Rafael Meza

Initial human transmission dynamics of the pandemic (H1N1) 2009 virus in North America.

Background  Between 5 and 25 April 2009, pandemic (H1N1) 2009 caused a substantial, severe outbreak in Mexico, and subsequently developed into the first global pandemic in 41 years. We determined the reproduction number of pandemic (H1N1) 2009 by analyzing the dynamics of the complete case series in Mexico City during this early period.

Age-specific incidence of cancer: Phases, transitions, and biological implications

The observation that the age-specific incidence curve of many carcinomas is approximately linear on a double logarithmic plot has led to much speculation regarding the number and nature of the critical events involved in carcinogenesis. By a consideration of colorectal and pancreatic cancers in the Surveillance Epidemiology and End Results (SEER) registry we show that the log-log model provides a poor description of the data, and that a much better description is provided by a multistage model that predicts two basic phases in the age-specific incidence curves, a first exponential phase until the age of ≈60 followed by a linear phase after that age. These two phases in the incidence curve reflect two phases in the process of carcinogenesis. Paradoxically, the early-exponential phase reflects events between the formation (initiation) of premalignant clones in a tissue and the clinical detection of a malignant tumor, whereas the linear phase reflects events leading to initiated cells that give rise to premalignant lesions because of abrogated growth/differentiation control. This model is consistent with Knudsons idea that renewal tissue, such as the colon, is converted into growing tissue before malignant transformation. The linear phase of the age-specific incidence curve represents this conversion, which is the result of recessive inactivation of a gatekeeper gene, such as the APC gene in the colon and the CDKN2A gene in the pancreas.

Impact of Reduced Tobacco Smoking on Lung Cancer Mortality in the United States During 1975–2000

Background Considerable effort has been expended on tobacco control strategies in the United States since the mid-1950s. However, we have little quantitative information on how changes in smoking behaviors have impacted lung cancer mortality. We quantified the cumulative impact of changes in smoking behaviors that started in the mid-1950s on lung cancer mortality in the United States over the period 1975–2000. Methods A consortium of six groups of investigators used common inputs consisting of simulated cohort-wise smoking histories for the birth cohorts of 1890 through 1970 and independent models to estimate the number of US lung cancer deaths averted during 1975–2000 as a result of changes in smoking behavior that began in the mid-1950s. We also estimated the number of deaths that could have been averted had tobacco control been completely effective in eliminating smoking after the Surgeon General’s first report on Smoking and Health in 1964. Results Approximately 795 851 US lung cancer deaths were averted during the period 1975–2000: 552 574 among men and 243 277 among women. In the year 2000 alone, approximately 70 218 lung cancer deaths were averted: 44 135 among men and 26 083 among women. However, these numbers are estimated to represent approximately 32% of lung cancer deaths that could have potentially been averted during the period 1975–2000, 38% of the lung cancer deaths that could have been averted in 1991–2000, and 44% of lung cancer deaths that could have been averted in 2000. Conclusions Our results reflect the cumulative impact of changes in smoking behavior since the 1950s. Despite a large impact of changing smoking behaviors on lung cancer deaths, lung cancer remains a major public health problem. Continued efforts at tobacco control are critical to further reduce the burden of this disease.

Analysis of lung cancer incidence in the nurses' health and the health professionals' follow-up studies using a multistage carcinogenesis model

We analyzed lung cancer incidence among non-smokers, continuing smokers, and ex-smokers in the Nurses Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) using the two-stage clonal expansion (TSCE) model. Age-specific lung cancer incidence rates among non-smokers are identical in the two cohorts. Within the framework of the model, the main effect of cigarette smoke is on the promotion of partially altered cells on the pathway to cancer. Smoking-related promotion is somewhat higher among women, whereas smoking-related malignant conversion is somewhat lower. In both cohorts the relative risk for a given daily level of smoking is strongly modified by duration. Among smokers, the incidence in NHS relative to that in HPFS depends both on smoking intensity and duration. The age-adjusted risk is somewhat larger in NHS, but not significantly so. After smokers quit, the risk decreases over a period of many years and the temporal pattern of the decline is similar to that reported in other recent studies. Among ex-smokers, the incidence in NHS relative to that in HPFS depends both on previous levels of smoking and on time since quitting. The age-adjusted risk among ex-smokers is somewhat higher in NHS, possibly due to differences in the age-distribution between the two cohorts.

