Current perspective on the global and United States cancer burden attributable to lifestyle and environmental risk factors.

Our objective is to provide a current perspective on the avoidable causes of global and US cancer incidence and mortality. Cancer registry-based incidence patterns, population behavioral risk-factor survey data, and systematic reviews of epidemiologic studies are the basis for estimates of relative risk, the prevalence of exposures to various lifestyle and environmental risk factors, and their impact expressed as population attributable fractions (PAFs). Of the total 59 million global deaths in 2008, 12-13% were attributed to cancer. The increasing burden of cancers in low- and middle-income countries (LMICs) is attributable in part to increasing urbanization, expansion of the adult population at risk, and increasing or persistent exposures to infectious agents, tobacco, and dietary deficiencies. Attributable fractions for lifestyle and environmental risk factors are summarized for the United States, the United Kingdom, and France. Assuming minimal overlap in the distribution of risk factors in the population and discounting the potential for interaction in their combined effects, we estimate that a maximum of 60% of cancer deaths in the United States may be attributed to eight risk factors: tobacco, alcohol, ionizing and solar radiations, occupations, infectious agents, obesity, and physical inactivity.

Inflammatory and non-inflammatory breast cancer survival by socioeconomic position in the Surveillance, Epidemiology, and End Results database, 1990-2008.

Although it has been previously reported that patients with inflammatory breast cancer (IBC) experience worse survival than patients with other breast cancer (BC) types, the socioeconomic and ethnic factors leading to this survival difference are not fully understood. The association between county-level percent of persons below the poverty level and BC-specific (BCS) survival for cases diagnosed from 1990 to 2008 in the Surveillance, Epidemiology, and End Results (SEER) database linked to census derived county attributes was examined. A sub-analysis of cases from 2000 to 2008 also examined BCS survival by an index combining percent below poverty and less than high school graduates as well as metropolitan versus non-metropolitan county of residence. The Kaplan-Meier estimator was used to construct survival curves by stage, inflammatory status, and county-level socioeconomic position (SEP). Stage and inflammatory status stratified proportional hazards models, adjusted for age, race/ethnicity, tumor and treatment characteristics were used to determine the hazard of BCS death by county-level SEP. Kaplan-Meier survival curves indicated IBC has worse survival than stage matched non-IBC, (stage III IBC median survival = 4.75 years vs. non-IBC = 13.4 years, p < 0.0001). Residing in a lower SEP, non-metro county significantly worsens BCS survival for non-IBC in multivariate proportional hazards models. African American cases appear to have worse survival than non-Hispanic Whites regardless of inflammatory status, stage, county-level SEP, tumor, or treatment characteristics. This is the first study to examine IBC survival by SEP in a nation-wide population-based tumor registry. As this analysis found generally poorer survival for IBC, regardless of SEP or race/ethnicity, it is important that interventions that help educate women on IBC symptoms target women in various SEP and race/ethnicity groups.

Genetic variation in glutathione S-transferase omega-1, arsenic methyltransferase and methylene-tetrahydrofolate reductase, arsenic exposure and bladder cancer: a case-control study.

BACKGROUND: Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, however studies have not consistently observed any elevation in risk at lower concentrations. Genetic variability in the metabolism and clearance of arsenic is an important consideration in any investigation of its potential health risks. Therefore, we examined the association between genes thought to play a role in the metabolism of arsenic and bladder cancer. METHODS: Single nucleotide polymorphisms (SNPs) in GSTO-1, As3MT and MTHFR were genotyped using DNA from 219 bladder cancer cases and 273 controls participating in a case-control study in Southeastern Michigan and exposed to low to moderate (<50 µg/L) levels of arsenic in their drinking water. A time-weighted measure of arsenic exposure was constructed using measures from household water samples combined with past residential history, geocoded and merged with archived arsenic data predicted from multiple resources. RESULTS: While no single SNP in As3MT was significantly associated with bladder cancer overall, several SNPs were associated with bladder cancer among those exposed to higher arsenic levels. Individuals with one or more copies of the C allele in rs11191439 (the Met287Thr polymorphism) had an elevated risk of bladder cancer (OR = 1.17; 95% CI = 1.04-1.32 per 1 µg/L increase in average exposure). However, no association was observed between average arsenic exposure and bladder cancer among TT homozygotes in the same SNP. Bladder cancer cases were also 60% less likely to be homozygotes for the A allele in rs1476413 in MTHFR compared to controls (OR = 0.40; 95% CI = 0.18-0.88). CONCLUSIONS: Variation in As3MT and MTHFR is associated with bladder cancer among those exposed to relatively low concentrations of inorganic arsenic. Further investigation is warranted to confirm these findings.

