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1.  Accuracy of Clinicians and Models for Estimating the Probability That a Pulmonary Nodule Is Malignant 
Rationale: Management of pulmonary nodules depends critically on the probability of malignancy. Models to estimate probability have been developed and validated, but most clinicians rely on judgment.
Objectives: The aim of this study was to compare the accuracy of clinical judgment with that of two prediction models.
Methods: Physician participants reviewed up to five clinical vignettes, selected at random from a larger pool of 35 vignettes, all based on actual patients with lung nodules of known final diagnosis. Vignettes included clinical information and a representative slice from computed tomography. Clinicians estimated the probability of malignancy for each vignette. To examine agreement with models, we calculated intraclass correlation coefficients (ICC) and kappa statistics. To examine accuracy, we compared areas under the receiver operator characteristic curve (AUC).
Measurements and Main Results: Thirty-six participants completed 179 vignettes, 47% of which described patients with malignant nodules. Agreement between participants and models was fair for the Mayo Clinic model (ICC, 0.37; 95% confidence interval [CI], 0.23–0.50) and moderate for the Veterans Affairs model (ICC, 0.46; 95% CI, 0.34–0.57). There was no difference in accuracy between participants (AUC, 0.70; 95% CI, 0.62–0.77) and the Mayo Clinic model (AUC, 0.71; 95% CI, 0.62–0.80; P = 0.90) or the Veterans Affairs model (AUC, 0.72; 95% CI, 0.64–0.80; P = 0.54).
Conclusions: In this vignette-based study, clinical judgment and models appeared to have similar accuracy for lung nodule characterization, but agreement between judgment and the models was modest, suggesting that qualitative and quantitative approaches may provide complementary information.
PMCID: PMC3960964  PMID: 24063427
solitary pulmonary nodule; diagnosis; prediction models
2.  Systematic reviews of observational studies of risk of thrombosis and bleeding in urological surgery (ROTBUS): introduction and methodology 
Systematic Reviews  2014;3:150.
Pharmacological thromboprophylaxis in the peri-operative period involves a trade-off between reduction in venous thromboembolism (VTE) and an increase in bleeding. Baseline risks, in the absence of prophylaxis, for VTE and bleeding are known to vary widely between urological procedures, but their magnitude is highly uncertain. Systematic reviews and meta-analyses addressing baseline risks are uncommon, needed, and require methodological innovation. In this article, we describe the rationale and methods for a series of systematic reviews of the risks of symptomatic VTE and bleeding requiring reoperation in urological surgery.
We searched MEDLINE from January 1, 2000 until April 10, 2014 for observational studies reporting on symptomatic VTE or bleeding after urological procedures. Additional studies known to experts and studies cited in relevant review articles were added. Teams of two reviewers, independently assessed articles for eligibility, evaluated risk of bias, and abstracted data. We derived best estimates of risk from the median estimates among studies rated at the lowest risk of bias. The primary endpoints were 30-day post-operative risk estimates of symptomatic VTE and bleeding requiring reoperation, stratified by procedure and patient risk factors.
This series of systematic reviews will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding. Our work advances standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at best estimates of risk (including modeling of timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate certainty in estimates of risk. The results will be incorporated in the upcoming European Association Urology Guideline on Thromboprophylaxis.
Systematic review registration
PROSPERO CRD42014010342.
Electronic supplementary material
The online version of this article (doi:10.1186/2046-4053-3-150) contains supplementary material, which is available to authorized users.
PMCID: PMC4307154  PMID: 25540016
Baseline risk; Bleeding; Hemorrhage; Modeling; Risk of bias; Surgical complications; Thromboprophylaxis; Thrombosis; Urology
3.  Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study protocol for a randomized controlled trial 
Trials  2014;15:502.
Venous thromboembolism (VTE) is a common complication of critical illness with important clinical consequences. The Prophylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) is a multicenter, blinded, randomized controlled trial comparing the effectiveness of the two most common pharmocoprevention strategies, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) dalteparin, in medical-surgical patients in the intensive care unit (ICU). E-PROTECT is a prospective and concurrent economic evaluation of the PROTECT trial.
The primary objective of E-PROTECT is to identify and quantify the total (direct and indirect, variable and fixed) costs associated with the management of critically ill patients participating in the PROTECT trial, and, to combine costs and outcome results to determine the incremental cost-effectiveness of LMWH versus UFH, from the acute healthcare system perspective, over a data-rich time horizon of ICU admission and hospital admission. We derive baseline characteristics and probabilities of in-ICU and in-hospital events from all enrolled patients. Total costs are derived from centers, proportional to the numbers of patients enrolled in each country. Direct costs include medication, physician and other personnel costs, diagnostic radiology and laboratory testing, operative and non-operative procedures, costs associated with bleeding, transfusions and treatment-related complications. Indirect costs include ICU and hospital ward overhead costs. Outcomes are the ratio of incremental costs per incremental effects of LMWH versus UFH during hospitalization; incremental cost to prevent a thrombosis at any site (primary outcome); incremental cost to prevent a pulmonary embolism, deep vein thrombosis, major bleeding event or episode of heparin-induced thrombocytopenia (secondary outcomes) and incremental cost per life-year gained (tertiary outcome). Pre-specified subgroups and sensitivity analyses will be performed and confidence intervals for the estimates of incremental cost-effectiveness will be obtained using bootstrapping.
