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1.  The Effect of Mass Azithromycin Distribution on Childhood Mortality: Beliefs and Estimates of Efficacy 
A cluster-randomized trial demonstrated that mass oral azithromycin distribution reduced childhood mortality 49.6% (Trachoma Amelioration in Northern Amhara [TANA]). The relative risk of childhood mortality was then estimated using two approaches: an expert survey and a Bayesian analysis. The survey asked public health experts to estimate the true effect of mass azithromycin distribution on childhood mortality. The Bayesian estimation used the TANA study's results and prior estimates of the efficacy of other effective population-level interventions. The experts believed mass azithromycin reduces childhood mortality (relative risk = 0.83, 95% credible intervals [CrI] = 0.70–1.00). The Bayesian analysis estimated a relative risk of 0.71 (95% CrI = 0.39–0.93). Both estimates suggest that azithromycin may have a true mortality benefit, though of a smaller magnitude than found in the single available trial. Prior information about nonantibiotic, population-level interventions may have informed the expert's opinions. Additional trials are needed to confirm a mortality benefit from mass azithromycin.
PMCID: PMC4703272  PMID: 26392160
3.  Inter-grader Agreement of the Ocular Staining Score in the Sjögren’s International Clinical Collaborative Alliance (SICCA) registry 
American journal of ophthalmology  2015;160(6):1150-1153.e3.
To determine the intra-observer and inter-observer reliability of a novel ocular staining score among trained ophthalmologists.
Reliability analysis within a prospective, observational, multi-center cohort study.
Those enrolled in the National Institutes of Health-funded Sjögren’s International Collaborative Clinical Alliance (SICCA) who presented for follow up at the University of California San Francisco, Aravind Eye Hospital, Johns Hopkins University, and the University of Pennsylvania were included. Study participants were graded using the ocular staining score by at least two masked SICCA-trained ophthalmologists. The primary outcome for this study was the intraclass correlation coefficient (ICC) for the total ocular staining score. ICC’s were also calculated for tear break up time (TBUT), conjunctival and corneal staining.
Total ocular staining score had an ICC of 0.91 for the right eye (95% CI 0.85 – 0.96) and 0.90 for the left eye (95% CI 0.83 – 0.97). Corneal staining (right eye 0.86, 95% CI 0.76 – 0.93, left eye 0.90, 95% CI 0.81 – 0.95) and conjunctival staining (right eye 0.87, 95% CI 0.80 –0.93, left eye 0.85, 95% CI 0.75 – 0.93) demonstrated excellent agreement. The ICC for TBUT was slightly lower (right eye 0.77, 95% CI 0.64 – 0.89; left eye 0.81, 95% CI 0.68 – 0.90).
Previous studies have shown that the ocular staining score is correlated with other diagnostic components of Sjögren syndrome. In this study, we demonstrate high reliability in grading among trained ophthalmologists, completing the validation of this test.
PMCID: PMC4651820  PMID: 26302236
4.  Vision-Related Quality-of-Life Outcomes in the Mycotic Ulcer Treatment Trial I 
JAMA ophthalmology  2015;133(6):642-646.
Given the limitations in health care resources, quality-of-life measures for interventions have gained importance.
To determine whether vision-related quality-of-life outcomes were different between the natamycin and voriconazole treatment arms in the Mycotic Ulcer Treatment Trial I, as measured by an Indian Vision Function Questionnaire.
Secondary analysis (performed October 11–25, 2014) of a double-masked, multicenter, randomized, active comparator–controlled, clinical trial at multiple locations of the Aravind Eye Care System in South India that enrolled patients with culture- or smear-positive filamentous fungal corneal ulcers who had a baseline visual acuity of 20/40 to 20/400 (logMAR of 0.3–1.3).
Study participants were randomly assigned to topical voriconazole, 1%, or topical natamycin, 5%.
Subscale score on the Indian Vision Function Questionnaire from each of the 4 subscales (mobility, activity limitation, psychosocial impact, and visual function) at 3 months.
A total of 323 patients were enrolled in the trial, and 292 (90.4%) completed the Indian Vision Function Questionnaire at 3 months. The majority of study participants had subscale scores consistent with excellent function. After adjusting for baseline visual acuity and organism, we found that study participants in the natamycin-treated group scored, on average, 4.3 points (95% CI, 0.1–8.5) higher than study participants in the voriconazole-treated group (P = .046). In subgroup analyses looking at ulcers caused by Fusarium species and adjusting for baseline best spectacle–corrected visual acuity, the natamycin-treated group scored 8.4 points (95% CI, 1.9–14.9) higher than the voriconazole-treated group (P = .01). Differences in quality of life were not detected for patients with Aspergillus or other non-Fusarium species as the causative organism (1.5 points [95% CI, −3.9 to 6.9]; P = .52).
