Beyond Randomized Clinical Trials: Use of External Controls.

Randomized controlled trials are the gold standard to investigate efficacy and safety of new treatments. In certain settings, however, randomizing patients to control may be difficult for ethical or feasibility reasons. Borrowing strength using relevant individual patient data on control from external trials or real-world data (RWD) sources may then allow us to reduce, or even eliminate, the concurrent control group. Naive direct use of external control data is not valid due to differences in patient characteristics and other confounding factors. Instead, we suggest the rigorous application of meta-analytic and propensity score methods to use external controls in a principled way. We illustrate these methods with two case studies: (i) a single-arm trial in a rare cancer disease, using propensity score matching to construct an external control from RWD; (ii) a randomized trial in children with multiple sclerosis, borrowing strength from past trials using a Bayesian meta-analytic approach.

Correction: Real-world management of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in the USA.

[This corrects the article DOI: 10.1371/journal.pone.0209709.].

Real-world management of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in the USA.

BACKGROUND: Randomized phase III trials have established the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line treatment for EGFR mutation-positive advanced non-small-cell lung cancer (EGFR Mut+ NSCLC). This retrospective cohort study examined the management patterns and outcomes of patients with EGFR Mut+ NSCLC in a real-world setting. MATERIALS AND METHODS: Data were extracted from the US Flatiron Electronic Health Record-derived database. Adult patients with stage IIIB/IV EGFR Mut+ NSCLC (exon 19 deletion or exon 21 L858R mutation) who had received first-line systemic therapy between 2011 and 2016 were included. Demographic and clinical characteristics were analyzed. Outcomes evaluated were time to next treatment (a surrogate for progression-free survival) and overall survival. RESULTS: Of the 22,258 patients with advanced NSCLC in the database, 961 met the inclusion criteria. Median age was 69.0 years (range: 61-78) and the majority were female (68.0%), with stage IV (93.9%), non-squamous cell carcinoma (97.4%). EGFR tyrosine kinase inhibitors were the most widely prescribed first-line therapy (72.8%). The likelihood of receiving an EGFR tyrosine kinase inhibitor or chemotherapy was unaffected by the type of medical insurance patients had. Patients treated with an EGFR tyrosine kinase inhibitor had significantly longer time to next treatment than those given other first-line systemic therapies (p < 0.0001). There were no significant differences in overall survival according to treatment type. CONCLUSION: Results from this large US cohort study reflect those obtained in randomized trials of patients with advanced EGFR Mut+ NSCLC and demonstrate their transferability into a real-world setting.

Identifying rare diseases using electronic medical records: the example of allergic bronchopulmonary aspergillosis.

PURPOSE: The purpose of the study is to evaluate whether primary care electronic medical records (EMRs) from patients with severe asthma can be used to identify allergic bronchopulmonary aspergillosis (ABPA) cases. METHODS: This cross-sectional feasibility study was conducted in adults with active and severe asthma registered with the Clinical Practice Research Datalink. A set of keywords flagged terms potentially indicative of ABPA in free-text comments of patients' EMRs to produce a grid on the basis of keywords' hit or miss. The grid was examined for occurrence and concurrence of keywords to discern patterns of concurrence potentially indicative of an underlying diagnosis of ABPA. RESULTS: The analyses included 3 653 169 free-text items from 21 054 patients. In total, 52 patients (0.25%) had at least one mention of 'ABPA' in their medical record; 67% of these patients also had a mention of 'aspergillus/aspergillosis', 54% of 'bronchiectasis', 42% of 'itraconazole' and 62% of 'IgE'. The term 'aspergillus/aspergillosis' occurred with a proportion of 1.84% (N = 387); 9% of these patients also had a mention of 'ABPA', and the remaining 91% were potential additional cases of ABPA. From the observed concurrence of keywords, we were able to devise a potential algorithm to identify cases with varying degrees of specificity. CONCLUSIONS: This study suggests that analysis of free text within asthmatic patients' EMRs may be used to identify potential cases of ABPA. This could be an efficient approach to identify rare conditions and to quantify their potential burden. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

A model-based analysis: what potential could there be for a S. aureus vaccine in a hospital setting on top of other preventative measures?

