensional measured lesions were included for MAX analysis, as well as the analysis comparing RECIST and MAX. Intrathoracic location significantly impacted percentage shrinkage and the response rate per RECIST. The response rates for pleural, intra-parenchymal and nodal lesions were 34.1%, 49.6%, and 68.3%, respectively (P = .0002). The MAX methodology both increased the apparent treatment effect and made it consistent between intrathoracic locations. For pleural, parenchymal and nodal lesions, the MAX calculated response rate were 83.7%, 72.2%, and 75.4%, respectively (P-value = .24). CONCLUSION: Intrathoracic lesion location affects RECIST-based treatment effectiveness estimations. The MAX methodology neutralizes location effect when examining impact of treatment and should be explored further.

The Intervention Probability Curve: Modeling the Practical Application of Threshold-Guided Decision-Making, Evaluated in Lung, Prostate, and Ovarian Cancers.

BACKGROUND: Diagnostic prediction models are useful guides when considering lesions suspicious for cancer, as they provide a quantitative estimate of the probability that a lesion is malignant. However, the decision to intervene ultimately rests on patient and physician preferences. The appropriate intervention in many clinical situations is typically defined by clinically relevant, actionable subgroups based upon the probability of malignancy. However, the "all-or-nothing" approach of threshold-based decisions is in practice incorrect. METHODS: Here, we present a novel approach to understanding clinical decision-making, the intervention probability curve (IPC). The IPC models the likelihood that an intervention will be chosen as a continuous function of the probability of disease. We propose the cumulative distribution function as a suitable model. The IPC is explored using the National Lung Screening Trial and the Prostate Lung Colorectal and Ovarian Screening Trial datasets. RESULTS: Fitting the IPC results in a continuous curve as a function of pretest probability of cancer with high correlation (R2 > 0.97 for each) with fitted parameters closely aligned with professional society guidelines. CONCLUSIONS: The IPC allows analysis of intervention decisions in a continuous, rather than threshold-based, approach to further understand the role of biomarkers and risk models in clinical practice. IMPACT: We propose that consideration of IPCs will yield significant insights into the practical relevance of threshold-based management strategies and could provide a novel method to estimate the actual clinical utility of novel biomarkers.

Integrated Biomarkers for the Management of Indeterminate Pulmonary Nodules.

Rationale: Patients with indeterminate pulmonary nodules (IPNs) at risk of cancer undergo high rates of invasive, costly, and morbid procedures. Objectives: To train and externally validate a risk prediction model that combined clinical, blood, and imaging biomarkers to improve the noninvasive management of IPNs. Methods: In this prospectively collected, retrospective blinded evaluation study, probability of cancer was calculated for 456 patient nodules using the Mayo Clinic model, and patients were categorized into low-, intermediate-, and high-risk groups. A combined biomarker model (CBM) including clinical variables, serum high sensitivity CYFRA 21-1 level, and a radiomic signature was trained in cohort 1 (n = 170) and validated in cohorts 2-4 (total n = 286). All patients were pooled to recalibrate the model for clinical implementation. The clinical utility of the CBM compared with current clinical care was evaluated in 2 cohorts. Measurements and Main Results: The CBM provided improved diagnostic accuracy over the Mayo Clinic model with an improvement in area under the curve of 0.124 (95% bootstrap confidence interval, 0.091-0.156; P < 2 × 10-16). Applying 10% and 70% risk thresholds resulted in a bias-corrected clinical reclassification index for cases and control subjects of 0.15 and 0.12, respectively. A clinical utility analysis of patient medical records estimated that a CBM-guided strategy would have reduced invasive procedures from 62.9% to 50.6% in the intermediate-risk benign population and shortened the median time to diagnosis of cancer from 60 to 21 days in intermediate-risk cancers. Conclusions: Integration of clinical, blood, and image biomarkers improves noninvasive diagnosis of patients with IPNs, potentially reducing the rate of unnecessary invasive procedures while shortening the time to diagnosis.

Determinants Associated With Longitudinal Adherence to Annual Lung Cancer Screening: A Retrospective Analysis of Claims Data.