We found evidence of improvement in vision-related quality of life among patients with fungal ulcers who were randomly assigned to natamycin compared with those randomly assigned to voriconazole, and especially among patients with Fusarium species as the causative organism. Incorporation of quality-of-life measures in clinical trials is important to fully evaluate the effect of the studied interventions.
TRIAL REGISTRATION Identifier: NCT00996736
PMCID: PMC4962866  PMID: 25764482
5.  ‘If an Eye Is Washed Properly, It Means It Would See Clearly’: A Mixed Methods Study of Face Washing Knowledge, Attitudes, and Behaviors in Rural Ethiopia 
PLoS Neglected Tropical Diseases  2016;10(10):e0005099.
Face cleanliness is a core component of the SAFE (Surgery, Antibiotics, Facial cleanliness, and Environmental improvements) strategy for trachoma control. Understanding knowledge, attitudes, and behaviors related to face washing may be helpful for designing effective interventions for improving facial cleanliness.
In April 2014, a mixed methods study including focus groups and a quantitative cross-sectional study was conducted in the East Gojjam zone of the Amhara region of Ethiopia. Participants were asked about face washing practices, motivations for face washing, use of soap (which may reduce bacterial load), and fly control strategies.
Overall, both knowledge and reported practice of face washing was high. Participants reported they knew that washing their own face and their children’s faces daily was important for hygiene and infection control. Although participants reported high knowledge of the importance of soap for face washing, quantitative data revealed strong variations by community in the use of soap for face washing, ranging from 4.4% to 82.2% of households reporting using soap for face washing. Cost and forgetfulness were cited as barriers to the use of soap for face washing. Keeping flies from landing on children was a commonly cited motivator for regular face washing, as was trachoma prevention.
Interventions aiming to improve facial cleanliness for trachoma prevention should focus on habit formation (to address forgetfulness) and address barriers to the use of soap, such as reducing cost. Interventions that focus solely on improving knowledge may not be effective for changing face-washing behaviors.
Author Summary
Facial cleanliness is a core component of the SAFE (Surgery, Antibiotics, Facial cleanliness, and Environmental improvements) strategy for trachoma control. We conducted a mixed methods study in a trachoma hyperendemic region of rural Ethiopia to better understand knowledge, attitudes, and behaviors related to face washing. Overall, knowledge of the benefits of face washing was high, and participants reported regularly engaging in face washing practices. However, the use of soap for face washing varied more between communities. Participants cited cost and forgetting to use soap as the primary barriers to using soap for face washing. Trachoma prevention, including keeping flies from landing on children’s faces, was a commonly-cited motivator for face washing discussed in focus groups. Given the near-universal knowledge of the benefits of face washing, interventions focused on changing face washing behavior for trachoma control should focus on habit formation and removal of barriers to the use of soap rather than simply educational interventions.
PMCID: PMC5082955  PMID: 27788186
6.  The distribution of the prevalence of ocular chlamydial infection in communities where trachoma is disappearing 
Epidemics  2015;11:85-91.
Mathematical models predict that the prevalence of infection in different communities where an infectious disease is disappearing should approach a geometric distribution. Trachoma programs offer an opportunity to test this hypothesis, as the World Health Organization (WHO) has targeted trachoma to be eliminated as a public health concern by the year 2020. We assess the distribution of the community prevalence of childhood ocular chlamydia infection from periodic, cross-sectional surveys in two areas of Ethiopia. These surveys were taken in a controlled setting, where infection was documented to be disappearing over time. For both sets of surveys, the geometric distribution had the most parsimonious fit of the distributions tested, and goodness-of-fit testing was consistent with the prevalence of each community being drawn from a geometric distribution. When infection is disappearing, the single sufficient parameter describing a geometric distribution captures much of the distributional information found from examining every community. The relatively heavy tail of the geometric suggests that the presence of an occasional high-prevalence community is to be expected, and does not necessarily reflect a transmission hot spot or program failure. A single cross-sectional survey can reveal which direction a program is heading. A geometric distribution of the prevalence of infection across communities may be an encouraging sign, consistent with a disease on its way to eradication.