Lifetime exposure to arsenic in drinking water and bladder cancer: a population-based case-control study in Michigan, USA.

OBJECTIVE: Arsenic in drinking water has been linked with the risk of urinary bladder cancer, but the dose-response relationships for arsenic exposures below 100 microg/L remain equivocal. We conducted a population-based case-control study in southeastern Michigan, USA, where approximately 230,000 people were exposed to arsenic concentrations between 10 and 100 microg/L. METHODS: This study included 411 bladder cancer cases diagnosed between 2000 and 2004, and 566 controls recruited during the same period. Individual lifetime exposure profiles were reconstructed, and residential water source histories, water consumption practices, and water arsenic measurements or modeled estimates were determined at all residences. Arsenic exposure was estimated for 99% of participants' person-years. RESULTS: Overall, an increase in bladder cancer risk was not found for time-weighted average lifetime arsenic exposure >10 microg/L when compared with a reference group exposed to <1 microg/L (odds ratio (OR) = 1.10; 95% confidence interval (CI): 0.65, 1.86). Among ever-smokers, risks from arsenic exposure >10 microg/L were similarly not elevated when compared to the reference group (OR = 0.94; 95% CI: 0.50, 1.78). CONCLUSIONS: We did not find persuasive evidence of an association between low-level arsenic exposure and bladder cancer. Selecting the appropriate exposure metric needs to be thoughtfully considered when investigating risk from low-level arsenic exposure.

An epidemiologic perspective on the stem cell hypothesis in human carcinogenesis.

BACKGROUND: Tomasetti and Vogelstein have hypothesized that the patterns of cancer incidence in various cells and tissues are highly correlated with the estimated lifetime number of stem cell divisions. The authors reviewed the risks in tissues of 17 types of cancer from the United States and 69 additional countries. Positive correlations were observed consistently between the tissue - specific cancer incidence and the estimated lifetime number of stem cell divisions. The authors concluded that approximately two-thirds of global cancer incidence may be attributed to random DNA replication errors. METHODS: An epidemiologic perspective is presented that may serve as a counterpoint in interpreting organ-specific cancer risks. The unifying nature of the Tomasetti/Vogelstein hypothesis must be viewed in the context of diverse and contrasting global trends and patterns of types and "causes" of cancers that are closely linked with economic development and cultural lifestyle practices. The presentation is organized by reviewing the global burden of cancer; concepts of causal inferences and counterfactual assumptions; multifactorial causes of hepatocellular carcinoma and a hierarchy of causes that varies internationally; tobacco carcinogenesis and the multiplex associations with 19 cancer sites and tissues; profile in contrasts in transit through the small and large intestine. OBSERVATIONS AND CONCLUSIONS: It is readily recognized that DNA replication errors and number of stem cell divisions may vary in individuals and populations due to external environmental genotoxic chemicals and biologic agents, and internal hormonal and metabolic factors. There is a striking contrast in the risk of adenocarcinoma in the small intestine with that in the large intestine. Tomasetti and Vogelstein indicated that the cumulative number of divisions of stem cells over a lifetime in normal epithelial mucosal cells from colorectal cancer patients was 4 time greater than in the epithelial tissue from patients with adenocarcinoma of the small intestine. Their conclusion would suggest a "seed" and "soil" interaction rather than exclusively the independence of either component. Namely, that the contrasting physiological, biochemical, microbial and immunological features in the lumen and on the mucosal surface of the large intestine, in contrast to that in the small intestine, would foster molecular genetic and epigenetic events that are advantageous to neoplasia in the large intestine.

Alleviating the burden of cancer: a perspective on advances, challenges, and future directions.