This economic evaluation employs a prospective costing methodology concurrent with a randomized controlled blinded clinical trial, with a pre-specified analytic plan, outcome measures, subgroup and sensitivity analyses. This economic evaluation has received only peer-reviewed funding and funders will not play a role in the generation, analysis or decision to submit the manuscripts for publication.
Trial registration Identifier: NCT00182143. Date of registration: 10 September 2005.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-502) contains supplementary material, which is available to authorized users.
PMCID: PMC4413997  PMID: 25528663
Economic; Cost-effectiveness; Venous; Thromboembolism; PROTECT; Unfractionated; Heparin; Low molecular weight; Intensive; Critical
4.  Sociodemographic Characteristics of Members of a Large, Integrated Health Care System: Comparison with US Census Bureau Data 
The Permanente Journal  2012;16(3):37-41.
Background: Data from the memberships of large, integrated health care systems can be valuable for clinical, epidemiologic, and health services research, but a potential selection bias may threaten the inference to the population of interest.
Methods: We reviewed administrative records of members of Kaiser Permanente Southern California (KPSC) in 2000 and 2010, and we compared their sociodemographic characteristics with those of the underlying population in the coverage area on the basis of US Census Bureau data.
Results: We identified 3,328,579 KPSC members in 2000 and 3,357,959 KPSC members in 2010, representing approximately 16% of the population in the coverage area. The distribution of sex and age of KPSC members appeared to be similar to the census reference population in 2000 and 2010 except with a slightly higher proportion of 40 to 64 year olds. The proportion of Hispanics/Latinos was comparable between KPSC and the census reference population (37.5% vs 38.2%, respectively, in 2000 and 45.2% vs 43.3% in 2010). However, KPSC members included more blacks (14.9% vs 7.0% in 2000 and 10.8% vs 6.5% in 2010). Neighborhood educational levels and neighborhood household incomes were generally similar between KPSC members and the census reference population, but with a marginal underrepresentation of individuals with extremely low income and high education.
Conclusions: The membership of KPSC reflects the socioeconomic diversity of the Southern California census population, suggesting that findings from this setting may provide valid inference for clinical, epidemiologic, and health services research.
PMCID: PMC3442759  PMID: 23012597
5.  Patient Preference and Contraindications in Measuring Quality of Care: What Do Administrative Data Miss? 
Journal of Clinical Oncology  2013;31(21):2716-2723.
Prior studies report that half of patients with lung cancer do not receive guideline-concordant care. With data from a national Veterans Health Administration (VHA) study on quality of care, we sought to determine what proportion of patients refused or had a contraindication to recommended lung cancer therapy.
Patients and Methods
Through medical record abstraction, we evaluated adherence to six quality indicators addressing lung cancer–directed therapy for patients diagnosed within the VHA during 2007 and calculated the proportion of patients receiving, refusing, or having contraindications to recommended treatment.
Mean age of the predominantly male population was 67.7 years (standard deviation, 9.4 years), and 15% were black. Adherence to quality indicators ranged from 81% for adjuvant chemotherapy to 98% for curative resection; however, many patients met quality indicator criteria without actually receiving recommended therapy by having a refusal (0% to 14%) or contraindication (1% to 30%) documented. Less than 1% of patients refused palliative chemotherapy. Black patients were more likely to refuse or bear a contraindication to surgery even when controlling for comorbidity; race was not associated with refusals or contraindications to other treatments.
Refusals and contraindications are common and may account for previously demonstrated low rates of recommended lung cancer therapy performance at the VHA. Racial disparities in treatment may be explained, in part, by such factors. These results sound a cautionary note for quality measurement that depends on data that do not reflect patient preference or contraindications in conditions where such considerations are important.
PMCID: PMC3709057  PMID: 23752110
6.  Resource Use and Guideline Concordance in Evaluation of Pulmonary Nodules for Cancer: Too much and too little care 
JAMA internal medicine  2014;174(6):871-880.
Pulmonary nodules are common, and more will be found with implementation of lung cancer screening. How potentially malignant pulmonary nodules are evaluated may affect patient outcomes, healthcare costs, and effectiveness of lung cancer screening programs. Guidelines for evaluating pulmonary nodules for cancer exist, but little is known about how nodules are evaluated in the usual care setting.
