Cluster-Randomized Test-Negative Design Trials: A Novel and Efficient Method to Assess the Efficacy of Community-Level Dengue Interventions

Anders, Katherine L.; Cutcher, Zoe; Kleinschmidt, Immo; Donnelly, Christl A.; Ferguson, Neil; Indriani, Citra; Ryan, Peter; O'Neill, Scott Leslie; Jewell, Nicholas P.; Simmons, Cameron P.

doi:10.1093/aje/kwy099

Cited by 24 publications

(33 citation statements)

References 46 publications

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“…Theoretically, randomization would control for this, but a penalization for human movement patterns in and out of clusters was not included in our original sample size calculations or study design. After our CRT had been carried out, a series of publications offered recommendations for how to enhance the design CRTs to assess the epidemiological effects of interventions against Aedes-transmitted viruses [50][51][52][53][54][55]. The geographic spacing of clusters and accounting for human movement will be critical for future CRT study designs [53].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

The impact of insecticide treated curtains on dengue virus transmission: A cluster randomized trial in Iquitos, Peru

et al. 2020

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Dengue is one of the most important vector-borne diseases, resulting in an estimated hundreds of millions of infections annually throughout the tropics. Control of dengue is heavily dependent upon control of its primary mosquito vector, Aedes aegypti. Innovative interventions that are effective at targeting the adult stage of the mosquito are needed to increase the options for effective control. The use of insecticide-treated curtains (ITCs) has previously been shown to significantly reduce the abundance of Ae. aegypti in and around homes, but the impact of ITCs on dengue virus (DENV) transmission has not been rigorously quantified. A parallel arm cluster-randomized controlled trial was conducted in Iquitos, Peru to quantify the impact of ITCs on DENV seroconversion as measured through plaque-reduction neutralization tests. Seroconversion data showed that individuals living in the clusters that received ITCs were at greater risk to seroconverting to DENV, with an average seroconversion rate of 50.6 per 100 person-years (PY) (CI: 29.9-71.9), while those in the control arm had an average seroconversion rate of 37.4 per 100 PY (CI: 15.2-51.7). ITCs lost their insecticidal efficacy within 6 months of deployment, necessitating re-treatment with insecticide. Entomological indicators did not show statistically significant differences between ITC and non-ITC clusters. It's unclear how the lack of protective efficacy reported here is attributable to simple failure of the intervention to protect against Ae. aegypti bites, or the presence of a faulty intervention during much of the follow-up period. The higher risk of dengue seroconversion that was detected in the ITC clusters may have arisen due to a false sense of security that inadvertently led to less routine protective behaviors on the part of households PLOS NEGLECTED TROPICAL DISEASES

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Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

The impact of insecticide treated curtains on dengue virus transmission: A cluster randomized trial in Iquitos, Peru

et al. 2020

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“…Upon recruitment at a clinic, a highly sensitive and specific laboratory test is used to distinguish test‐positive cases (those with the disease of interest) from the test‐negative controls (those without). The full extent of these assumptions have been critically discussed in the literature . The key property of negative controls regarding differential ascertainment is explicitly achieved since participants do not know their disease status until they are ascertained and so it theoretically not possible for the test‐positives and test‐negatives to suffer from differential relative ascertainment, that is, the relative ascertainment α RA is the same for D s (test‐positives) as for

\overline{D}

s (test‐negatives).…”

Section: Differential Case Ascertainmentmentioning

confidence: 99%

“…Focusing on the test-negatives, our assumptions show that RA = Pr(A = 1|E, D)∕ Pr(A = 1|Ē, D). Provided the other CR-TND assumptions hold, 5 and with the assumption of no intervention effect on the negative controls, RA can be estimated by the identical approach previously outlined for case count-only estimation of the RR, that is,̂R A = B T ∕H T . This provides an unbiased estimator of the relative ascertainment parameter.…”

Section: Estimation Of Differential Case Ascertainmentmentioning

confidence: 99%

“…An example of a design that explicitly uses negative controls is the test‐negative design (TND) that was recently extended to allow for cluster randomization of an intervention . Test‐negative designs are explicitly used to address ascertainment bias caused by differential health‐care seeking behavior .…”