OBJECTIVE: Lung cancer screening (LCS) efficacy is highly dependent on adherence to annual screening, but little is known about real-world adherence determinants. We used insurance claims data to examine associations between LCS annual adherence and demographic, comorbidity, health care usage, and geographic factors. MATERIALS AND METHODS: Insurance claims data for all individuals with an LCS low-dose CT scan were obtained from the Colorado All Payer Claims Dataset. Adherence was defined as a second claim for a screening CT 10 to 18 months after the index claim. Cox proportional hazards regression was used to define the relationship between annual adherence and age, gender, insurance type, residence location, outpatient health care usage, and comorbidity burden. RESULTS: After exclusions, the final data set consisted of 9,056 records with 3,072 adherent, 3,570 nonadherent, and 2,414 censored (unclassifiable) individuals. Less adherence was associated with ages 55 to 59 (hazard ratio [HR] = 0.80, 99% confidence interval [CI] = 0.67-0.94), 60 to 64 (HR = 0.83, 99% CI = 0.71-0.97), and 75 to 79 (HR = 0.79, 99% CI = 0.65-0.97); rural residence (HR = 0.56, 99% CI = 0.43-0.73); Medicare fee-for-service (HR = 0.45, 99% CI = 0.39-0.51), and Medicaid (HR = 0.50, 99% CI = 0.40-0.62). A significant interaction between outpatient health care usage and comorbidity was also observed. Increased outpatient usage was associated with increased adherence and was most pronounced for individuals without comorbidities. CONCLUSIONS: This population-based description of LCS adherence determinants provides insight into populations that might benefit from specific interventions targeted toward improving adherence and maximizing LCS benefit. Quantifying population-based adherence rates and understanding factors associated with annual adherence are critical to improving screening adherence and reducing lung cancer death.

Impact of a Hybrid Lung Cancer Screening Model on Patient Outcomes and Provider Behavior.

BACKGROUND: Lung cancer screening (LCS) implementation is complicated by the Centers for Medicare and Medicaid Services reimbursement requirements of shared decision-making and tobacco cessation counseling. LCS programs can utilize different structures to meet these requirements, but the impact of programmatic structure on provider behavior and screening outcomes is poorly described. PATIENTS AND METHODS: In a retrospective chart review of 624 patients in a hybrid structure, academic LCS program, we compared characteristics and outcomes of primary care provider (PCP)- and specialist-screened patients. We also assessed the impact of the availability of an LCS specialty clinic and best practice advisory (BPA) on PCP ordering patterns using electronic medical record generated reports. RESULTS: During the study period of July 1, 2014 through June 30, 2018, 48% of patients were specialist-screened and 52% were PCP-screened; there were no clinically relevant differences in patient characteristics or screening outcomes between these populations. PCPs demonstrate distinct practice patterns when offered the choice of specialist-driven or PCP-driven screening. Increased exposure to a LCS BPA is associated with increased PCP screening orders. The addition of a nurse navigator into the LCS program increased documentation of shared decision-making and tobacco cessation counseling to > 95% and virtually eliminated screening of ineligible patients. CONCLUSIONS: Systematic interventions including a BPA and nurse navigator are associated with increased screening and improved program quality, as evidenced by reduced screening of ineligible patients, increased lung cancer risk of the screened population, and improved compliance with LCS guidelines. Individual PCPs demonstrate clear preferences regarding LCS that should be considered in program design.

Quantifying the incremental value of deep learning: Application to lung nodule detection.

We present a case study for implementing a machine learning algorithm with an incremental value framework in the domain of lung cancer research. Machine learning methods have often been shown to be competitive with prediction models in some domains; however, implementation of these methods is in early development. Often these methods are only directly compared to existing methods; here we present a framework for assessing the value of a machine learning model by assessing the incremental value. We developed a machine learning model to identify and classify lung nodules and assessed the incremental value added to existing risk prediction models. Multiple external datasets were used for validation. We found that our image model, trained on a dataset from The Cancer Imaging Archive (TCIA), improves upon existing models that are restricted to patient characteristics, but it was inconclusive about whether it improves on models that consider nodule features. Another interesting finding is the variable performance on different datasets, suggesting population generalization with machine learning models may be more challenging than is often considered.