To characterize nodule evaluation and concordance with guidelines
Retrospective cohort study, including detailed chart review from nodule detection through evaluation completion, cancer diagnosis, or study end (12/31/12)
Fifteen VA hospitals
300 adult patients with pulmonary nodules
Main outcomes and measures
Resources used for evaluation at any VA facility; guideline-concordant evaluation.
Among 300 patients with pulmonary nodules, 9% (27/300) were ultimately diagnosed with lung cancer: 1/57 (2%) with a nodule ≤4 mm, 4/134 (3%) with a nodule 5–8 mm, and 20% (22/109) with a nodule >8 mm. Nodule evaluation entailed 1044 imaging studies, 147 consultations, 76 biopsies, 13 resections, and 21 hospitalizations. Radiographic surveillance (n=277) lasted a median of 13 months, but ranged from <1 month to 8.5 years. Forty-six patients underwent invasive procedures (range per patient 1–4): 42% (19/46) did not have cancer, and 17% (8/46) experienced complications, including one death. Notably, 15/300 (5%) “fell through the cracks,” without purposeful evaluation or obvious reason for deferral. Among 197 patients with a nodule detected after release of the Fleischner Society guidelines, 45% received care inconsistent with guidelines (18% over-evaluation, 27% under-evaluation). In multivariable analyses, the strongest predictor of guideline-inconsistent care was inappropriate radiologist recommendations (over-evaluation: RR 4.5, [95% CI 2.3–8.7]; under-evaluation: RR 4.3 [2.7–6.8]). Other systems factors associated with under-evaluation included receiving care at more than one facility (RR 2.0 [1.5–2.7]) and nodule detection during an inpatient or preoperative visit (RR 1.6 [1.1–2.5]).
Conclusions and Relevance
Pulmonary nodule evaluation is often inconsistent with guidelines, including cases with no work-up and others with prolonged surveillance or unneeded procedures that may cause harm. Systems to improve quality (e.g., aligning radiologist recommendations with guidelines; facilitating communication across providers) are needed before lung cancer screening is widely implemented.
PMCID: PMC4266552  PMID: 24710850
7.  Predicting In-Hospital Mortality among Critically-Ill Patients with End-Stage Liver Disease 
Journal of critical care  2012;27(6):740.e1-740.e7.
Critically-ill patients with end-stage liver disease (ESLD) are at high risk for death during intensive care unit (ICU) hospitalization, and currently available prognostic models have limited accuracy in this population. We aimed to identify variables associated with in-hospital mortality among critically-ill ESLD patients, and to develop and validate a simple, parsimonious model for bedside use.
Materials and Methods
We performed a retrospective chart review of 653 ICU admissions for ESLD patients; modeled in-hospital mortality using multivariable logistic regression; and compared the predictive ability of several different models using the area under receiver operating characteristic (AU-ROC) curves.
Multivariable predictors of in-hospital mortality included Model for End-stage Liver Disease (MELD) score, Acute Physiology and Chronic Health Evaluation (APACHE) II score, mechanical ventilation, and gender; there was also an interaction between MELD score and gender (p<0.02). MELD alone had better discrimination (AU-ROC 0.83) than APACHE II alone (AU-ROC 0.76), and adding mechanical ventilation to MELD achieved the single largest increase in model discrimination (AU-ROC 0.85; p<0.01). In a parsimonious, two-predictor model, higher MELD scores (OR 1.14 per 1-point increase; 95% CI 1.11 – 1.16), and mechanical ventilation (OR 6.20; 95% CI 3.05 – 12.58) were associated with increased odds of death. Model discrimination was also excellent in the validation cohort (AU-ROC 0.90).
In critically-ill ESLD patients, a parsimonious model including only MELD and mechanical ventilation is more accurate than APACHE II alone for predicting in-hospital mortality. This simple bedside model can provide clinicians and patients with valuable prognostic information for medical decision-making.
PMCID: PMC4405501  PMID: 23059012
8.  The Use and Misuse of Positron Emission Tomography in Lung Cancer Evaluation 
Clinics in chest medicine  2011;32(4):749-762.
Positron emission tomography (PET) has been studied for a variety of indications in patients with known or suspected non-small cell lung cancer (NSCLC). In this review, we discuss the potential benefits and limitations of PET for characterizing lung nodules, staging the mediastinum, identifying occult distant metastasis, determining prognosis and treatment response, guiding plans for radiation therapy, restaging during and after treatment, and selecting targets for tissue sampling. (Table 1) Evidence from randomized, controlled trials supports the use of PET for initial staging in NSCLC, while lower quality evidence from studies of diagnostic accuracy and modeling studies supports the use of PET for characterizing lung nodules. For most other indications in NSCLC, additional studies are required to clarify the role of PET and determine who is most likely to benefit.