COLORECTAL CANCER INCIDENCE TRENDS IN THE UNITED STATES AND UNITED KINGDOM: EVIDENCE OF RIGHT- TO LEFT-SIDED BIOLOGICAL GRADIENTS WITH IMPLICATIONS FOR SCREENING

Several lines of evidence support the premise that screening colonoscopy reduces colorectal cancer (CRC) incidence, but there may be differential benefits for right- and left-sided tumors. To better understand the biological basis of this differential effect, we derived biomathematical models of CRC incidence trends in U.S. and U.K. populations, representing relatively high- and low-prevalence screening, respectively. Using the Surveillance Epidemiology and End Results (SEER) and the Office for National Statistics (ONS) registries (both 1973-2006), we derived stochastic multistage clonal expansion (MSCE) models for right-sided (proximal colon) and left-sided (distal colon and rectal) tumors. The MSCE concept is based on the initiation-promotion-progression paradigm of carcinogenesis and provides a quantitative description of natural tumor development from the initiation of an adenoma (via biallelic tumor suppressor gene inactivation) to the clinical detection of CRC. From 1,228,036 (SEER: 340,582; ONS: 887,454) cases, parameter estimates for models adjusted for calendar-year and birth-cohort effects showed that adenoma initiation rates were higher for right-sided tumors, whereas, paradoxically, adenoma growth rates were higher for left-sided tumors. The net effect was a higher cancer risk in the right colon only after age 70 years. Consistent with this finding, simulations of adenoma development predicted that the relative prevalence for right- versus left-sided tumors increases with increasing age, a differential effect most striking in women. Using a realistic biomathematical description of CRC development for two nationally representative registries, we show age- and sex-dependent biological gradients for right- and left-sided colorectal tumors. These findings argue for an age-, sex-, and site-directed approach to CRC screening.

Lung Cancer Incidence Trends by Gender, Race and Histology in the United States, 1973–2010

Background Lung cancer (LC) incidence in the United States (US) continues to decrease but with significant differences by histology, gender and race. Whereas squamous, large and small cell carcinoma rates have been decreasing since the mid-80s, adenocarcinoma rates remain stable in males and continue to increase in females, with large racial disparities. We analyzed LC incidence trends by histology in the US with an emphasis on gender and racial differences. Methods LC incidence rates from 1973–2010 were obtained from the SEER cancer registry. Age-adjusted incidence trends of five major histological types by gender and race were evaluated using joinpoint regression. Trends of LC histology and stage distributions from 2005–2010 were analyzed. Results US LC incidence varies by histology. Squamous, large and small cell carcinoma rates continue to decrease for all gender/race combinations, whereas adenocarcinoma rates remain relatively constant in males and increasing in females. An apparent recent increase in the incidence of squamous cell carcinoma and adenocarcinoma since 2005 can be explained by a concomitant decrease in the number of cases classified as other non-small cell carcinoma. Black males continue to be disproportionally affected by squamous LCs, and blacks continue to be diagnosed with more advanced cancers than whites. Conclusions LC incidence by histology continues to change over time. Additional variations are expected as screening becomes disseminated. It is important to continue to monitor LC rates to evaluate the impact of screening on current trends, assess the continuing benefits of tobacco control, and focus efforts on reducing racial disparities.

Patterns of Birth Cohort–Specific Smoking Histories, 1965–2009

BACKGROUND Characterizing the smoking patterns for different birth cohorts is essential for evaluating the impact of tobacco control interventions and predicting smoking-related mortality, but the process of estimating birth cohort smoking histories has received limited attention. PURPOSE Smoking history summaries were estimated beginning with the 1890 birth cohort in order to provide fundamental parameters that can be used in studies of cigarette smoking intervention strategies. METHODS U.S. National Health Interview Surveys conducted from 1965 to 2009 were used to obtain cross-sectional information on current smoking behavior. Surveys that provided additional detail on history for smokers including age at initiation and cessation and smoking intensity were used to construct smoking histories for participants up to the date of survey. After incorporating survival differences by smoking status, age-period-cohort models with constrained natural splines were used to estimate the prevalence of current, former, and never smokers in cohorts beginning in 1890. This approach was then used to obtain yearly estimates of initiation, cessation, and smoking intensity for the age-specific distribution for each birth cohort. These rates were projected forward through 2050 based on recent trends. RESULTS This summary of smoking history shows clear trends by gender, cohort, and age over time. If current patterns persist, a slow decline in smoking prevalence is projected from 2010 through 2040. CONCLUSIONS A novel method of generating smoking histories has been applied to develop smoking histories that can be used in micro-simulation models, and has been incorporated in the National Cancer Institutes Smoking History Generator. These aggregate estimates developed by age, gender, and cohort will provide a complete source of smoking data over time.