BACKGROUND: Over the past decade, there has been sustained interest and efforts to develop a S. aureus vaccine. There is a need to better evaluate the potential public health impact of S. aureus vaccination, particularly given that preventative measures exist to reduce infection. To our knowledge, there is no previous work to assess the potential of a S. aureus vaccine to yield additional MRSA infection reduction in a hospital setting, on top of other preventative measures that already proved efficient. METHODS: The main objectives were to propose a versatile simulation framework for assessing potential added benefits of a hypothetical S. Aureus vaccine in conjunction with other preventative measures, and to illustrate possibilities in a given hospital setting. To this end, we employed a recently published dynamic transmission modelling framework that we further adapted and expanded to include a hypothetical S. aureus vaccination component in order to estimate potential benefits of vaccinating patients prior to hospital admission. RESULTS: Model-based projections indicate that even with other hygiene prevention measures in place, vaccination of patients prior to hospital admission has the potential to provide additional reduction of MRSA infection. Vaccine coverage and vaccine efficacy are key factors that would ultimately impact the magnitude of this reduction. For example, in an average case scenario with 50% decolonization, 50% screening and 50% hygiene compliance level in place, S. aureus vaccination with 25% vaccine coverage, 75% vaccine efficacy against infection, and 0% vaccine efficacy against colonization, may lead to 12% model-projected additional reduction in MRSA infection prevalence due to vaccination, while this reduction could reach 37% for vaccination with 75% vaccine coverage and 75% vaccine efficacy against infection in the same average case scenario. CONCLUSIONS: S. aureus vaccination could potentially provide additional reduction of MRSA infection in a hospital setting, on top of reductions from hygiene prevention measures. The magnitude of such additional reductions can vary significantly depending on the level of hygiene prevention measures in place, as well as key vaccine factors such as coverage and efficacy. Identifying appropriate combinations of preventative measures may lead to optimal strategies to effectively reduce MRSA infection in hospitals.

Incidence and cost of hospitalizations associated with Staphylococcus aureus skin and soft tissue infections in the United States from 2001 through 2009.

BACKGROUND: The emergence of community-associated methicillin-resistant Staphylococcus aureus (SA) and its role in skin and soft tissue infections (SSTIs) accentuated the role of SA-SSTIs in hospitalizations. METHODS: We used the Nationwide Inpatient Sample and Census Bureau data to quantify population-based incidence and associated cost for SA-SSTI hospitalizations. RESULTS: SA-SSTI associated hospitalizations increased 123% from 160,811 to 358,212 between 2001 and 2009, and they represented an increasing share of SA- hospitalizations (39% to 51%). SA-SSTI incidence (per 100,000 people) doubled from 57 in 2001 to 117 in 2009 (p<0.01). A significant increase was observed in all age groups. Adults aged 75+ years and children 0-17 years experienced the lowest (27%) and highest (305%) incidence increase, respectively. However, the oldest age group still had the highest SA-SSTI hospitalization incidence across all study years. Total annual cost of SA-SSTI hospitalizations also increased and peaked in 2008 at $4.84 billion, a 44% increase from 2001. In 2009, the average associated cost of a SA-SSTI hospitalization was $11,622 (SE=$200). CONCLUSION: There has been an increase in the incidence and associated cost of SA-SSTI hospitalizations in U.S.A. between 2001 and 2009, with the highest incidence increase seen in children 0-17 years. However, the greatest burden was still seen in the population over 75 years. By 2009, SSTI diagnoses were present in about half of all SA-hospitalizations.

Burden of acute gastroenteritis, norovirus and rotavirus in a managed care population.

This study assessed and described the episode rate, duration of illness, and health care utilization and costs associated with acute gastroenteritis (AGE), norovirus gastroenteritis (NVGE), and rotavirus gastroenteritis (RVGE) in physician office, emergency department (ED), and inpatient care settings in the United States (US). The retrospective analysis was conducted using an administrative insurance claims database (2006-2011). AGE episode rates were assessed using medical (ICD-9-CM) codes for AGE; whereas a previously published "indirect" method was used in assessing estimated episode rates of NVGE and RVGE. We calculated per-patient, per-episode and total costs incurred in three care settings for the three diseases over five seasons. For each season, we extrapolated the total economic burden associated with the diseases to the US population. The overall AGE episode rate in the physician office care setting declined by 15% during the study period; whereas the AGE episode rate remained stable in the inpatient care setting. AGE-related total costs (inflation-adjusted) per 100 000 plan members increased by 28% during the 2010-2011 season, compared with the 2006-2007 season ($832,849 vs. $1 068 116) primarily due to increase in AGE-related inpatient costs. On average, the duration of illness for NVGE and RVGE was 1 day longer than the duration of illness for AGE (mean: 2 days). Nationally, the average AGE-related estimated total cost was $3.88 billion; NVGE and RVGE each accounted for 7% of this total. The episodes of RVGE among pediatric populations have declined; however, NVGE, RVGE and AGE continue to pose a substantial burden among managed care enrollees. In conclusion, the study further reaffirms that RVGE has continued to decline in pediatric population post-launch of the rotavirus vaccination program and provides RVGE- and NVGE-related costs and utilization estimates which can serve as a resource for researchers and policy makers to conduct cost-effectiveness studies for prevention programs.