PMCID: PMC3210441  PMID: 22054883
9.  Disparities in lung cancer staging with positron emission tomography in the Cancer Care Outcomes Research and Surveillance (CanCORS) study 
Disparities in treatment exist for non-white and Hispanic patients with non-small-cell lung cancer, but little is known about disparities in the use of staging tests or their underlying causes.
Prospective, observational cohort study of 3638 patients with newly diagnosed non-small-cell lung cancer from 4 large, geographically-defined regions, 5 integrated health care systems and 13 VA health care facilities.
Median age was 69 years, 62% were men, 26% were Hispanic or non-white, 68% graduated high school, 50% had private insurance, and 41% received care in the VA or another integrated health care system. After adjustment, PET use was 13% lower among non-whites and Hispanics than non-Hispanic whites (RR 0.87, 95% CI 0.77 to 0.97), 13% lower among those with Medicare than those with private insurance (RR 0.87, 95% CI 0.76 to 0.99), and 24% lower among those with an elementary school education than those with a graduate degree (RR 0.76, 95% CI 0.57 to 0.98). Disparate use of PET was not observed among patients who received care in an integrated health care setting, but the association between race/ethnicity and PET use was similar in magnitude across all other subgroups. Further analysis showed that income, education, insurance and health care setting do not explain the association between race/ethnicity and PET use.
Hispanics and non-whites with non-small-cell lung cancer are less likely to receive PET imaging. This finding is consistent across subgroups and not explained by differences in income, education, or insurance coverage.
PMCID: PMC3092472  PMID: 21572580
lung neoplasms; carcinoma; non-small-cell lung; neoplasm staging; tomography; emission-computed; healthcare disparities
10.  A Clinical Model To Estimate the Pretest Probability of Lung Cancer in Patients With Solitary Pulmonary Nodules 
Chest  2007;131(2):383-388.
Estimating the clinical probability of malignancy in patients with a solitary pulmonary nodule (SPN) can facilitate the selection and interpretation of subsequent diagnostic tests.
We used multiple logistic regression analysis to identify independent clinical predictors of malignancy and to develop a parsimonious clinical prediction model to estimate the pretest probability of malignancy in a geographically diverse sample of 375 veterans with SPNs. We used data from Department of Veterans Affairs (VA) administrative databases and a recently completed VA Cooperative Study that evaluated the accuracy of positron emission tomography (PET) scans for the diagnosis of SPNs.
The mean (± SD) age of subjects in the sample was 65.9 ± 10.7 years. The prevalence of malignant SPNs was 54%. Most participants were either current smokers (n = 177) or former smokers (n = 177). Independent predictors of malignant SPNs included a positive smoking history (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.6 to 23.6), older age (OR, 2.2 per 10-year increment; 95% CI, 1.7 to 2.8), larger nodule diameter (OR, 1.1 per 1-mm increment; 95% CI, 1.1 to 1.2), and time since quitting smoking (OR, 0.6 per 10-year increment; 95% CI, 0.5 to 0.7). Model accuracy was very good (area under the curve of the receiver operating characteristic, 0.79; 95% CI, 0.74 to 0.84), and there was excellent agreement between the predicted probability and the observed frequency of malignant SPNs.
Our prediction rule can be used to estimate the pretest probability of malignancy in patients with SPNs, and thereby facilitate clinical decision making when selecting and interpreting the results of diagnostic tests such as PET imaging.
PMCID: PMC3008547  PMID: 17296637
coin lesion; diagnosis; lung neoplasms; pulmonary; receiver operating characteristic curve; statistical models; veterans
11.  “The thing is not knowing”: Patients' perspectives on surveillance of an indeterminate pulmonary nodule 
The hundreds of thousands of patients found to have a potentially malignant pulmonary nodule each year are faced with tremendous uncertainty regarding what the nodule is and how it should be evaluated.
To explore Patients' responses to the detection and evaluation of a pulmonary nodule
Qualitative study based on 4 focus group discussions. We performed inductive analysis using principles of grounded theory to identify themes relating to responses to the nodule and strategies to manage uncertainty.
Setting and Participants
22 patients from 2 medical centers who were undergoing surveillance for an indeterminate pulmonary nodule
Patient responses to an indeterminate pulmonary nodule were varied and evolved over time. Although almost all patients reported an initial fear about cancer, subsequent depictions of the nodule diverged into 4 types defined on two dimensions: cognitive (“it's cancer” vs. “I don't know what it is” vs. “it's nothing serious”) and emotional (anxiety vs. equanimity). Most eventually accepted that the nodule was unlikely to be malignant; however, some remained anxious, convinced the nodule could turn into cancer at any time and should be aggressively monitored for life. Patients used results of surveillance tests as well as their own strategies (e.g., vigilance for symptoms, information-seeking, contemplating and controlling modifiable risk factors, avoidance, faith) to manage uncertainty.