Chlamydia Public Health Programs and the Epidemiology of Pelvic Inflammatory Disease and Ectopic Pregnancy

BACKGROUND Many countries have witnessed a disturbing increase in cases of Chlamydia trachomatis infection despite enhanced control programs. Since the goal of Chlamydia control is to prevent reproductive complications such as pelvic inflammatory disease and ectopic pregnancy, an understanding of recent trends in these conditions is needed to fully evaluate the effect of control efforts. METHODS We analyzed 2 provincial, comprehensive health services administrative databases (encompassing hospitalizations and all physician-delivered services) for pelvic inflammatory disease and ectopic pregnancy trends from 1992 through 2009 in women of reproductive age in British Columbia, Canada. Trends were compared to provincial Chlamydia surveillance data by time-series analysis, using the cross-correlation function method and Granger causality testing. RESULTS Chlamydia cases substantially increased from 1992 through 2009. Inpatient, outpatient, and total diagnoses of pelvic inflammatory disease and ectopic pregnancy declined from 1992 through 2003. After 2003, pelvic inflammatory disease rates continued to fall, while ectopic pregnancy rates significantly increased. The male Chlamydia urethritis rate increased from 39.4 to 173.6 cases/100,000 from 1996 to 2009. CONCLUSIONS In the context of increasing Chlamydia infection rates, the reproductive complications of Chlamydia infection in women are declining overall. A recent increase in rates of ectopic pregnancies is cause for concern.

Opinion: Mathematical models: A key tool for outbreak response

The 2014 outbreak of Ebola in West Africa is unprecedented in its size and geographic range, and demands swift, effective action from the international community. Understanding the dynamics and spread of Ebola is critical for directing interventions and extinguishing the epidemic; however, observational studies of local conditions have been incomplete and limited by the urgent need to direct resources to patient care.

The Application of a Decision-Theoretic Model to Estimate the Public Health Impact of Vaporized Nicotine Product Initiation in the United States.

Introduction: The public health impact of vaporized nicotine products (VNPs) such as e-cigarettes is unknown at this time. VNP uptake may encourage or deflect progression to cigarette smoking in those who would not have otherwise smoked, thereby undermining or accelerating reductions in smoking prevalence seen in recent years. Methods: The public health impact of VNP use are modeled in terms of how it alters smoking patterns among those who would have otherwise smoked cigarettes and among those who would not have otherwise smoked cigarettes in the absence of VNPs. The model incorporates transitions from trial to established VNP use, transitions to exclusive VNP and dual use, and the effects of cessation at later ages. Public health impact on deaths and life years lost is estimated for a recent birth cohort incorporating evidence-informed parameter estimates. Results: Based on current use patterns and conservative assumptions, we project a reduction of 21% in smoking-attributable deaths and of 20% in life years lost as a result of VNP use by the 1997 US birth cohort compared to a scenario without VNPs. In sensitivity analysis, health gains from VNP use are especially sensitive to VNP risks and VNP use rates among those likely to smoke cigarettes. Conclusions: Under most plausible scenarios, VNP use generally has a positive public health impact. However, very high VNP use rates could result in net harms. More accurate projections of VNP impacts will require better longitudinal measures of transitions into and out of VNP, cigarette and dual use. Implications: Previous models of VNP use do not incorporate whether youth and young adults initiating VNP would have been likely to have been a smoker in the absence of VNPs. This study provides a decision-theoretic model of VNP use in a young cohort that incorporates tendencies toward smoking and shows that, under most plausible scenarios, VNP use yields public health gains. The model makes explicit the type of surveillance information needed to better estimate the effect of new products and thereby inform public policy.