The control of the burden of cancer would be achievable by promoting health-maintaining lifestyle behavioral practices in conjunction with facilitated access to affordable and effective periodic screening and early detection examinations combined with comprehensive treatment services. In a global population exceeding six billion in the year 2002, there were approximately 10.9 million new cancer cases, 6.7 million cancer deaths, and 22.4 million persons surviving from cancer diagnosed in the previous 5 years. In 2020, the world's population is projected to increase to 7.5 billion and will experience 15 million new cancer cases and 12 million cancer deaths. This perspective on advances, challenges, and future directions in cancer epidemiology and prevention reviews the conceptual foundation for multistep carcinogenesis, causal mechanisms associated with chronic inflammation and the microenvironment of the cancer cell, and obesity, energy expenditure, and insulin resistance. Strategic priorities in global cancer control initiatives should embrace these fundamental concepts by targeting tobacco and alcohol consumption, the increasing prevalence of obesity and metabolic sequelae, and persistent microbial infections.

The epidemiology of chronic venous insufficiency and varicose veins.

Chronic venous disease is a common condition presenting to physicians in Western Europe and the United States. This article provides a comprehensive review of the published literature in the English language, from 1942 to the present, and focuses on the prevalence of chronic venous insufficiency and varicose veins, as well as the involved risk factors. Prevalence estimates vary widely by geographic location, with the highest reported rates in Western countries. Reports of prevalence of chronic venous insufficiency vary from < 1% to 40% in females and from < 1% to 17% in males. Prevalence estimates for varicose veins are higher, <1% to 73% in females and 2% to 56% in males. The reported ranges in prevalence estimations presumably reflect differences in the population distribution of risk factors, accuracy in application of diagnostic criteria, and the quality and availability of medical diagnostic and treatment resources. Established risk factors include older age, female gender, pregnancy, family history of venous disease, obesity, and occupations associated with orthostasis. Yet, there are several factors that are not well documented, such as diet, physical activity and exogenous hormone use, which may be important in the development of chronic venous disease and its clinical manifestations.

The cancer burden attributable to biologic agents.

PURPOSE: A review of cohort and case-control studies that attempt to quantify the proportion of cancer cases diagnosed in the United States and throughout the world that may be attributed to biologic or infectious agents. METHODS: Epidemiologic studies published primarily since the year 2000 are summarized that estimate population attributable fractions based on consensus estimates of relative risk and of the exposure prevalence to putative oncogenic infectious agents in representative populations. RESULTS: The proportion of incident cancers attributable to infectious agents diagnosed in low- and middle-income countries, comprising more than 80% of the world's population, has been estimated to vary from 20% to 30%, in contrast to a range of 5% or less to 10% in the United States and other highly industrialized populations. More than 90% of the global cancer cases attributed to infectious agents have been caused by hepatitis B virus, hepatitis C virus, human papillomaviruses, and the gram-negative bacterium, Helicobacter pylori. CONCLUSIONS: Epidemiologic and pathologic studies that use molecular diagnostic probes and immunologic and biochemical assays have described the substantial impact of infectious agents on global cancer incidence. These compelling observations have stimulated the development of effective hepatitis B virus and human papillomavirus vaccines and the rationale for eradication of Helicobacter pylori.

Biomarkers and their use in cervical cancer chemoprevention.

Cervical cancer chemoprevention agents under study include diet and micronutrients (particularly beta-carotene, folate, and vitamins A, C, and E); medications such as retinoids (retinyl acetate gel, all-trans-retinoic acid, and 4-hydroxyphenylretinamide) that are chemically related to micronutrients; and other chemopreventives meant to affect the carcinogenic process at the cellular level, including such polyamine synthesis inhibitors as alpha-difluoromethylornithine. Agents become reasonable candidates for study when they have a biologic rationale, they are of low toxicity, and they can be taken for a long period of time. Since the human papillomavirus (HPV) is the major etiologic agent, the medication should show activity against HPV-positive preinvasive and invasive cell lines. The medication needs to be of low toxicity because it may be taken for long periods of time and less toxicity is tolerated in the precancerous setting. Until 1995, none of the studies used surrogate end point biomarkers (SEBs), relying instead on histologic and colposcopic regression as end points. All studies typically included subjects with cervical intraepithelial neoplasia. Conclusions to be drawn from these studies include the following: Though micronutrients are logical candidates for chemoprevention, they haven't worked consistently, and the reasons remain unclear. Furthermore, SEBs need to be validated in phase I trials. Finally, a better understanding of the role of HPV needs elucidation, including an understanding of the relationship of the medication to HPV status and of the immunobiology of HPV throughout the trial.