Model-based projections of the population-level impact of hepatitis A vaccination in Mexico.

There are indications of a shift in the pattern of hepatitis A (HAV) in Mexico from high to intermediate endemicity, progressively increasing the mean age of infection and the proportion of cases which are symptomatic. This study estimated the potential impact of universal infant HAV vaccination in Mexico with two doses of Havrix™ at 12 and 18 mo of age on all HAV infections and symptomatic HAV infections. We developed a dynamic transmission model that accounts for changes in demography and HAV epidemiology. It was calibrated using Mexican age-specific seroprevalence and symptomatic HAV incidence data. With 70% first-dose coverage and 85% second-dose coverage, the calibrated model projected that HAV vaccination would reduce the incidence of all HAV infections (symptomatic and asymptomatic) after the first 25 y of vaccination by 71-76% (minimum and maximum for different transmission scenarios). The projected reduction in cumulative incidence of symptomatic HAV infections over the first 25 y of vaccination was 45-51%. With 90% first-dose coverage and 85% second-dose coverage, the projected reduction in incidence of all HAV infections was 85-93%, and the projected reduction in the cumulative incidence of symptomatic HAV infections was 61-67%, over a 25-y time frame. Sensitivity analyses indicated that second-dose coverage is important under the conservative base-case assumptions made about the duration of vaccine protection. The model indicated that universal infant HAV vaccination could substantially reduce the burden of HAV disease in Mexico.

Predictive accuracy of the Liverpool Lung Project risk model for stratifying patients for computed tomography screening for lung cancer: a case-control and cohort validation study.

BACKGROUND: External validation of existing lung cancer risk prediction models is limited. Using such models in clinical practice to guide the referral of patients for computed tomography (CT) screening for lung cancer depends on external validation and evidence of predicted clinical benefit. OBJECTIVE: To evaluate the discrimination of the Liverpool Lung Project (LLP) risk model and demonstrate its predicted benefit for stratifying patients for CT screening by using data from 3 independent studies from Europe and North America. DESIGN: Case-control and prospective cohort study. SETTING: Europe and North America. PATIENTS: Participants in the European Early Lung Cancer (EUELC) and Harvard case-control studies and the LLP population-based prospective cohort (LLPC) study. MEASUREMENTS: 5-year absolute risks for lung cancer predicted by the LLP model. RESULTS: The LLP risk model had good discrimination in both the Harvard (area under the receiver-operating characteristic curve [AUC], 0.76 [95% CI, 0.75 to 0.78]) and the LLPC (AUC, 0.82 [CI, 0.80 to 0.85]) studies and modest discrimination in the EUELC (AUC, 0.67 [CI, 0.64 to 0.69]) study. The decision utility analysis, which incorporates the harms and benefit of using a risk model to make clinical decisions, indicates that the LLP risk model performed better than smoking duration or family history alone in stratifying high-risk patients for lung cancer CT screening. LIMITATIONS: The model cannot assess whether including other risk factors, such as lung function or genetic markers, would improve accuracy. Lack of information on asbestos exposure in the LLPC limited the ability to validate the complete LLP risk model. CONCLUSION: Validation of the LLP risk model in 3 independent external data sets demonstrated good discrimination and evidence of predicted benefits for stratifying patients for lung cancer CT screening. Further studies are needed to prospectively evaluate model performance and evaluate the optimal population risk thresholds for initiating lung cancer screening.

Welding and lung cancer in Central and Eastern Europe and the United Kingdom.

