and measurement error (Wong et al. 2003). It is not possible to manipulate exposure preva- lence or genotype prevalence, but measure- ment error can be directly influenced by study design (Vineis 2004; Wong et al. 2003). Measurement error can be reduced through refined research questions, accurate genotyping, improved understanding of the mechanism of effect, repeated measurements of exposure, and improved timing of expo- sure measurements (Vineis 2004; Wong et al. 2003). Improved exposure assessment will lead to more precise exposure estimates as well as decreased measurement error and significantly increased study power (Armstrong 1996; London 2007; Wong et al. 2003). Timing and duration of exposure meas­ ures. Questions about when, where, and how often to measure exposure are inherent in each of the prioritization schemes presented. Environmental exposures are likely to change over time and over space; thus, repeated meas- urements of exposure are desired. In this case, the timing, location, and duration of each sample within the life course and the micro- environments occupied by the subject will have to be determined. It is crucial to consider the biologically rel- evant time scales of exposure. Is the exposure of interest short and intense or longer term and cumulative? And when is the relevant expo- sure period (window of susceptibility) in the continuum of development? Beyond this, the physicochemical properties of the exposure and the toxicokinetics must be considered. If bio- markers of exposure are being measured, then the relevant metabolites and half-life of the compound within the body must be known so that samples are collected at times that will accurately assess the exposure period of inter- est. If these values are unknown in humans, extrapolation from animal studies may be necessary, while recognizing that the dose and route of exposure in animal studies may not be the same for human environmental exposures. In the case of studies on the development of childhood asthma, the outcome is a chronic (but in some cases transient or recurrent) dis- ease. Depending on the exposure, we may be interested in either short-term peak exposures or in long-term chronic exposures occur- ring in the prenatal, perinatal, or postnatal period. Increased understanding of mecha- nisms, gene–environment interactions, and critical windows of exposure will facilitate decisions regarding the specific exposures and approaches for assessment. Determination of the correct time to measure exposure is often impossible with the current state of knowledge. Information gener- ated by birth cohort studies, including mecha- nisms of effect, may help determine when important windows of exposure occur. The need for plausible biological mechanisms must be highlighted. The biological target of the exposure must be considered, and the relevant developmental trajectory of the target organ or system must be at least partially understood. Without this knowledge, sample collection is more likely to be haphazard. Environmental exposures from conception through the prenatal and perinatal periods and into childhood have been linked to the devel- opment of childhood asthma; thus the deci- sion on when to measure exposure is difficult. Environmental exposures during pregnancy are important, but exposures during the first and second year of life are currently considered to be the most important (Dietert and Zelikoff 2008; Holt and Jones 2000; Peden 2000). This perspective may change as understand- ing of how epigenetic mechanisms impact the development of asthma deepens. In relation to asthma, the development of both the respiratory and immune systems is relevant. These systems begin to develop in the early prenatal period and continue through the perinatal and postnatal periods (Becklake and Kauffmann 1999; Dietert and Zelikoff 2008; Holt and Jones 2000; Peden 2000; Pinkerton and Joad 2000; Pirruccello et al. 1989). It is possible that there are multiple windows of exposure, which may necessitate collection of multiple samples over the course of development. Further complicating this is the interaction between some exposures, such as endotoxin, and immune system develop- ment. This may mean that for the same com- pound there may be a window of protection as well as susceptibility in asthma (von Mutius 2007; von Mutius and Radon 2008). Methodologic advances in exposure assess­ ment. Individuals are exposed to many xeno- biotic substances in the course of daily life. The challenge for epidemiology is to separate the effects of different exposures and the con- tribution of one’s genetic profile. One potential strategy to overcome these challenges is to assign exposure profiles to an individual based on their exposure to a com- bination of agents. First, a group of exposures (the exposure profile) is linked to the out- come; the next step determines which of the exposures in the profile is dominant. This is similar to risk stratification strategies in cardio- vascular and other chronic diseases (Cannon and Greenberg 2008; Sabir et al. 2008). We often use composite exposures such as envi- ronmental tobacco smoke and traffic pollution to define complex mixtures. The agents that make up these mixtures are highly correlated, and it often makes more sense to use them as a composite rather than a set of separate but related exposures. This is similar to many risk factors for asthma that can be highly correlated in some populations. In 2005, Wild published an editorial encouraging the development of an exposome Environmental Health Perspectives • volume 119 | number 5 | May 2011 Exposure assessment and childhood asthma to complement the genome (Wild 2005). The exposome would “encompass life course envi- ronmental exposures (including lifestyle factors) from the prenatal period onwards” and would evolve over the life course. The characteriza- tion of the exposome of an individual would be dependent on biomarkers (of exposure and/or effect) as well as improved questionnaire- based methods for assessing exposure. Detailed characterization of exposomes and subsequent linkage to different asthma phenotypes would theoretically aid in identification of groups of genes responsive to an exposure and groups of exposures that act through common pathways. Clearly, a considerable amount of detailed expo- sure data on large numbers of individuals would need to be compiled to begin to assess the extent to which a manageable number of unique expo- somes exists. Optimally, such an effort should take place within the context of a cohort. In the long term, this approach may facilitate exposure profiling, leading to more effective and targeted preventative measures or treatments. To sample exposure more frequently at minimal cost, participants can be engaged in data collection. This technique has been demonstrated using vacuum socks (Schram- Bijkerk et al. 2006), electrostatic wipes (Arbes et al. 2005; Cozen et al. 2008; Schram-Bijkerk et al. 2006), and passive samplers (Johnson et al. 2009). New methods for exposure measurement by subjects have also been proposed (Karlsson et al. 2002; Noss et al. 2008; Sercombe et al. 2005). However, there is a limit to subject participation in collect- ing exposure samples; subjects are unlikely to undertake a complicated or time-consuming protocol, and ethical issues surrounding sub- ject burden may also need to be addressed. The collection of additional samples, or additional sample volume for archiving, per- mits the future study of hypotheses that were not feasible or not yet relevant during the cohort planning stages. Often these analyses will take the form of nested case–control stud- ies within the larger cohort. The collection of additional samples requires storage methods that preserve the integrity of samples over the entire storage period. The maximum dura- tion of storage and ideal storage environment will depend on the type of sample (e.g., dust, blood) as well as the analyte of interest (e.g., endotoxin, hormones) (Douwes et al. 1995; Holl et al. 2008; Macher 2001). Ethical considerations. In addition to the ethical considerations inherent in all cohort studies, when exposure measurements are made in private residences, the findings can have seri- ous implications for property values and occu- pant health. In the case of critical problems, there is responsibility to report the issue to the relevant authority immediately (i.e., child abuse or neglect). More generally, there is a duty to report back to the homeowner the findings of 595