Site-specific cancer incidence and mortality after cerebral angiography with radioactive thorotrast.

Few opportunities exist to evaluate the carcinogenic effects of long-term internal exposure to alpha-particle-emitting radionuclides. Patients injected with Thorotrast (thorium-232) during radiographic procedures, beginning in the 1930s, provide one such valuable opportunity. We evaluated site-specific cancer incidence and mortality among an international cohort of 3,042 patients injected during cerebral angiography with either Thorotrast (n = 1,650) or a nonradioactive agent (n = 1,392) and who survived 2 or more years. Standardized incidence ratios (SIR) for Thorotrast and comparison patients (Denmark and Sweden) were estimated and relative risks (RR), adjusted for population, age and sex, were generated with multivariate statistical modeling. For U.S. patients, comparable procedures were used to estimate standardized mortality ratios (SMR) and RR, representing the first evaluation of long-term, site-specific cancer mortality in this group. Compared with nonexposed patients, significantly increased risks in Thorotrast patients were observed for all incident cancers combined (RR = 3.4, 95% CI 2.9-4.1, n = 480, Denmark and Sweden) and for cancer mortality (RR = 4.0, 95% CI 2.5-6.7, n = 114, U.S.). Approximately 335 incident cancers were above expectation, with large excesses seen for cancers of the liver, bile ducts and gallbladder (55% or 185 excess cancers) and leukemias other than CLL (8% or 26 excess cancers). The RR of all incident cancers increased with time since angiography (P < 0.001) and was threefold at 40 or more years; significant excesses (SIR = 4.0) persisted for 50 years. Increasing cumulative dose of radiation was associated with an increasing risk of all incident cancers taken together and with cancers of the liver, gallbladder, and peritoneum and other digestive sites; similar findings were observed for U.S. cancer mortality. A marginally significant dose response was observed for the incidence of pancreas cancer (P = 0.05) but not for lung cancer. Our study confirms the relationship between Thorotrast and increased cancer incidence at sites of Thorotrast deposition and suggests a possible association with pancreas cancer. After injection with >20 ml Thorotrast, the cumulative excess risk of cancer incidence remained elevated for up to 50 years and approached 97%. Caution is needed in interpreting the excess risks observed for site-specific cancers, however, because of the potential bias associated with the selection of cohort participants, noncomparability with respect to the internal or external comparison groups, and confounding by indication. Nonetheless, the substantial risks associated with liver cancer and leukemia indicate that unique and prolonged exposure to alpha-particle-emitting Thorotrast increased carcinogenic risks.

Association of inflammatory and noninflammatory breast cancer with socioeconomic characteristics in the Surveillance, Epidemiology, and End Results database, 2000-2007.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and highly aggressive form of primary breast cancer. Little is known about the risk factors for IBC, specifically the association with socioeconomic position (SEP). METHODS: The association between breast cancer type (IBC vs. non-IBC) with county-level SEP in the Surveillance, Epidemiology, and End Results database for cases diagnosed from 2000 to 2007 was examined. County-level SEP characteristics included metropolitan versus non-metropolitan residence, percentage below the poverty level, percentage less than high-school graduate, and an index combining the poverty and high-school variables. IBC and non-IBC age-adjusted incidence rates were calculated, stratified on SEP and race/ethnicity. The odds of IBC versus non-IBC given a particular SEP characteristic, adjusting for age and race/ethnicity, was examined through fitting of hierarchical logistic regression models (HLM). RESULTS: Incidence rates for IBC generally increased as SEP decreased, whereas the opposite was found for non-IBC. HLM results showed that low SEP is associated with higher odds of IBC: highest (≥ 20%) versus lowest (<10%) persons below the poverty level [OR (95% confidence interval, CI) = 1.25 (1.09-1.43)]; highest (>28.76%) versus lowest (≤ 15.99%) persons less than high-school graduate [OR (95% CI) = 1.25 (1.10-1.42)]; and low SEP as measured by poverty-high school index versus high SEP [OR (95% CI)= 1.26 (1.11-1.44)]. CONCLUSION: Overall breast cancer has been found to be positively associated with SEP, whereas in this analysis, IBC was associated with decreasing SEP. IMPACT: Studies focused on understanding the disparity in IBC incidence, as well as interventions to eliminate these differences are needed.