Surveillance for a pulmonary nodule can weigh heavily on some patients for months or years. Our findings may help clinicians prepare patients with a newly detected pulmonary nodule for the burden of the prolonged uncertainty of surveillance.
PMCID: PMC3880393  PMID: 23252477
Watchful Waiting; Solitary Pulmonary Nodule; Qualitative research; Patient centered care; Uncertainty; Anxiety
12.  Advancing Clinical Practice and Policy through Guidelines. The Role of the American Thoracic Society 
In the face of an overwhelmingly large and growing medical literature, providers often turn to clinical practice guidelines to inform the decisions they make with patients. By systematically appraising the evidence and providing transparent recommendations for practice, guidelines have the potential to improve both bedside decision-making and health policy. This potential has not been fully realized because most guidelines lack transparency, are tainted by conflicts of interest, or fail to employ rigorous methods to appraise the evidence. To address the shortcomings of past guidelines, the Institute of Medicine (IOM) published recommendations for trustworthy guidelines, effectively setting the “gold standard” for what constitutes a high-quality guideline. Along with many other groups that develop guidelines, the American Thoracic Society (ATS) is rapidly evolving processes for development and implementation to meet many of the IOM standards. This Pulmonary Perspective describes the rapidly changing landscape of clinical practice guidelines, the role of the ATS in this landscape, and the activities the ATS is engaged in to ensure that the guidelines it produces are of the highest quality with the broadest impact.
PMCID: PMC3707361  PMID: 23392437
clinical practice variation; standards of care; evidence-based medicine; professional organizations; pay for performance
13.  Risks of Transthoracic Needle Biopsy: How High? 
Clinical pulmonary medicine  2013;20(1):29-35.
Transthoracic needle lung biopsy is a commonly performed diagnostic procedure for pulmonary nodules and masses. To make an informed decision about whether to pursue this procedure, doctors and patients must be aware of the possible risks of the procedure. We performed a MEDLINE search, 2003–2012 to identify relevant English-language studies that included at least 100 subjects and reported data on complications of transthoracic needle lung biopsy performed within the last 10 years. We found the most common complication to be any pneumothorax (risk 15–25%), with pneumothorax requiring chest tube occurring less often (risk 4-6%). Hemorrhage, defined as radiographically visualized blood along the needle tract was common, but clinically significant hemorrhage was infrequent (~1%). Rare complications, including air embolism and tumor seeding of the biopsy tract, occurred in fewer than 1% of cases but were potentially serious. We summarize data on factors associated with complications, including patient age, COPD, lesion size and location, and number of punctures. We also provide data on techniques to mitigate severity of pneumothorax post-biopsy, such as rapid patient rollover, manual aspiration, and instillation of substances into the biopsy tract.
PMCID: PMC3601755  PMID: 23525679
Needle Biopsy; Pulmonary nodule; Complications
14.  Automated Identification of Patients with Pulmonary Nodules in an Integrated Health System Using Administrative Health Plan Data, Radiology Reports, and Natural Language Processing 
Lung nodules are commonly encountered in clinical practice, yet little is known about their management in community settings. An automated method for identifying patients with lung nodules would greatly facilitate research in this area.
Using members of a large, community-based health plan in 2006–2010, we developed a method to identify patients with lung nodules by combining five diagnostic codes, four procedural codes and a natural language processing (NLP) algorithm that performed free text searches of radiology transcripts. An experienced pulmonologist reviewed a random sample of 116 radiology transcripts, providing a reference standard for the NLP algorithm.
We identified 7,112 unique members as having one or more incident lung nodules using an automated method. The mean age was 65 (SD 14) years. There were slightly more women (54%) than men, and Hispanics and non-whites comprised 45% of the lung nodule cohort. Thirty-six percent were never smokers while 11% were current smokers. Fourteen percent were subsequently diagnosed with lung cancer. The sensitivity and specificity of the NLP algorithm for identifying the presence of lung nodule(s) were 96% and 86%, respectively, compared with clinician review. Among the true positive transcripts in the validation sample, only 35% were solitary and unaccompanied by one or more associated findings and 56% measured 8–30 mm in diameter.
A combination of diagnostic codes, procedural codes and an NLP algorithm for free text searching of radiology reports can accurately and efficiently identify patients with incident lung nodules, many of whom are subsequently diagnosed with lung cancer.
PMCID: PMC3443078  PMID: 22627647
lung nodules; pulmonary coin lesion; lung cancer; natural language processing (NLP); validation study
15.  Benefits and Harms of CT Screening for Lung Cancer: A Systematic Review 
Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low five-year survival rate. Screening may reduce the risk of death from lung cancer.
A multi-society collaborative initiative (involving the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network) was undertaken to conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low dose computed tomography (LDCT), in order to create the foundation for development of an evidence-based clinical guideline.