PMCID: PMC4986606  PMID: 25979286
Trachoma; Eradication; Mass drug administration; Transmission model; Geometric distribution
7.  Seasonal trends of microbial keratitis in south India 
Cornea  2012;31(10):1123-1127.
Prior studies suggest that fungal keratitis is more common in hot, humid climates while bacterial keratitis is independent of seasonal variation. This study analyzes seasonal trends in the incidence of fungal and bacterial keratitis at the Aravind Eye Hospital in southeast India.
Using microbiology records from August 2006 to July 2009, retrospective analyses of infectious keratitis were performed. Bacterial and fungal keratitis incidence data were analyzed for seasonal patterns.
Among the 6,967 infectious keratitis cases, cultures were performed in 5,221 (74.9%) and positive in 3,028 (58%). Of the positive cultures cases, 1,908 (63%) and 1,081 (35.7%) were of fungal and bacterial etiology, respectively. The predominant fungal organism was Fusarium spp (42.3%) and the predominant bacterial organisms were Streptococcus pneumoniae (35.1%), Pseudomonas aeruginosa (24.3%), and Nocardia spp (8.1%). Analyses revealed an uneven distribution of fungal keratitis throughout the year (p<0.001) with peaks in July and January. No significant seasonal trend was observed for the combined bacterial keratitis group.
A higher incidence of fungal keratitis occurs during the months corresponding to the windy and harvest seasons, during which time infection from vegetative corneal injury may be more likely. Robust screening efforts during these periods may mitigate visually debilitating sequelae from infectious keratitis.
PMCID: PMC4986607  PMID: 22868629
infectious keratitis; season; India
9.  Trachoma: An Update on Prevention, Diagnosis, and Treatment 
Current opinion in ophthalmology  2012;23(4):288-295.
Purpose of review
To review recent clinical and epidemiological studies regarding the prevention, diagnosis, and treatment of trachoma.
Recent Findings
Newer studies propose novel diagnostic tests that appear sensitive for the detection of ocular chlamydial infection. Immunologic studies suggest that chronic inflammation can lead to progressive scarring, even in the absence of chlamydia. Confocal microscopy can obtain accurate grading of scarring progression. Mass oral azithromycin distributions remain a mainstay of treatment; studies have assessed the appropriate frequency and duration of treatment programs. Current studies have also explored ancillary effects of azithromycin distribution on mortality and bacterial infections.
Trachoma programs have had remarkable success at reducing chlamydial infection and clinical signs of trachoma. Recent work suggests improved methods to monitor infection and scarring, and better ways to distribute treatment. While studies continue to demonstrate reduction in infection in hyperendemic areas, more work will need to be done to achieve elimination of this blinding disease.
PMCID: PMC4791051  PMID: 22569465
trachoma; chlamydia; neglected tropical disease; azithromycin; confocal microscopy
12.  Antibiotic resistance as collateral damage: the tragedy of the commons in a two-disease setting 
Mathematical biosciences  2015;263:121-132.
We propose a simple two-disease epidemic model where one disease exhibits only a drug-sensitive strain, while the other exhibits both drug-sensitive and drug-resistant strains. Treatment for the first disease may select for resistance in the other. We model antibiotic use as a mathematical game through the study of individual incentives and community welfare. The basic reproduction number is derived and the existence and local stability of the model equilibria are analyzed. When the force of infection of each disease is unaffected by the presence of the other, we find that there is a conflict of interest between individual and community, known as a tragedy of the commons, under targeted treatment towards persons infected by the single strain disease, but there is no conflict under mass treatment. However, we numerically show that individual and social incentive to use antibiotics may show disaccord under mass treatment if the restriction on the transmission ability of the dually infected people is removed, or drug resistant infection is worse than drug sensitive infection, or the uninfected state has a comparative disutility over the infected states.
PMCID: PMC4414057  PMID: 25726716
drug-resistance; game theory; two diseases; tragedy of the commons; mass treatment; targeted treatment
13.  Inter-rater agreement between trachoma graders: comparison of grades given in field conditions versus grades from photographic review 
Ophthalmic epidemiology  2015;22(3):162-169.