The epidemiology and pathogenesis of neoplasia in the small intestine.

PURPOSE: The mucosa of the small intestine encompasses about 90% of the luminal surface area of the digestive system, but only 2% of the total annual gastrointestinal cancer incidence in the United States. METHODS: The remarkable contrast in age-standardized cancer incidence between the small and large intestine has been reviewed with respect to the cell type patterns, demographic features, and molecular characteristics of neoplasms. RESULTS: Particularly noteworthy is the predominance of adenocarcinoma in the colon, which exceeds 98% of the total incidence by cell type, in contrast to that of 30% to 40% in the small intestine, resulting in an age-standardized ratio of rates exceeding 50-fold. The prevalence of adenomas and carcinomas is most prominent in the duodenum and proximal jejunum. The positive correlation in global incidence rates of small and large intestinal neoplasms and the reciprocal increases in risk of second primary adenocarcinomas suggest that there are common environmental risk factors. The pathophysiology of Crohn inflammatory bowel disease and the elevated risk of adenocarcinoma demonstrate the significance of the impaired integrity of the mucosal barrier and of aberrant immune responses to luminal indigenous and potentially pathogenic microorganisms. CONCLUSION: In advancing a putative mechanism for the contrasting mucosal susceptibilities of the small and large intestine, substantial differences are underscored in the diverse taxonomy, concentration and metabolic activity of anaerobic organisms, rate of intestinal transit, changing pH, and the enterohepatic recycling and metabolism of bile acids. Experimental and epidemiologic studies are cited that suggest that the changing microecology, particularly in the colon, is associated with enhanced metabolic activation of ingested and endogenously formed procarcinogenic substrates.

Validity of spatial models of arsenic concentrations in private well water.

OBJECTIVE: Arsenic is a pervasive contaminant in underground aquifers worldwide, yet documentation of health effects associated with low-to-moderate concentrations (<100microg/L) has been stymied by uncertainties in assessing long-term exposure. A critical component of assessing exposure to arsenic in drinking water is the development of models for predicting arsenic concentrations in private well water in the past; however, these models are seldom validated. The objective of this paper is to validate alternative spatial models of arsenic concentrations in private well water in southeastern Michigan. METHODS: From 1993 to 2002, the Michigan Department of Environmental Quality analyzed arsenic concentrations in water from 6050 private wells. This dataset was used to develop several spatial models of arsenic concentrations in well water: proxy wells based on nearest-neighbor relationships, averages across geographic regions, and geostatistically derived estimates based on spatial correlation and geologic factors. Output from these models was validated using arsenic concentrations measured in 371 private wells from 2003 to 2006. RESULTS: The geostatisical model and nearest-neighbor approach outperformed the models based on geographic averages. The geostatistical model produced the highest degree of correlation using continuous data (Pearson's r=0.61; Spearman's rank rho=0.46) while the nearest-neighbor approach produced the strongest correlation (kappa(weighted)=0.58) using an a priori categorization of arsenic concentrations (<5, 5-9.99, 10-19.99, > or = 20microg/L). When the maximum contaminant level was used as a cut-off in a two-category classification (<10, > or =10microg/L), the nearest-neighbor approach and geostatistical model had similar values for sensitivity (0.62-0.63), specificity (0.80), negative predictive value (0.85), positive predictive value (0.53), and percent agreement (75%). DISCUSSION: This validation study reveals that geostatistical modeling and nearest-neighbor approaches are effective spatial models for predicting arsenic concentrations in private well water. Further validation analyses in other regions are necessary to indicate how widely these findings may be generalized.

Chronic inflammation: a common and important factor in the pathogenesis of neoplasia.

A causal link between chronic inflammation and carcinogenesis is explored by reviewing illustrative examples of specific cancers and causal agents and mechanisms. The causal agents or pathologic conditions include microbial agents, gastroesophageal reflux, chronic cholecystitis and cholelithiasis, inflammatory bowel disease, and specific agents that cause chronic obstructive or diffuse interstitial lung disease. The proportion of total cancer deaths attributable to infectious agents is estimated to be about 20% to 25% in developing countries and 7% to 10% in more industrialized countries. Recurrent or persistent inflammation may induce, promote, or influence susceptibility to carcinogenesis by causing DNA damage, inciting tissue reparative proliferation, and/or creating a stromal "soil" that is enriched with cytokines and growth factors. Future research on the complex cascade of cellular and humoral factors participating in the chronic inflammatory process will further understanding of the pathogenesis of various cancers and potentially provide a rationale for targeted chemopreventive interventions.