Data Sources
MEDLINE (OVID: 1996 to April 2012), EMBASE (OVID: 1996 to April 2012), and the Cochrane Library (April 2012).
Study Selection
Of 591 citations identified and reviewed, eight randomized controlled trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation.
Data Extraction
Critical appraisal using pre-defined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus.
Three randomized studies provided evidence on the impact of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer-specific mortality, 247 vs 309 events per 100,000 person-years for LDCT and control groups, respectively; Relative Risk [RR] = 0.80, 95% Confidence Interval [CI] 0.73–0.93; Absolute Risk Reduction [ARR] = 0.33%, P=0.004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, about 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and the percent of surgical procedures performed in those with benign lesions. Major complications in those with benign conditions were rare.
LDCT screening may benefit individuals at an elevated risk for lung cancer, but uncertainty exists about potential harms and the generalizability of results.
PMCID: PMC3709596  PMID: 22610500
16.  Decision Making in Patients with Pulmonary Nodules 
Integrating current evidence with fundamental concepts from decision analysis suggests that management of patients with pulmonary nodules should begin with estimating the pretest probability of cancer from the patient's clinical risk factors and computed tomography characteristics. Then, the consequences of treatment should be considered, by comparing the benefits of surgery if the patient has lung cancer with the potential harm if the patient does not have cancer. This analysis determines the “treatment threshold,” which is the point around which the decision centers. This varies widely among patients depending on their cardiopulmonary reserve, comorbidities, and individual preferences. For patients with a very low probability of cancer, careful observation with serial computed tomography is warranted. For those with a high probability of cancer, surgical diagnosis is warranted. For patients in the intermediate range of probabilities, either computed tomography–guided fine-needle aspiration biopsy or positron emission tomography, possibly followed by computed tomography–guided fine-needle aspiration biopsy, is best. Patient preferences should be considered because the absolute difference in outcome between strategies may be small. The optimal approach to the management of patients with pulmonary nodules is evolving as technologies develop. Areas of uncertainty include quantifying the hazard of delayed diagnosis; determining the optimal duration of follow-up for ground-glass and semisolid opacities; establishing the roles of volumetric imaging, advanced bronchoscopic technologies, and limited surgical resections; and calculating the cost-effectiveness of different strategies.
PMCID: PMC3361350  PMID: 21980032
lung cancer; solitary pulmonary nodule; lung cancer screening; positron emission tomography; lung nodule
17.  Lung cancer stage at diagnosis: Individual associations in the prospective VITamins and lifestyle (VITAL) cohort 
BMC Cancer  2011;11:228.
Lung cancer is the leading cause of cancer death in the United States. Identifying factors associated with stage of diagnosis can improve our understanding of biologic and behavioral pathways of lung cancer development and detection. We used data from a prospective cohort study to evaluate associations of demographic, health history, and health behaviors with early versus late stage at diagnosis of non-small cell lung cancer (NSCLC).
We calculated odds ratios (ORs) for the association of patient-level characteristics with advanced stage of diagnosis for NSCLC. The OR's were then adjusted for age, gender, race/ethnicity, smoking status, income, education, chronic obstructive pulmonary disease, and a comorbidity index.
We identified 612 cases of NSCLC among 77,719 adults, aged 50 to 76 years from Washington State recruited in 2000-2002, with followup through December 2007. In univariate analyses, subjects who quit smoking <10 years (OR 2.56, 95% CI 1.17 - 5.60) and were college graduates (OR 1.67, 95% CI, 1.00 - 2.76) had increased risks of being diagnosed with advanced stage NSCLC, compared to never smokers and non-college graduates, respectively. Receipt of sigmoidoscopy/colonoscopy, compared to no receipt, was associated with a decreased risk of advanced stage (OR 0.65, 95% CI, 0.43 - 0.99). The adjusted OR for receipt of sigmoidoscopy/colonoscopy was 0.55 (95% CI, 0.36 - 0.86). There was evidence that increasing the number of screening activities was associated with a decreased risk of advanced stage NSCLC (P for trend = 0.049).
Smoking status, education, and a screening activity were associated with stage at diagnosis of NSCLC. These results may guide future studies of the underlying mechanisms that influence how NSCLC is detected and diagnosed.
PMCID: PMC3129325  PMID: 21649915
18.  Impact of the Lung Allocation Score on Lung Transplantation for Pulmonary Arterial Hypertension 
Rationale: In 2005, lung allocation for transplantation in the United States changed from a system based on waiting time to a system based on the Lung Allocation Score (LAS).
Objectives: To study the effect of the LAS on lung transplantation for idiopathic pulmonary arterial hypertension (IPAH) compared with other major diagnoses.
Methods: We studied 7,952 adults listed for lung transplantation between 2002 and 2008. Analyses were restricted to patients with IPAH, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). Transplantation, waiting list mortality, and post-transplant mortality were compared between diagnoses for patients listed before and after implementation of the LAS.
