subgroup (p = 0.0008 for morning wheeze and p = 0.0001 for evening wheeze). No signifi- cant estimated effects of heater type on wheeze scores were observed in the overall ITT or per-protocol analyses. However, in the atopic subgroup, there was a significantly increased wheeze score in the evening during exposure to the unflued gas heater in the ITT analysis (p = 0.05), and this was more significant in the per- protocol analysis in this subgroup (p = 0.02). Number needed to treat. The absolute dif- ference in daily prevalence of wheeze between when the low-NOx unflued gas heater was scheduled to operate and days when the flued gas heater was scheduled to operate was 0.5% (4.9% vs. 4.4%). This is equivalent to a num- ber needed to harm of 200 (1/0.005). Hence, 200 children need to be removed from expo- sure to low-NOx unflued gas heaters during the 6-week period in which this study was conducted to prevent one child reporting wheeze in the morning on an average day. Discussion We have shown that in-class exposure to unflued gas heaters is associated with a) increased reporting of wheeze in the morn- ing and possibly with increased cough and wheeze during the day (reported in the eve- ning) and b) in children with current asthma, an increase in airway inflammation, manifest as eNO. However, exposure to unflued gas heaters was not associated with a significant reduction in lung function, whether measured at home or at school. In fact, there was a para- doxical increase in evening PEF with exposure to unflued gas heaters when the analysis was restricted to days when heater use was ≥ 30% of school time and in subjects with asthma. The association of unflued gas heating with cough and wheeze was greatest in atopic (aller- gic) subjects, who represented over half the study population. Atopic subjects were also more likely to use bronchodilator (reliever) medications during exposure to unflued gas heaters. We have also shown that mean NO2 and formaldehyde levels were substantially increased in classrooms during the operation of unflued (compared with flued) gas heaters. Table 6. continued. Morning wheeze OR (95% CI) 1.381 (1.041–1.832) 1.577 (0.640–3.888) 1.603 (1.171–2.194) p-Value 0.03 0.32 0.003 Strengths and limitations. The major strengths of this study design are the random- ized crossover design, the blinding of partici- pants and researchers to exposure allocation, the inclusion of items designed to detect infor- mation bias, and the use of objective outcome measures. Taken together, these attributes give a high level of confidence that selection bias, confounding, and information bias have been avoided by design or would have been detected if present. The absence of consistent evidence of an adverse association with stomachache or sore teeth gives some confidence that the adverse effect on wheeze and cough was not attributable to information bias. Another strength of the study is the high participation rate. This lends weight to the external validity of the study in relation to primary school children in NSW. The preva- lence of asthma in this population (15.3%) is very close to the estimate for 9- to 15-year-olds in the recent NSW Health Survey (13.9%) (Centre for Epidemiology and Research 2010). The main limitation of the study, as implemented, was the low usage of heaters during the study period, presumably because of the unseasonably warm weather in late August and early September. Temperature data for the three main towns in the study area are shown in Supplemental Material, Table E2 (doi:10.1289/ehp.1002186). This table shows that the temperatures increased toward the latter part of the study period. The lack of use of the heaters limited our capacity to assess their impact on children’s health. Another limitation, which is inherent in this crossover study design, is inability to assess impacts on long-term health outcomes. Only short-term (acute) effects can be meas- ured. However, studies designed to assess long-term effects are likely to have problems with selection bias and confounding, because it is not feasible to adopt a randomized design as we have in this study. Discordance between lung function and symptom findings. The discordance between the symptom and lung function data was unexpected, although it is consistent with the findings of the two previous randomized Health effects of low-NOx unflued gas heaters controlled trials in this field (Howden- Chapman et al. 2008; Pilotto et al. 2004). One possible explanation is that subjects with asthma used additional bronchodilators to relieve symptoms and that this resulted in an increase in their lung function at the time the measurements were made. The finding of increased reliever use in people with asthma tends to support this explanation. An alternative explanation is that exposure to the unflued gas heater emissions results in sensory changes without effects on airway function. Indeed, there is evidence that NO2 does have effects on sensory neuropeptides in the respiratory tract in an animal model (Lucchini et al. 1996). Sensitive subgroups. There is evidence that NO2 exposure attributable to traffic is associ- ated with an increase risk of wheezing illness in children (Pershagen et al. 1995; Peters et al. 1999) and an increased risk of hospitalizations for asthma (Simpson et al. 2005). Hence, we expected that children with asthma would be more susceptible to the adverse effects of expo- sure to unflued gas heaters. In fact, the find- ings do not generally support this conclusion. We did find that atopic status defined a large subgroup of the population who were more likely to report symptoms with exposure to unflued gas heaters. This is consistent with the observation that pre-exposure NO2 was associated with increased early and late asth- matic response to house dust mite allergen chal- lenge in sensitized subjects (Tunnicliffe et al. 1994). However, in that study, this effect was seen only at high levels of exposure (400 ppb) and not at 100 ppb. There is also evidence from some epidemiological studies that the effects of exposure to gas appliance were more marked in atopic subjects (Corbo et al. 2001; Garrett et al. 1998; Jarvis et al. 1996; Kerkhof et al. 1999), although others have not observed this result (Ponsonby et al. 2001b). Conclusion We conclude that, when compared with expo- sure to flued gas heaters, classroom exposure to newer-style low-NOx unflued gas heaters increased respiratory symptoms, particularly Use of bronchodilators for relief of symptoms OR (95% CI) p-Value 0.870 (0.590–1.282) 0.843 (0.273– 2.602) 0.890 (0.596–1.329) 0.48 0.77 0.57 Evening wheeze OR (95% CI) 1.116 (0.856–1.454) 1.582 (0.714–3.507) 1.123 (0.856–1.473) p-Value 0.42 0.26 0.40 Sore teeth OR (95% CI) 0.861 (0.630–1.179) 1.357 (0.584–3.149) 0.897 (0.644–1.249) p-Value 0.35 0.48 0.52 Stomachache OR (95% CI) 1.156 (0.894– 1.496) 0.993 (0.513–1.923) 1.309 (0.997–1.718) p-Value 0.27 0.98 0.05 1.849 (1.258–2.718) 0.002 1.144 (0.814–1.607) 0.44 0.846 (0.524–1.365) 0.49 1.627 (1.064–2.488) 0.02 1.868 (1.075–3.247) 0.03 7.721 (1.551– 38.434) 0.01 3.968 (1.369–11.502) 0.01 1.427 (0.436–4.674) 0.56 1.311 (0.444– 3.867) 0.62 7.040 (0.945–52.442) 0.06 1,668 observations for morning wheeze and 1,986 observations for evening wheeze. f ITT analysis adjusted for home use of gas heating, open fire, and exposure to ETS; all observations were analyzed according to the heater type exposure to which they were assigned. The additional time-variable covariates were included in the model. There were 7,179 observations for morning wheeze and 7,604 observations for evening wheeze. gITT analysis limited to subjects with atopy. There were 3,418 observations for morning wheeze and 3,320 observations for evening wheeze. hPer-protocol analysis limited to subjects with atopy. There were 596 observations for morning wheeze and 706 observations for evening wheeze. Environmental Health Perspectives • volume 118 | number 10 | October 2010 1481