Sexual behavior, sexually transmitted diseases and prostatitis: the risk of prostate cancer in black men.

PURPOSE: Black men are diagnosed with prostate cancer more often than white men, present with more advanced disease and have worse stage specific survival. Given the high risk of incidence and mortality in this population, determining potentially modifiable factors is important. Recent studies have suggested a link between chronic inflammation and development of prostate cancer. In concurrence, population based studies of white men have revealed an increased risk of prostate cancer with history of sexually transmitted diseases and prostatitis. MATERIALS AND METHODS: We explored the chronic inflammation hypothesis of prostate cancer development among black men by examining sexual activity, sexually transmitted diseases and prostatitis in a population based study of 129 patients and 703 controls 40 to 79 years old. RESULTS: After adjusting for age, income, cigarette smoking, and history of digital rectal examination and prostate specific antigen tests in the last 5 years, we observed that a history of gonorrhea infection and prostatitis increased the odds of prostate cancer 1.78-fold (95% CI 1.13, 2.79) and 4.93-fold (95% CI 2.79, 8.74), respectively. Men reporting 25 or more sexual partners were 2.80 (95% CI 1.29, 6.09) times more likely to be diagnosed with cancer compared to men with 5 or fewer partners. CONCLUSIONS: Our findings support the significance of prior sexual practices, exposure to sexually transmitted microbial agents and history of prostatic infection in the natural history of prostate cancer in black men. Additional prospective research incorporating serological markers of infectious agents or predictive markers of chronic inflammation should serve to elucidate the possible causal pathway of recurring or persistent infection in the etiology of prostate cancer in black men.

Differing molecular pathology of pancreatic adenocarcinoma in Egyptian and United States patients.

Variations in genetic mutations in pancreatic carcinoma between different populations have not been studied extensively, especially in developing countries where pancreatic cancer is rare. We studied the molecular pathology of 44 pancreatic carcinomas from patients residing in a heavily polluted region in the Nile River delta and compared the findings with tumors from 44 United States (US) patients. We evaluated K-ras mutations in codon 12, p53 mutations in exons 5-8, and Gadd45a mutations in exons 1 and 4. Overall, rates of K-ras, p53 and Gadd45 mutations were not statistically different in tumors of patients from Egypt and the US (67.4 vs. 63.4%; 27.3 vs. 36.4% and 9.1 vs. 4.5%, respectively). However, there were distinct differences in the specific types of K-ras and p53 mutations between the 2 groups. In K-ras, G --> T transversion mutation was more frequent in the tumors from Egypt than from the US (58.6 vs. 26.9%), whereas G --> C transversion was detected in 26.9% of US tumors but none from Egypt (p = 0.003). We also found a trend toward differences in the p53 exons in which mutations occurred, with higher frequency of exon 5 mutation and lower frequency of exon 6 mutation in Egyptian tumors. Logistic regression showed that K-ras G --> T transversion mutations and p53 exon 6 mutations were predicted by the country of residence of the patients. Our study identifies that there are differences in the types of mutations found in tumors from pancreatic carcinoma patients in Egypt and the US, and suggests that environmental factors may explain these differences.

Advances in cancer epidemiology: understanding causal mechanisms and the evidence for implementing interventions.

In a worldwide population of 6 billion, in the year 2000, approximately 10 million cancers were diagnosed, and there were an estimated 6.2 million cancer deaths. Whereas the universality of cancer incidence and mortality is established, the burden of cancer by type or organ site is distributed unequally between developing and industrialized nations. Populations in developing countries are disproportionately affected by cancers in which infectious agents are causal. Our review of advances in cancer epidemiology underscores the complexity of pathogenic mechanisms mediated by chronic inflammation, obesity, and gene-environment interactions as in tobacco and alcohol carcinogenesis. Ultimately, the implementation of effective cancer control interventions that will serve to alleviate the cancer burden must integrate basic and applied research in the behavioral, social, biomedical, and population sciences.