Measurements and Main Results: The likelihood of transplantation from the waiting list increased for all diagnoses after implementation of the LAS. Waiting list mortality decreased for every diagnosis, except for IPAH, which remained unchanged. Implementation of the LAS was not associated with changes in post-transplant mortality for any diagnosis. Under the LAS system, patients with IPAH were less likely to be transplanted than patients with IPF (hazard ratio [HR], 0.53; P < 0.001) or CF (HR, 0.49; P < 0.001) and at greater risk of death on the waiting list than patients with COPD (HR, 3.09; P < 0.001) or CF (HR, 1.83; P = 0.025) after adjustment for demographics and transplant type. Post-transplant mortality for IPAH was not statistically different from that of other diagnoses.
Conclusions: Implementation of the LAS has improved the likelihood of lung transplantation for listed patients with IPAH, but mortality on the waiting list remains high compared with other major diagnoses.
PMCID: PMC2742763  PMID: 19520906
lung transplantation; pulmonary arterial hypertension; lung allocation score
19.  Brief Report: Variation in Experts’ Beliefs about Lung Cancer Growth, Progression and Prognosis 
Little is known about the natural history of malignant solitary pulmonary nodules (SPN). Experts’ beliefs may help fill these knowledge gaps and explain variation in clinical practices.
Using a modified Delphi process, we surveyed a group of lung cancer experts about tumor growth, disease progression and prognosis in patients with malignant SPN. After completing the first survey, experts were given the opportunity during a second survey to revise their responses in light of their peers’ beliefs.
The response rate was 100% (14/14) for both surveys. There was consensus that disease progression depends on the tumor growth rate, that survival for patients with untreated lung cancer is approximated by a declining exponential function, and that treatment is delayed by approximately 1 tumor volume doubling time (TVDT) in patients who undergo a period of “watchful waiting”. Just over half of experts (8/14) agreed that lung cancer progresses in 3steps (from local to regional to distant disease), while 43% (6/14) preferred a 2-step model (from local to systemic disease). Likewise, 64% of experts (9/14) believed that malignant nodules grow exponentially, while 36% (5/14) believed that growth is slower than exponential. Experts’ estimates of the risk of disease progression during a period of observation lasting 1 TVDT varied from 1% to 50%. Estimates of 5-year survival for patients in whom diagnosis and treatment were delayed by 1 TVDT varied between 40% and 80%.
There is substantial variability in experts’ beliefs about the natural history of untreated, malignant SPN. Different beliefs may be partly responsible for variation in management practices.
PMCID: PMC2903546  PMID: 18379363
Lung Neoplasms; Coin lesion; pulmonary; Delphi technique; survival; disease progression; tumor growth
20.  Validation of Two Models to Estimate the Probability of Malignancy in Patients with Solitary Pulmonary Nodules 
Thorax  2007;63(4):335-341.
Effective strategies for managing patients with solitary pulmonary nodules (SPN) depend critically on the pre-test probability of malignancy.
To validate two previously developed models that estimate the probability that an indeterminate solitary pulmonary nodule (SPN) is malignant, based on clinical characteristics and radiographic findings.
We retrospectively collected data on age, smoking and cancer history, nodule size, location, and spiculation from the medical records of 151 veterans (145 men, 6 women; range 39 to 87 years) with an SPN measuring 7 to 30 mm (inclusive) and a final diagnosis established by histopathology or 2-year follow-up. We compared each patient's final diagnosis to the probability of malignancy predicted by two models: one developed by investigators at the Mayo Clinic and another that we developed from patients enrolled in a VA Cooperative Study. We assessed model accuracy by calculating areas under the receiver operating characteristic (ROC) curve and model calibration by comparing predicted and observed rates of malignancy.
The area under the ROC curve for the Mayo Clinic model (0.80; 95% CI 0.72-0.88) was higher than that of the VA model (0.73; 95% CI 0.64-0.82), but this difference was not statistically significant (P=0.10). Calibration curves showed that the probability of malignancy was underestimated by the Mayo Clinic model and overestimated by the VA model.
Two existing prediction models are sufficiently accurate to guide decisions about the selection and interpretation of subsequent diagnostic tests in patients with SPNs, although clinicians should also consider the prevalence of malignancy in their practice setting when choosing a model.
PMCID: PMC2882437  PMID: 17965070
Lung Neoplasms; Coin Lesion; pulmonary; Diagnosis; Models; statistical; Receiver Operating Characteristic (ROC) curve
21.  Identification of Early Acute Lung Injury at Initial Evaluation in an Acute Care Setting Prior to the Onset of Respiratory Failure* 
Chest  2009;135(4):936-943.
