Detecting infection hotspots: Modeling the surveillance challenge for elimination of lymphatic filariasis

<div><p>Background</p><p>During the past 20 years, enormous efforts have been expended globally to eliminate lymphatic filariasis (LF) through mass drug administration (MDA). However, small endemic foci (microfoci) of LF may threaten the presumed inevitable decline of infections after MDA cessation. We conducted microsimulation modeling to assess the ability of different types of surveillance to identify microfoci in these settings.</p><p>Methods</p><p>Five or ten microfoci of radius 1, 2, or 3 km with infection marker prevalence (intensity) of 3, 6, or 10 times background prevalence were placed in spatial simulations, run in R Version 3.2. Diagnostic tests included microfilaremia, immunochromatographic test (ICT), and Wb123 ELISA. Population size was fixed at 360,000 in a 60 x 60 km area; demographics were based on literature for Sub-Saharan African populations. Background ICT prevalence in 6–7 year olds was anchored at 1.0%, and the prevalence in the remaining population was adjusted by age. Adults≥18 years, women aged 15–40 years (WCBA), children aged 6–7 years, or children≤5 years were sampled. Cluster (CS), simple random sampling (SRS), and TAS-like sampling were simulated, with follow-up testing of the nearest 20, 100, or 500 persons around each infection-marker-positive person. A threshold number of positive persons in follow-up testing indicated a suspected microfocus. Suspected microfoci identified during surveillance and actual microfoci in the simulation were compared to obtain a predictive value positive (PVP). Each parameter set was referred to as a protocol. Protocols were scored by efficiency, defined as the most microfoci identified, the fewest persons requiring primary and follow-up testing, and the highest PVP. Negative binomial regression was used to estimate aggregate effects of different variables on efficiency metrics.</p><p>Results</p><p>All variables were significantly associated with efficiency metrics. Additional follow-up tests beyond 20 did not greatly increase the number of microfoci detected, but significantly negatively impacted efficiency. Of 3,402 protocols evaluated, 384 (11.3%) identified all five microfoci (PVP 3.4–100.0%) and required testing 0.73–35.6% of the population. All used SRS and 378 (98.4%) only identified all five microfoci if they were 2–3 km diameter or high-intensity (6x or 10x); 374 (97.4%) required ICT or Wb123 testing to identify all five microfoci, and 281 (73.0%) required sampling adults or WCBA. The most efficient CS protocols identified two (40%) microfoci. After limiting to protocols with 1-km radius microfoci of 3x intensity (n = 378), eight identified all five microfoci; all used SRS and ICT and required testing 31.2–33.3% of the population. The most efficient CS and TAS-like protocols as well as those using microfilaremia testing identified only one (20%) microfocus when they were limited to 1-km radius and 3x intensity.</p><p>Conclusion</p><p>In this model, SRS, ICT, and sampling of adults maximized microfocus detection efficiency. Follow-up sampling of more persons did not necessarily increase protocol efficiency. Current approaches towards surveillance, including TAS, may not detect small, low-intensity LF microfoci that could remain after cessation of MDA. The model provides many surveillance protocols that can be selected for optimal outcomes.</p></div

Efficiency of TAS-like sampling at detecting microfoci using ICT.

<p>Efficiency of TAS-like sampling at detecting microfoci using ICT.</p

Effect of varying the model variables on the median predictive value positive of identifying microfoci, the median proportion of the population requiring testing, and the median proportion of microfoci detected.

<p>In this analysis, both TAS-like protocols and Wb123 protocols are excluded. The threshold for all microfilaremia testing is set at 1. For ICT tests, the threshold for identification of a suspected microfocus is 1 positive when 20 follow-up tests are used, and 2 in all other cases.</p

The most efficient protocols using microfilaria testing using a 1-km radius, 3x intensity, and threshold of 1 for 6–7 yo, WCBA, and adults>18 years.

<p>The most efficient protocols using microfilaria testing using a 1-km radius, 3x intensity, and threshold of 1 for 6–7 yo, WCBA, and adults>18 years.</p

Characteristics of microfoci.

<p>Shaded boxes represent those with <80% of microfoci in each simulation being statistically significantly different from background, in terms of infection prevalence. Test: test type. Rad: Microfocus radius. Int: Microfocus intensity. Med pop size: median target population size in microfocus. Med pos: Median number of positives by test type in microfocus. Expected pos: Expected number of positives by test type in microfocus at background prevalence. Prop microfoci p<0.05: Proportion of microfoci across all simulations in that category with more positive persons (p<0.05) in target age group than background.</p

The most efficient protocols using microfilaremia testing when microfoci are limited to 1 km radius and 3x intensity.

<p>The most efficient protocols using microfilaremia testing when microfoci are limited to 1 km radius and 3x intensity.</p

Example of simulation model.

<p>An area of the total population on which five microfoci are place is shown in an expanded view to describe the process when a person tests infection marker-positive. In this example, the trigger is one, trigger-based follow-up number is 20, and the threshold for action is two additional positives. An example of how the predictive value positive for identification of microfoci is calculated is shown on the far right, where persons testing positive during follow-up sampling either do or do not fall within an actual microfocus.</p

Inputs and outputs of the most efficient surveillance protocols.

<p>Test: Test type used. Samp: Sampling methodology. PP: Population proportion sampled. Ages: ages sampled during primary sampling. Radius: microfocus radius. Int: microfocus intensity. TBS: Number tested in trigger-based sampling (all ages). TH: Threshold (number of positives required during trigger-based sampling for program manager to believe they have identified a microfocus). Pos/Test: Proportion of persons tested who are positive. Pos/PopPos: Proportion of all positive persons in the population who are identified in testing. Test/Pop: Proportion of total population tested. <b>μf</b> PVP: Proportion of all suspected microfoci that are true microfoci (correctly identified as microfoci). <b>μf</b> Sens: Proportion of all microfoci found through the sampling protocol.</p

The most efficient protocols using cluster sampling methodology without limiting microfocus radius or intensity.

<p>The most efficient protocols using cluster sampling methodology without limiting microfocus radius or intensity.</p

Number of protocols identifying 100% of the microfoci at different microfocus sizes and intensities.

<p>Number of protocols identifying 100% of the microfoci at different microfocus sizes and intensities.</p