Effectiveness of NPIs for Flu p-value{ 0.99 1.00 0.97 0.52 0.69 0.76 0.98 0.44 0.30 0.71 0.99 0.79 Any Laboratory confirmed influenza Clinical influenza definition 1{ Clinical influenza definition 2{ Clinical influenza definition 3{ Clinical influenza definition 1{ Clinical influenza definition 2{ Clinical influenza definition 3{ Clinical influenza definition 1{ Clinical influenza definition 2{ Clinical influenza definition 3{ #36 hours Laboratory confirmed influenza .36 hours Laboratory confirmed influenza Control (n = 205) (n = 110) 0.06 0.18 0.11 0.04 0.06 0.17 0.11 0.04 0.05 0.19 0.12 0.05 (n = 95) (0.03, 0.10) (0.13, 0.24) (0.07, 0.16) (0.02, 0.08) (0.03, 0.13) (0.11, 0.26) (0.06, 0.18) (0.01, 0.09) (0.02, 0.12) (0.12, 0.28) (0.06, 0.20) (0.02, 0.12) Face mask (n = 61) 0.07 0.18 0.10 0.08 0.12 0.25 0.09 0.09 0.00 0.10 0.10 0.07 (n = 32) (n = 29) (0.02, 0.16) (0.09, 0.30) (0.04, 0.20) (0.03, 0.18) (0.04, 0.29) (0.11, 0.43) (0.02, 0.25) (0.02, 0.25) (0.00, 0.12) (0.02, 0.27) (0.02, 0.27) (0.01, 0.23) Hand hygiene (n = 84) 0.06 0.18 0.11 0.04 0.10 0.17 0.10 0.05 0.01 0.19 0.12 0.02 (n = 41) (n = 43) (0.02, 0.13) (0.10, 0.28) (0.05, 0.19) (0.01, 0.10) (0.03, 0.23) (0.07, 0.32) (0.03, 0.23) (0.01, 0.17) (0.00, 0.12) (0.08, 0.33) (0.04, 0.25) (0.00, 0.12) Table 2. Secondary attack ratios of laboratory-confirmed influenza and clinical influenza in the contacts of 122 analyzed households, by intervention arm. Interval between symptom onset and intervention Secondary attack ratio (95% CI*) *Confidence intervals were calculated by the exact binomial method, not accounting for within-household correlation, and the resulting intervals may therefore slightly underestimate the uncertainty about the SARs. {By Pearson chi-square test adjusted for within-household correlation. {Clinical influenza definition 1 is fever$38uC or at least 2 of headache, runny nose, sore throat, aches or pains in muscles or joints, cough, or fatigue. Clinical influenza definition 2 is at least 2 of fever$37.8uC, cough, headache, sore throat, aches or pains in muscles or joints. Clinical influenza definition 3 is the standard CDC classification of fever$37.8uC plus cough or sore throat. doi:10.1371/journal.pone.0002101.t002 found that the most predictive (with highest area under the ROC curve) was at least two of the following signs and symptoms: fever $37.8uC, cough, headache, sore throat, aches or pains in muscles or joints (Appendix Table S1). While the clinical SARs rely on self-reported symptoms, the diaries were checked for completeness and accuracy by trained nurses during home visits every 3 days. The proportion of asymptomatic infection in our study was lower than might have been expected (i.e. closer to 50%) based on earlier studies with paired serology [31], perhaps suggesting that we might have missed some infections when assessing the secondary outcomes of clinical influenza. The corollary is that the true secondary infection rate might well have been higher than estimated (and estimable) by our SARs. The dropout was higher than anticipated; all subjects were advised of the study requirements and gave informed consent before being recruited into the study (and tested by rapid influenza test without charge), but 35% of randomized subjects/ households refused to allow any home visits. These decisions were independent of the allocated intervention, since the interventions were only revealed during the first home visit. Dropout was higher among the group randomized with a negative result on the rapid diagnostic test (after June 1, 2008), perhaps because subjects interpreted their negative result as indicating they did not have influenza thus did not require follow-up. A negative rapid test result does not rule out influenza virus infection [39], and we chose to randomize such subjects to allow wider generalizability in terms of including index subjects with a likely greater range of influenza viral shedding profiles albeit with the limitation that some index subjects might have been infected with a different pathogen; in the latter case those households would be unnecessarily followed up since only households with index subjects with confirmed influenza (by viral culture or RT-PCR) were included in the final analyses. We found that dropout rates were lower when the index subject wasaged 15 years or younger (Table 1) perhaps because the accompanying parent would have also given immediate consent. Other limitations of our study design include the potential bias from recruiting symptomatic subjects, resulting in three distinct effects. First, the use of a point-of-care test to detect influenza virus infection, ensuring that the majority of followed-up households will include an index case with laboratory-confirmed influenza (98% in our study), could also preferentially detect those potential recruits with higher viral shedding and subjects with lower levels of viral shedding would be more likely to receive a false negative rapid test results, and not be recruited. However we note that statistical power would be generally increased if index cases were more infectious since we might therefore observe more secondary transmission; the limitation here relates more to generalizability. Secondly, our design results in an unavoidable delay between onset of symptoms in the index subject and the application of the intervention (Figure 2c). If a significant amount of influenza transmission occurred prior to the intervention, we might have underestimated the efficacy of the non-pharmaceutical interventions or lacked the statistical power to find significant differences. In our analyses we investigated the SARs for those households where the interven- tion was applied within 36 hours of symptom onset but there was PLoS ONE | www.plosone.org 7 May 2008 | Volume 3 | Issue 5 | e2101