Occupation as a welder has been associated with a 25%-40% increase in lung cancer risk. This study aims to elucidate to what extent confounding by smoking and asbestos drives this association and to evaluate the role of welding-related exposures such as chromium. The study included 2,197 male incident lung cancer cases and 2,295 controls from Romania, Hungary, Poland, Russia, Slovakia, the Czech Republic, and the United Kingdom from 1998 to 2001. Information on risk factors was collected through face-to-face interviews. Experts assessed exposure to 70 agents, and risk estimates were adjusted for smoking and occupational exposures. Occupation as a welder/flame cutter (prevalence controls: 3.7%) was associated with an odds ratio of 1.36 (95% confidence interval (CI): 1.00, 1.86) after adjustment for smoking and occupational exposures including asbestos. An odds ratio of 1.18 (95% CI: 1.01, 1.38) was found for welding fumes (prevalence controls: 22.8%), increasing to 1.38 for more than 25 exposure years (95% CI: 1.09, 1.75). A duration-response association was also observed for mild steel welding without chromium exposure. In this population, occupational exposure to welding fumes accounted for approximately 4% of lung cancer cases, to which both stainless and mild steel welding contributed equally. Given that welding remains a common task for many workers, exposure to welding fumes represents an important risk factor for lung cancer.

Occupational exposure to organic dust increases lung cancer risk in the general population.

BACKGROUND: Organic dust is a complex mixture of particulate matter from microbial, plant or animal origin. Occupations with exposure to animal products have been associated with an increased lung cancer risk, while exposure to microbial components (eg, endotoxin) has been associated with a decreased risk. To date there has not been a comprehensive evaluation of the possible association between occupational organic dust exposure (and its specific constituents) and lung cancer risk in the general population. METHODS: The SYNERGY project has pooled information on lifetime working and smoking from 13 300 lung cancer cases and 16 273 controls from 11 case-control studies conducted in Europe and Canada. A newly developed general population job-exposure matrix (assigning no, low or high exposure to organic dust, endotoxin, and contact with animals or fresh animal products) was applied to determine level of exposure. ORs for lung cancer were estimated by logistic regression, adjusted for age, sex, study, cigarette pack-years, time since quitting smoking, and ever employment in occupations with established lung cancer risk. RESULTS: Occupational organic dust exposure was associated with increased lung cancer risk. The second to the fourth quartile of cumulative exposure showed significant risk estimates ranging from 1.12 to 1.24 in a dose-dependent manner (p<0.001). This association remained in the highest quartile after restricting analyses to subjects without chronic obstructive pulmonary disease or asthma. No association was observed between lung cancer and exposure to endotoxin or contact with animals or animal products. CONCLUSION: Occupational exposure to organic dust was associated with increased lung cancer risk in this large pooled case-control study.

Cigarette smoking and lung cancer--relative risk estimates for the major histological types from a pooled analysis of case-control studies.

Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8-143.2) for SqCC, 111.3 (95% CI: 69.8-177.5) for SCLC and 21.9 (95% CI: 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5-124.6), 108.6 (95% CI: 50.7-232.8) and 16.8 (95% CI: 9.2-30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.

Hepatitis B vaccine effectiveness in the face of global HBV genotype diversity.

Recombinant hepatitis B vaccines are of the A2 genotype; one of ten known genotypes whose distribution varies globally. Reports of rare HBV infections in blood donors with an imbalance of non-A2 genotype HBV in vaccinated subjects have raised questions about the cross-protection afforded by HBV-A2 vaccines. Infections in HBV vaccinees were asymptomatic and transient, indicating that vaccination prevented clinical disease. Preclinical data demonstrate cross-reactivity and cross-protection by A2 vaccines against non-A2 HBV genotypes. Substantial improvements in HBV control have been demonstrated in countries with diverse genotype distribution that have introduced universal childhood HBV vaccination programs. Available data show that current HBV-A2 vaccines are highly effective in preventing infections and clinical disease caused by all known HBV genotypes.

Occupational exposure to metal compounds and lung cancer. Results from a multi-center case-control study in Central/Eastern Europe and UK.