Variation in contrast-associated acute kidney injury prophylaxis for percutaneous coronary intervention: insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) program.

BACKGROUND: Contrast-Associated Acute Kidney Injury (CA-AKI) is a serious complication associated with percutaneous coronary intervention (PCI). Patients with chronic kidney disease (CKD) have an elevated risk for developing this complication. Although CA-AKI prophylactic measures are available, the supporting literature is variable and inconsistent for periprocedural hydration and N-acetylcysteine (NAC), but is stronger for contrast minimization. METHODS: We assessed the prevalence and variability of CA-AKI prophylaxis among CKD patients undergoing PCI between October 2007 and September 2015 in any cardiac catheterization laboratory in the VA Healthcare System. Prophylaxis included periprocedural hydration with normal saline or sodium bicarbonate, NAC, and contrast minimization (contrast volume to glomerular filtration rate ratio ≤ 3). Multivariable hierarchical logistic regression models quantified site-specific prophylaxis variability. As secondary analyses, we also assessed CA-AKI prophylaxis measures in all PCI patients regardless of kidney function, periprocedural hydration in patients with comorbid CHF, and temporal trends in CA-AKI prophylaxis. RESULTS: From 2007 to 2015, 15,729 patients with CKD underwent PCI. 6928 (44.0%) received periprocedural hydration (practice-level median rate 45.3%, interquartile range (IQR) 35.5-56.7), 5107 (32.5%) received NAC (practice-level median rate 28.3%, IQR 22.8-36.9), and 4656 (36.0%) received contrast minimization (practice-level median rate 34.5, IQR 22.6-53.9). After adjustment for patient characteristics, there was significant site variability with a median odds ratio (MOR) of 1.80 (CI 1.56-2.08) for periprocedural hydration, 1.95 (CI 1.66-2.29) for periprocedural hydration or NAC, and 2.68 (CI 2.23-3.15) for contrast minimization. These trends were similar among all patients (with and without CKD) undergoing PCI. Among patients with comorbid CHF (n = 5893), 2629 (44.6%) received periprocedural hydration, and overall had less variability in hydration (MOR of 1.56 (CI 1.38-1.76)) compared to patients without comorbid CHF (1.89 (CI 1.65-2.18)). Temporal trend analysis showed a significant and clinically relevant decrease in NAC use (64.1% of cases in 2008 (N = 1059), 6.2% of cases in 2015 (N = 128, p = < 0.0001)) and no significant change in contrast-minimization (p = 0.3907). CONCLUSIONS: Among patients with CKD undergoing PCI, there was low utilization and significant site-level variability for periprocedural hydration and NAC independent of patient-specific risk. This low utilization and high variability, however, was also present for contrast minimization, a well-established measure. These findings suggest that a standardized approach to CA-AKI prophylaxis, along with continued development of the evidence base, is needed.

Medical Therapy Utilization and Long-Term Outcomes Following Percutaneous Coronary Intervention: Five-Year Results From the Veterans Affairs Clinical Assessment, Reporting, and Tracking System Program.