Section: Introductionmentioning

confidence: 99%

“…An example of a design that explicitly uses negative controls is the test-negative design (TND) that was recently extended to allow for cluster randomization of an intervention. 5 Test-negative designs are explicitly used to address ascertainment bias caused by differential health-care seeking behavior. 6,7 We thus interpret our findings in the context of cluster randomized TNDs with analytic methods that either only use case count data or use negative control (in addition to case count) information.…”

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confidence: 99%

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Analysis of counts for cluster randomized trials: Negative controls and test‐negative designs

Dufault

Jewell

2020

Statistics in Medicine

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In cluster randomized trials (CRTs), the outcome of interest is often a count at the cluster level. This occurs, for example, in evaluating an intervention with the outcome being the number of infections of a disease such as HIV or dengue or the number of hospitalizations in the cluster. Standard practice analyzes these counts through cluster outcome rates using an appropriate denominator (eg, population size). However, such denominators are sometimes unknown, particularly when the counts depend on a passive community surveillance system. We consider direct comparison of the counts without knowledge of denominators, relying on randomization to balance denominators. We also focus on permutation tests to allow for small numbers of randomized clusters. However, such approaches are subject to bias when there is differential ascertainment of counts across arms, a situation that may occur in CRTs that cannot implement blinded interventions. We suggest the use of negative control counts as a method to remove, or reduce, this bias, discussing the key properties necessary for an effective negative control. A current example of such a design is the recent extension of test‐negative designs to CRTs testing community‐level interventions. Via simulation, we compare the performance of new and standard estimators based on CRTs with negative controls to approaches that only use the original counts. When there is no differential ascertainment by intervention arm, the count‐only approaches perform comparably to those using debiasing negative controls. However, under even modest differential ascertainment, the count‐only estimators are no longer reliable.

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Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue

Utarini¹,

Indriani²,

Ahmad³

et al. 2021

N Engl J Med

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400

333

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Background: Aedes aegypti mosquitoes infected with Wolbachia pipientis ( w Mel strain) have reduced potential to transmit dengue viruses. Methods: We conducted a cluster randomised trial of deployments of w Mel-infected Ae. aegypti for control of dengue in Yogyakarta City, Indonesia. Twenty-four geographic clusters were randomly allocated to receive w Mel deployments as an adjunct to local mosquito control measures; or to continue with local mosquito control measures only. A test-negative design was used to measure efficacy. Study participants were persons 3–45 years old attending primary care clinics with acute undifferentiated fever. Laboratory testing identified virologically-confirmed dengue cases and test-negative controls. The primary endpoint was efficacy of w Mel in reducing the incidence of symptomatic, virologically-confirmed dengue, caused by any dengue virus serotype. Results: Following successful introgression of w Mel in intervention clusters, 8144 participants were enrolled; 3721 from w Mel-treated clusters and 4423 from untreated clusters. In the ITT analysis virologically-confirmed dengue occurred in 67 of 2905 (2.3%) participants in the w Mel-treated and 318 of 3401 (9.4%) in the untreated arm (OR 0.23, 95% CI, 0.15 to 0.35; P=0.004): protective efficacy of 77.1% (95% CI, 65.3 to 84.9). Protective efficacy was similar for the four serotypes. Hospitalisation for virologically-confirmed dengue was less frequent for participants resident in the w Mel-treated (13/2905, 2.8%) compared to the untreated arm (102/3401, 6.3%): protective efficacy 86.2% (95% CI, 66.2 to 94.3) Conclusions: w Mel introgression into Ae. aegypti populations was efficacious in reducing the incidence of symptomatic dengue, and also led to fewer dengue hospitalisations. Trial registration number: ClinicalTrials.gov Identifier: NCT03055585 and INA-A7OB6TW

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Cluster-Randomized Test-Negative Design Trials: A Novel and Efficient Method to Assess the Efficacy of Community-Level Dengue Interventions

Cited by 24 publications

References 46 publications

The impact of insecticide treated curtains on dengue virus transmission: A cluster randomized trial in Iquitos, Peru

The impact of insecticide treated curtains on dengue virus transmission: A cluster randomized trial in Iquitos, Peru

Analysis of counts for cluster randomized trials: Negative controls and test‐negative designs

Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue

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