PURPOSE: To study the association between occupational exposure to metals including chromium, cadmium, nickel, and arsenic compounds, within a population-based study design, while adjusting for confounding factors. METHODS: A population-based lung cancer case-control study in Central/Eastern Europe and UK was conducted in 1998-2003, including 2,853 cases and 3,104 controls. Exposure to 70 occupational agents was assessed by local expert-teams for all subjects. Odds ratios (OR) for exposure to dust and fumes/mist of chromium, nickel, cadmium, arsenic, as well as inorganic pigment dust and inorganic acid mist, were adjusting for smoking, age, center, sex, and exposure to other occupational agents including the metals under study. RESULTS: Exposure to arsenic (prevalence = 1.4%) was associated with an increased lung cancer risk ((OR) 1.65, 95% confidence interval (95% CI):1.05-2.58). For chromium dust (prevalence = 4.8%, OR: 1.25, 95% CI: 0.95-1.65), a linear upward trend for duration and cumulative exposure was observed. A weak association was observed for exposure to cadmium fumes (prevalence = 1.8%, OR: 1.19, 95% CI: 0.77-1.82), which was strongest for the highest category of cumulative exposure (OR: 2.04, 95% CI: 1.07-3.90). No increased risk was observed for inorganic acid mist, inorganic pigment dust, or nickel, after adjustment for other metals. An independent effect of nickel cannot be excluded, due to its collinearity with chromium exposure. CONCLUSIONS: Occupational exposure to metals is an important risk factor for lung cancer. Although the strongest risk was observed for arsenic, exposure to chromium dust was most important in terms of attributable risk due to its high prevalence.

Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy.

BACKGROUND: Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC). METHODS: To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided. RESULTS: SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35). CONCLUSION: These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.

Comparison of exposure assessment methods for occupational carcinogens in a multi-centre lung cancer case-control study.

OBJECTIVES: Retrospective exposure assessment remains a problematic aspect of population-based case-control studies. Different methods have been developed, including case-by-case expert assessment and job-exposure matrices (JEM). The present analyses compare exposure prevalence and risk estimates derived by different exposure assessment methods. METHODS: In the context of a case-control study conducted in seven European countries, exposure was estimated for asbestos, diesel motor emissions (DME) and crystalline silica, using three different assessment methods. First, experts assigned exposures to all reported jobs on a case-by-case basis. Second, a population-specific JEM (PSJEM) was developed using the expert assessments of controls only, and re-applied to all study subjects. Third, an independent general population JEM (GPJEM) was created by occupational exposure experts not involved in the original study, and applied to study subjects. Results from these methods were compared. RESULTS: There was poor to fair agreement in assigned exposure between expert assessment and the GPJEM (kappas: asbestos 0.17; DME 0.48; silica 0.38). Exposure prevalence was significantly heterogeneous (p<0.01) between countries for all three agents and assessment methods. For asbestos and DME, significant country heterogeneity in risk estimates was observed when using expert assessment. When applying the GPJEM, the heterogeneity in risk estimates for asbestos and, to some extent, silica diminished. CONCLUSIONS: It has been previously advocated that the expert assessment approach to assign exposures based on detailed questionnaire responses provides more accurate exposure estimates than JEM-based results. However, current results demonstrated little, if any, advantage of case-by-case assessment when compared to a JEM approach.

Exposure to diesel motor exhaust and lung cancer risk in a pooled analysis from case-control studies in Europe and Canada.

RATIONALE: Diesel motor exhaust is classified by the International Agency for Research on Cancer as probably carcinogenic to humans. The epidemiologic evidence is evaluated as limited because most studies lack adequate control for potential confounders and only a few studies have reported on exposure-response relationships. OBJECTIVES: Investigate lung cancer risk associated with occupational exposure to diesel motor exhaust, while controlling for potential confounders. METHODS: The SYNERGY project pooled information on lifetime work histories and tobacco smoking from 13,304 cases and 16,282 controls from 11 case-control studies conducted in Europe and Canada. A general population job exposure matrix based on ISCO-68 occupational codes, assigning no, low, or high exposure to diesel motor exhaust, was applied to determine level of exposure. MEASUREMENTS AND MAIN RESULTS: Odds ratios of lung cancer and 95% confidence intervals were estimated by unconditional logistic regression, adjusted for age, sex, study, ever-employment in an occupation with established lung cancer risk, cigarette pack-years, and time-since-quitting smoking. Cumulative diesel exposure was associated with an increased lung cancer risk highest quartile versus unexposed (odds ratio 1.31; 95% confidence interval, 1.19-1.43), and a significant exposure-response relationship (P value < 0.01). Corresponding effect estimates were similar in workers never employed in occupations with established lung cancer risk, and in women and never-smokers, although not statistically significant. CONCLUSIONS: Our results show a consistent association between occupational exposure to diesel motor exhaust and increased risk of lung cancer. This association is unlikely explained by bias or confounding, which we addressed by adjusted models and subgroup analyses.