BACKGROUND: Optimal medical therapy is endorsed by national guidelines in the management of ischemic heart disease; however, few studies have examined its long-term utilization following percutaneous coronary intervention (PCI) and association with clinical outcomes. We sought to assess longitudinal trends in medical therapy use after PCI and its prognostic significance. METHODS AND RESULTS: From the Veteran Affairs Clinical Assessment, Reporting, and Tracking System Program, we retrospectively identified 57 900 Veteran's Affairs patients undergoing PCI from January 2005 to May 2014. Using prescription fill dates, the utilization of 4 classes of medical therapy including statins, ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, P2Y12 inhibitors, and their composites were assessed at discharge, 6 months, 1, 3, and 5 years post-PCI. Multivariable Cox regression models were developed to assess the association between medical therapy status and major adverse cardiovascular events, defined as all-cause mortality, rehospitalization for myocardial infarction, rehospitalization for stroke, or repeat revascularization. At discharge following PCI, 58.3% of patients received all 4 classes of medical therapy. Utilization of statins, ß-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers decreased from 89%, 84.9%, and 72.2% on discharge, respectively, to 72.7%, 67.9%, and 57.9% at 5 years. Prescription refills of P2Y12 inhibitors declined from 96.5% on discharge to 28.3% at 5 years, driven by a large decline in P2Y12 inhibitor use after 1 year. Use of each class of medical therapy, and its composite use, was associated with a significant reduction in major adverse cardiovascular events at 5 years, with the largest effect size seen by the use of statins (HR, 0.77; 95% CI, 0.75-0.79; P<0.0001) and P2Y12 inhibitors (HR, 0.82; 95% CI, 0.79-0.85; P<0.0001). CONCLUSIONS: Consistent declines in medical therapy use following PCI were observed over time, which is associated with worse outcomes. Further efforts are needed to promote long-term adherence to secondary prevention therapies after revascularization.

Association of Coronary Anatomical Complexity With Clinical Outcomes After Percutaneous or Surgical Revascularization in the Veterans Affairs Clinical Assessment Reporting and Tracking Program.

Importance: Anatomical scoring systems for coronary artery disease, such as the SYNTAX (Synergy Between Percutaneous Coronary Intervention [PCI] With Taxus and Cardiac Surgery) score, are well established tools for understanding patient risk. However, they are cumbersome to compute manually for large data sets, limiting their use across broad and varied cohorts. Objective: To adapt an anatomical scoring system for use with registry data, allowing facile and automatic calculation of scores and association with clinical outcomes among patients undergoing percutaneous or surgical revascularization. Design, Setting, and Participants: This cross-sectional observational cohort study involved procedures performed in all cardiac catheterization laboratories in the largest integrated health care system in the United States, the Veterans Affairs (VA) Healthcare System. Patients undergoing coronary angiography in the VA Healthcare System followed by percutaneous or surgical revascularization within 90 days were observed and data were analyzed from January 1, 2010, through September 30, 2017. Main Outcomes and Measures: An anatomical scoring system for coronary artery disease complexity before revascularization was simplified and adapted to data from the VA Clinical Assessment, Reporting, and Tracking Program. The adjusted association between quantified anatomical complexity and major adverse cardiovascular and cerebrovascular events (MACCEs), including death, myocardial infarction, stroke, and repeat revascularization, was assessed for patients undergoing percutaneous or surgical revascularization. Results: A total of 50 226 patients (49 359 men [98.3%]; mean [SD] age, 66 [9] years) underwent revascularization during the study period, with 34 322 undergoing PCI and 15 904 undergoing coronary artery bypass grafting (CABG). After adjustment, the highest tertile of anatomical complexity was associated with increased hazard of MACCEs (adjusted hazard ratio [HR], 2.12; 95% CI, 2.01-2.23). In contrast, the highest tertile of anatomical complexity among patients undergoing CABG was not independently associated with overall MACCEs (adjusted HR, 1.04; 95% CI, 0.92-1.17), and only repeat revascularization was associated with increasing complexity (adjusted HR, 1.34; 95% CI, 1.06-1.70) in this subgroup. Conclusions and Relevance: These findings suggest that an automatically computed score assessing anatomical complexity can be used to assess longitudinal risk for patients undergoing revascularization. This simplified scoring system appears to be an alternative tool for understanding longitudinal risk across large data sets.

Advancing Symptom Alleviation with Palliative Treatment (ADAPT) trial to improve quality of life: a study protocol for a randomized clinical trial.

