Mechanistic Indicators of Childhood Asthma (MICA) Study: piloting an integrative design for evaluating environmental health

Asthma is a chronic disease of the airways involving airway inflammation, variable obstruction, hyper responsiveness, and respiratory symptoms. Asthma is a significant problem worldwide that causes substantial social impacts and costs to public and private health systems [1]. Asthma is poorly understood in part because of the myriad of complex genetic and environmental components which influence both the development and exacerbation of asthma.

Understanding the complex relationships between environmental exposures and health outcomes such as asthma requires consideration of a wide range of factors--both extrinsic (e.g., ambient air quality) and intrinsic (e.g., genotypic) that must be integrated to assess cumulative risk and to support epidemiological studies investigating gene-environment interactions. As understanding of how to assess and mitigate health risks resulting from exposures to individual environmental pollutants improves, environmental health scientists are turning their attention toward characterizing relationships between multiple environmental factors and complex diseases. Although the association of genetic and environmental factors in the development of disease has long been recognized, promising tools for characterizing global human genetic variation have only recently been developed [2]. The study of the role of genetic variation in human response to environmental exposures, "ecogenetics" [3], focuses on identifying markers of susceptibility and characterizing the modification of risk in susceptible individuals. Recent technological advances have led to the development of toxicogenomics which examines the effects that chemicals have on living organisms and/or the environment using genomic, proteomic, and metabonomic methods [4]. These emerging tools in molecular biology provide the potential for development of cellular and molecular indicators of exposure and health status that can be used to assess the vulnerability of humans to environmental stressors.

In the Mechanistic Indicators of Childhood Asthma study (MICA), biomonitoring and other health data are used to characterize potential exposures and asthma-related health outcomes. By considering an array of metrics across the exposure-outcome continuum, this framework begins to address the multi-factorial nature of environmental disease and cumulative risk. Because it is unlikely that a single "ideal" biomarker (a single measure with all the important characteristics for relating health outcomes with a particular exposure) will be identified, an array of biomarkers is measured to evaluate the relationships.

An overarching hypothesis of MICA is that genomic data viewed together with a spectrum of exposure, effects, clinical and susceptibility markers: a) increases the sensitivity needed to define exposure-response-effects relationships, and b) provides mechanistic insight useful from a clinical and environmental health context. Specifically this rich data set will also be used to:

• Segregate asthma phenotypes and develop hypotheses related to underlying biological mechanisms through the application of multidimensional statistical and knowledge-based approaches

• Identify panels of biomarkers from the array of MICA exposure to health outcome covariates for future application in large population studies by evaluating reliability, predictive value, sensitivity, specificity, affordability, and applicability.

• Identify impact of exposures on key pathways identified from the gene expression data.

• Evaluate genetic variants previously associated with asthma outcomes in the MICA study population.

• Estimate individual and combined effects of environmental exposures and genetic susceptibility in determining the likelihood of childhood asthma related outcomes.

The study design and protocols were approved by the Institutional Review Boards at Henry Ford Health System (Detroit, MI), Westat Inc. (Rockville, MD), and the University of North Carolina at Chapel Hill (Chapel Hill, NC - US EPA's IRB of record). Written consent was obtained from guardians, and written assent was obtained from each child, with an oral review of both consent and assent prior to study enrollment. The (MICA) study was conducted by the United States Environmental Protection Agency between November 2006 and January 2007 in Detroit, Michigan. MICA is a cross-sectional study based on a stratified sample of children using two strata: children with asthma and children without asthma, selected in an approximately 1:1 ratio. A total of 205 children age 9-13 years old participated in the clinical study.

The integrated study design and framework for MICA is shown in Figure 1. The MICA design focuses on environmental exposures, susceptibility, asthma and other health measures, including risk factors associated with obesity and cardiovascular disease. Information on a wide range of risk factors relevant to asthma and asthma exacerbations were characterized through collection of exposure (indoor and outdoor air pollution monitors and home vacuum dust) lung function tests and biological and clinical indicators measured in blood, urine, and finger nails as shown in additional file 1, Table 1.

Past approaches for designing studies and evaluating collected data have tended to focus on a limited number of environmental factors and/or measures of outcome and are rarely conducted with children. The (MICA) study design represents an integrative approach in children's health research that incorporates exposure metrics, internal dose measures, clinical indicators and blood gene expression measures to decipher the biological complexity inherent in diseases with etiology related to complex gene-environment interactions. The coordinated collection of these complimentary data provides a platform for applying systems approaches to evaluate complex relationships between environmental factors, physiological biomarkers, and health outcomes. The study can be used to inform the design of future environmental health studies and facilitate the interpretation of study results for public health decision making.

The analysis of transcriptional responses in blood coupled with biomonitoring data should provide mechanistic insight into the biological pathways that are perturbed in response to single chemicals or complex mixture exposures. Bioindicators for these biological pathways can then be incorporated into future biomonitoring studies to link the biomarkers of exposure to a relevant apical endpoint.

While MICA is an asthma study, this rich data set can be explored for relationships between early indicators of cardiovascular disease, obesity, and asthma and to demonstrate the complex nature of childhood health and environmental disease. For example, a myriad of disease risk factors/modifiers often compromise the evaluation of a single disease. The risk of developing heart disease increases to over six fold [6] with the combination of the following three risk factors: high blood pressure, high cholesterol and diabetes. Obesity is associated with numerous co-morbidities such as cardiovascular diseases, type 2 diabetes, hypertension, and certain cancers [7]. Metabolic syndrome as described by Wilson et al. [8] occurs as a constellation of obesity, hypertension, dyslipidemia, and insulin resistance leading to diabetes. MICA blood gene expression data, viewed in the context of phenotypic data relevant to asthma, cardiovascular risk, and obesity, may provide insight into exposure assessment, pathophysiology of asthma and early indications of cardiovascular disease and metabolic syndrome.

MICA provides an opportunity to pilot the application of a more holistic analytical approach to improve the interpretation of biomarker data to advance both mechanistic based toxicology and risk assessments of chemical (single, multiple, and complex mixtures) exposures. Whether and to what extent these exposures impact such a distinctive and diverse set of health outcomes such as asthma, cardiovascular disease and metabolic syndrome, are central to the MICA study objectives. Ultimately, the goal is to identify a specific and sensitive panel of molecular and traditional environmental and clinical markers from the myriad of indicators included in the MICA study design, and in doing so, gain mechanistic understanding of potential gene environment interactions that will inform design of future clinical and epidemiological studies in humans.