Despite being a focus of intensive investigation, acute lung injury (ALI) remains a major cause of morbidity and mortality. However, the current consensus definition impedes identification of patients with ALI before they require mechanical ventilation. To establish a definition of early ALI (EALI), we carried out a prospective cohort study to identify clinical predictors of progression to ALI.
Potential cases of EALI were identified by daily screening of chest radiographs (CXRs) for all adult emergency department and new medicine service admissions at Stanford University Hospital.
Of 1,935 screened patients with abnormal CXRs, we enrolled 100 patients admitted with bilateral opacities present < 7 days and not due exclusively to left atrial hypertension. A total of 33 of these 100 patients progressed to ALI requiring mechanical ventilation during their hospitalization. Progression to ALI was associated with immunosuppression, the modified Rapid Emergency Medicine Score, airspace opacities beyond the bases, systemic inflammatory response syndrome, and the initial oxygen requirement (> 2 L/min). On multivariate analysis, only an initial oxygen requirement > 2 L/min predicted progression to ALI (odds ratio, 8.1; 95% confidence interval, 2.7 to 24.5). A clinical diagnosis of EALI, defined by hospital admission with bilateral opacities on CXR not exclusively due to left atrial hypertension and an initial oxygen requirement of > 2 L/min, was 73% sensitive and 79% specific for progression to ALI.
A new clinical definition of EALI may have value in identifying patients with ALI early in their disease course.
PMCID: PMC2758305  PMID: 19188549
acute lung injury; ARDS; diagnosis; multivariate analysis; prognosis; sensitivity; specificity
22.  Lung cancer incidence in never-smokers 
Lung cancer is a leading cause of cancer death worldwide. While smoking remains the predominant cause of lung cancer, lung cancer in never-smokers is an increasingly prominent public health issue. Data on this topic, particularly lung cancer incidence rates in never-smokers, however, are limited.
We review the existing literature on lung cancer incidence and mortality rates among never-smokers and present new data regarding rates in never-smokers from large, population-based cohorts: 1) Nurses’ Health Study, 2) Health Professionals Follow-up Study, 3) California Teachers Study, 4) Multiethnic Cohort Study, 5) Swedish Lung Cancer Register in the Uppsala/Örebro region, and the 6) First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.
Truncated age-adjusted incidence rates of lung cancer among never-smokers aged 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never-smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never-smokers.
Lung cancer in never-smokers is an important public health issue needing further exploration of its incidence patterns, etiology, and biology.
PMCID: PMC2764546  PMID: 17290054
23.  Patients' perspectives on how idiopathic pulmonary fibrosis affects the quality of their lives 
Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with a survival of only three to five years from the time of diagnosis. Due to a paucity of studies, large gaps remain in our understanding of how IPF affects the quality of patients' lives. In only one other study did investigators ask patients directly for their perspectives on this topic. Further, currently there is no disease-specific instrument to measure health-related quality of life (HRQL) in patients with IPF. A carefully constructed measurement instrument, sensitive to underlying change, is needed for use in clinical trials and longitudinal studies of patients with IPF. Before developing such an instrument, researchers must improve their understanding of the relevant effects of IPF on patients' lives. On a broader scale, to provide the best care for people with IPF, clinicians must appreciate – from patients' perspectives – how this disease affects various aspects of their lives.
We used focus groups and individual in-depth interviews with 20 IPF patients to collect their perspectives on how IPF affects their lives (with a focus on the quality of their lives). We then analyzed these perspectives and organized them into a conceptual framework for describing HRQL in patients with IPF. Next, we examined how well certain existing measurement instruments – which have been administered to IPF patients in prior studies – covered the domains and topics our patients identified.
In our framework, we identified 12 primary domains: symptoms, IPF therapy, sleep, exhaustion, forethought, employment and finances, dependence, family, sexual relations, social participation, mental and spiritual well-being, mortality. Each domain is composed of several topics, which describe how IPF affects patients' lives. When we compared the content of our conceptual framework with the existing instruments, we found the coverage of the existing instruments to be inadequate for several reasons, including they may tap general areas of QOL or HRQL but not some areas that appear to be most directly affected by IPF, and they include items that are relevant to symptoms and effects of other respiratory diseases but not IPF.
Collecting patients' perspectives and developing an organized inventory of the relevant effects of IPF on patients' lives provides valuable information for improving our understanding of the impact of this disease on patients and their loved ones. We believe our findings will help alert clinicians and researchers to IPF patients' experiences and concerns. Based on the comparison or our conceptual framework with the content of four existing instruments, it would appear that developing an IPF-specific measurement instrument is justified. Our conceptual framework for describing health-related quality of life in patients with IPF lays a solid foundation for constructing such an instrument.
PMCID: PMC1276807  PMID: 16212668
Pulmonary fibrosis; interstitial lung disease; quality of life; Health-related quality of life; qualitative.

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