BACKGROUND: People living with chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD) suffer impaired quality of life due to burdensome symptoms and depression. The Advancing Symptom Alleviation with Palliative Treatment (ADAPT) trial aims to determine the effect of a multidisciplinary, team-based intervention on quality of life in people with these common diseases. METHODS/DESIGN: The ADAPT trial is a two-site, patient-level randomized clinical trial that examines the effectiveness of the ADAPT intervention compared to usual care on patient-reported quality of life at 6 months in veterans with CHF, COPD or ILD with poor quality of life and increased risk for hospitalization or death. The ADAPT intervention involves a multidisciplinary team-a registered nurse, social worker, palliative care specialist, and primary care provider (with access to a pulmonologist and cardiologist)-who meet weekly to make recommendations and write orders for consideration by participants' individual primary care providers. The nurse and social worker interact with participants over six visits to identify and manage a primary bothersome symptom and complete a structured psychosocial intervention and advance care planning. The primary outcome is change in patient-reported quality of life at 6 months as measured by the Functional Assessment of Chronic Illness Therapy-General questionnaire. Secondary outcomes at 6 months include change in symptom distress, depression, anxiety, disease-specific quality of life hospitalizations, and advance care planning communication and documentation. Intervention implementation will be assessed using a mixed-methods approach including a qualitative assessment of participants' and intervention personnel experiences and a quantitative assessment of care delivery, resources, and cost. DISCUSSION: The ADAPT trial studies an innovative intervention designed to improve quality of life for veterans with common, burdensome illnesses by targeting key underlying factors-symptoms and depression-that impair quality of life but persist despite disease-specific therapies. Leveraging the skills of affiliate health providers with physician supervision will extend the reach of palliative care and improve quality of life for those with advanced disease within routine outpatient care. The hybrid effectiveness/implementation design of the ADAPT trial will shorten the time to broader dissemination if effective and create avenues for future research. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02713347 . Registered March 19, 2016.

Gluten Intake and Risk of Celiac Disease: Long-Term Follow-up of an At-Risk Birth Cohort.

OBJECTIVES: To determine the association between the amount of gluten intake in childhood and later celiac disease (CD), for which data are currently scarce. METHODS: The prospective Diabetes Autoimmunity Study in the Young cohort includes 1875 at-risk children with annual estimates of gluten intake (grams/d) from age 1 year. From 1993 through January 2017, 161 children, using repeated tissue transglutaminase (tTGA) screening, were identified with CD autoimmunity (CDA) and persistent tTGA positivity; of these children, 85 fulfilled CD criteria of biopsy-verified histopathology or persistently high tTGA levels. Cox regression, modeling gluten intake between ages 1 and 2 years (i.e., in 1-year-olds), and joint modeling of cumulative gluten intake throughout childhood were used to estimate hazard ratios adjusted for confounders (aHR). RESULTS: Children in the highest third of gluten intake between the ages of 1 and 2 years had a 2-fold greater hazard of CDA (aHR 2.17; 95% confidence interval [CI], 1.22-3.88; P value = 0.01) and CD (aHR 1.96; 95% CI, 0.90-4.24; P value = 0.09) than those in the lowest third. The risk of developing CDA increased by 5% per daily gram increase in gluten intake (aHR 1.05; 95% CI, 1.00-1.09; P value = 0.04) in 1-year-olds. The association between gluten intake in 1-year-olds and later CDA or CD did not differ by the child's human leukocyte antigen genotype. The incidence of CD increased with increased cumulative gluten intake throughout childhood (e.g., aHR 1.15 per SD increase in cumulative gluten intake at age 6; 95% CI, 1.00-1.32; P value = 0.04). DISCUSSION: Gluten intake in 1-year-olds is associated with the future onset of CDA and CD in children at risk for the disease.

Detection of oligoprogressive disease in oncogene-addicted non-small cell lung cancer using PET/CT versus CT in patients receiving a tyrosine kinase inhibitor.