A systematic review of occupational exposure to particulate matter and cardiovascular disease.

Exposure to ambient particulate air pollution is a recognized risk factor for cardiovascular disease; however the link between occupational particulate exposures and adverse cardiovascular events is less clear. We conducted a systematic review, including meta-analysis where appropriate, of the epidemiologic association between occupational exposure to particulate matter and cardiovascular disease. Out of 697 articles meeting our initial criteria, 37 articles published from January 1990 to April 2009 (12 mortality; 5 morbidity; and 20 intermediate cardiovascular endpoints) were included. Results suggest a possible association between occupational particulate exposures and ischemic heart disease (IHD) mortality as well as non-fatal myocardial infarction (MI), and stronger evidence of associations with heart rate variability and systemic inflammation, potential intermediates between occupational PM exposure and IHD. In meta-analysis of mortality studies, a significant increase in IHD was observed (meta-IRR = 1.16; 95% CI: 1.06-1.26), however these data were limited by lack of adequate control for smoking and other potential confounders. Further research is needed to better clarify the magnitude of the potential risk of the development and aggravation of IHD associated with short and long-term occupational particulate exposures and to clarify the clinical significance of acute and chronic changes in intermediate cardiovascular outcomes.

Incorporation of a genetic factor into an epidemiologic model for prediction of individual risk of lung cancer: the Liverpool Lung Project.

The Liverpool Lung Project (LLP) has previously developed a risk model for prediction of 5-year absolute risk of lung cancer based on five epidemiologic risk factors. SEZ6L, a Met430IIe polymorphic variant found on 22q12.2 region, has been previously linked with an increased risk of lung cancer in a case-control population. In this article, we quantify the improvement in risk prediction with addition of SEZ6L to the LLP risk model. Data from 388 LLP subjects genotyped for SEZ6L single-nucleotide polymorphism (SNP) were combined with epidemiologic risk factors. Multivariable conditional logistic regression was used to predict 5-year absolute risk of lung cancer with and without this SNP. The improvement in the model associated with the SEZ6L SNP was assessed through pairwise comparison of the area under the receiver operating characteristic curve and the net reclassification improvements (NRI). The extended model showed better calibration compared with the baseline model. There was a statistically significant modest increase in the area under the receiver operating characteristic curve when SEZ6L was added into the baseline model. The NRI also revealed a statistically significant improvement of around 12% for the extended model; this improvement was better for subjects classified into the two intermediate-risk categories by the baseline model (NRI, 27%). Our results suggest that the addition of SEZ6L improved the performance of the LLP risk model, particularly for subjects whose initial absolute risks were unable to discriminate into "low-risk" or "high-risk" group. This work shows an approach to incorporate genetic biomarkers in risk models for predicting an individual's lung cancer risk.

Family history and lung cancer risk: international multicentre case-control study in Eastern and Central Europe and meta-analyses.

Lung cancer is the most common neoplastic disease in Eastern and Central Europe. The role of hereditary factors in lung carcinogenesis is not fully understood. Family history (FH) of lung cancer and other tobacco-related cancers might be a strong predictor of the lung cancer risk. We investigated family history of cancer among first-degree relatives of 2,861 patients with lung cancer and 3,118 controls from the Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, and United Kingdom within the IARC Multicenter Case-Control Study. Odds ratios (ORs) and 95% CI were calculated using logistic regression, adjusting for age, gender, study center, education, tobacco smoking, and number of first-degree relatives. In addition, we conducted a meta-analysis of 41 studies on FH of cancer and lung cancer risk. Positive FH of lung cancer increased risk of lung cancer with OR of 1.63 (95%CI: 1.31-2.01), and having two or more affected relatives with lung cancer further increased the risk of lung cancer with OR 3.60 (95%CI: 1.56-8.31). Among subjects aged less than 50, the OR for FH of lung cancer was 2.08 (95%CI: 1.18-3.63). The associations were generally stronger for squamous cell carcinoma and large cell carcinoma subtypes. Heterogeneity in results was not found with respect to smoking status and gender. A significant association was not observed for FH of other smoking-related tumors. The results of meta-analysis were consistent with that of our study with regard to young onset, non-smokers and histology. FH of lung cancer is a predictor of an increased risk of lung cancer, especially in subjects aged less than 50.