OBJECTIVES: In oncogene-addicted non-small cell lung cancer (NSCLC), oligoprogressive disease (OPD) can be treated with local ablative therapy (LAT) to prolong benefit from tyrosine kinase inhibitors (TKIs). A comparison of PET/CT vs. CT for the detection of OPD at first extra central nervous system (eCNS) progression was performed to determine which modality was more sensitive for OPD detection. MATERIALS AND METHODS: Patients with metastatic EGFR-MT, ALK + or ROS-1+ NSCLC on a relevant TKI from 2010 to 2016 were identified. Scan methodology at first eCNS progression (index scan) was noted and progression was categorized as OPD (≤ 4 lesions) or non-OPD (> 4 lesions). RESULTS: Of the 67 analyzable patients (EGFR-MT = 37, ALK+ = 28, ROS1+ = 2), OPD was detected in 81.3% (26/32) by PET/CT vs. 68.6% (24/35) by CT (p = 0.363). Of these, 17/26(65.4%) in PET/CT and 5/24(20.8%) in CT group had LAT (p = 0.004). Among patients receiving an alternate modality scan within 6 weeks of the index scan that showed first eCNS progression, 91.7% (11/12) had CT prior to index PET/CT, 75% (6/8) had post-index PET/CT showing further progression, whereas 0% (0/5) had post-index CT showing further progression. Time to progression (TTP), Post-progression TKI benefit (TTP2) and overall survival (OS) were longer in the PET/CT-detected group (p = 0.001, p = 0.032, and p = 0.01, respectively). In both PET/CT (N = 26) and CT-detected (N = 24) OPD subgroups, TTP2 and OS were longer in those that received LAT (65.4% [17/26] and 20.8% [5/24]) versus those that did not, although the difference was not statistically significant. CONCLUSION: PET/CT demonstrated a non-significant trend to detect more eCNS OPD and a significantly higher rate of OPD suitable for LAT than CT. Peri-progression alternate modality scans were also consistent with PET/CT being more sensitive. A prospective randomized study is required to assess the long-term impact of PET/CT vs CT in oncogene-addicted NSCLC patients on TKI therapy.

Trajectories of Nevus Development From Age 3 to 16 Years in the Colorado Kids Sun Care Program Cohort.

Importance: Nevi are a risk factor for melanoma and other forms of skin cancer, and many of the same factors confer risk for both. Understanding childhood nevus development may provide clues to possible causes and prevention of melanoma. Objectives: To describe nevus acquisition from the ages of 3 to 16 years among white youths and evaluate variation by sex, Hispanic ethnicity, and body sites that are chronically vs intermittently exposed to the sun. Design, Setting, and Participants: This annual longitudinal observational cohort study of nevus development was conducted between June 1, 2001, and October 31, 2014, among 1085 Colorado youths. Data analysis was conducted between February 1, 2015, and August 31, 2017. Main Outcomes and Measures: Total nevus counts on all body sites and on sites chronically and intermittently exposed to the sun separately. Results: A total of 557 girls and 528 boys (150 [13.8%] Hispanic participants) born in 1998 were included in this study. Median total body nevus counts increased linearly among non-Hispanic white boys and girls between the age of 3 years (boys, 6.31; 95% CI, 5.66-7.03; and girls, 6.61; 95% CI, 5.96-7.33) and the age of 16 years (boys, 81.30; 95% CI, 75.95-87.03; and girls, 77.58; 95% CI, 72.68-82.81). Median total body nevus counts were lower among Hispanic white children (boys aged 16 years, 51.45; 95% CI, 44.01-60.15; and girls aged 16 years, 53.75; 95% CI, 45.40-63.62) compared with non-Hispanic white children, but they followed a largely linear trend that varied by sex. Nevus counts on body sites chronically exposed to the sun increased over time but leveled off by the age of 16 years. Nevus counts on sites intermittently exposed to the sun followed a strong linear pattern through the age of 16 years. Hispanic white boys and girls had similar nevus counts on sites intermittently exposed to the sun through the age of 10 years, but increases thereafter were steeper for girls, with nevus counts surpassing those of boys aged 11 to 16 years. Conclusions and Relevance: Youths are at risk for nevus development beginning in early childhood and continuing through midadolescence. Patterns of nevus acquisition differ between boys and girls, Hispanic and non-Hispanic white youths, and body sites that are chronically exposed to the sun and body sites that are intermittently exposed to the sun. Exposure to UV light during this period should be reduced, particularly on body sites intermittently exposed to the sun, where nevi accumulate through midadolescence in all children. Increased attention to sun protection appears to be merited for boys, in general, because they accumulated more nevi overall, and for girls, specifically, during the adolescent years.