Trachoma surveillance is most commonly performed by direct observation, usually by non-ophthalmologists using the World Health Organization (WHO) simplified grading system. However, conjunctival photographs may offer several benefits over direct clinical observation, including the potential for greater inter-rater agreement. This study assesses whether inter-rater agreement of trachoma grading differs when trained graders review conjunctival photographs versus when they perform conjunctival examinations in the field.
3 trained trachoma graders each performed an independent examination of the everted right tarsal conjunctiva of 269 children aged 0-9 years, and then reviewed photographs of these same conjunctivae in a random order. For each eye, the grader documented the presence or absence of follicular trachoma (TF) and intense trachomatous inflammation (TI) according to the WHO simplified grading system.
Inter-rater agreement for grade of TF was significantly higher in the field (kappa coefficient, κ, 0.73, 95% confidence interval, CI 0.67-0.80) than by photographic review (κ=0.55, 95% CI 0.49-0.63; difference in κ between field grading and photo grading 0.18, 95% CI 0.09-0.26). When field and photographic grades were each assessed as the consensus grade from the 3 graders, agreement between in-field and photographic graders was high for TF (κ=0.75, 95% CI 0.68-0.84).
In an area with hyperendemic trachoma, inter-rater agreement was lower for photographic assessment of trachoma than for in-field assessment. However, the trachoma grade reached by a consensus of photographic graders agreed well with the grade given by a consensus of in-field graders.
PMCID: PMC4802863  PMID: 26158573
inter-rater agreement; observer variation; trachoma; diagnosis; photography
14.  Visual recovery in treated bacterial keratitis 
Ophthalmology  2014;121(6):1310-1311.e3.
Bacterial keratitis is a leading cause of visual impairment worldwide. However, the natural history of treated bacterial keratitis has not been well characterized. We performed a secondary analysis of the Steroids for Corneal Ulcers Trial (SCUT; #NCT00324168) to better characterize the rate of visual acuity improvement after successful antimicrobial treatment.
PMCID: PMC4047131  PMID: 24612976
prospective; visual acuity; outcomes; keratitis; clinical trial
15.  Evidence for Clonal Expansion After Antibiotic Selection Pressure: Pneumococcal Multilocus Sequence Types Before and After Mass Azithromycin Treatments 
The Journal of Infectious Diseases  2014;211(6):988-994.
Background. A clinical trial of mass azithromycin distributions for trachoma created a convenient experiment to test the hypothesis that antibiotic use selects for clonal expansion of preexisting resistant bacterial strains.
Methods. Twelve communities in Ethiopia received mass azithromycin distributions every 3 months for 1 year. A random sample of 10 children aged 0–9 years from each community was monitored by means of nasopharyngeal swab sampling before mass azithromycin distribution and after 4 mass treatments. Swab specimens were tested for Streptococcus pneumoniae, and isolates underwent multilocus sequence typing.
Results. Of 82 pneumococcal isolates identified before treatment, 4 (5%) exhibited azithromycin resistance, representing 3 different sequence types (STs): 177, 6449, and 6494. The proportion of isolates that were classified as one of these 3 STs and were resistant to azithromycin increased after 4 mass azithromycin treatments (14 of 96 isolates [15%]; P = .04). Using a classification index, we found evidence for a relationship between ST and macrolide resistance after mass treatments (P < .0001). The diversity of STs—as calculated by the unbiased Simpson index—decreased significantly after mass azithromycin treatment (P = .045).
Conclusions. Resistant clones present before mass azithromycin treatments increased in frequency after treatment, consistent with the theory that antibiotic selection pressure results in clonal expansion of existing resistant strains.
PMCID: PMC4416126  PMID: 25293366
Streptococcus pneumoniae; Africa; MLST; multilocus sequence typing; clonal expansion
16.  Impact of Mass Azithromycin Distribution on Malaria Parasitemia during the Low-Transmission Season in Niger: A Cluster-Randomized Trial 
We assessed the effect of mass azithromycin treatment on malaria parasitemia in a trachoma trial in Niger. Twenty-four study communities received treatment during the wet, high-transmission season. Twelve of the 24 communities were randomized to receive an additional treatment during the dry, low-transmission season. Outcome measurements were conducted at the community-level in children < 1–72 months of age in May–June 2011. Parasitemia was higher in the 12 once-treated communities (29.8%, 95% confidence interval [CI] = 21.5–40.0%) than in the 12 twice-treated communities (19.5%, 95% CI = 13.0–26.5%, P = 0.03). Parasite density was higher in once-treated communities (354 parasites/μL, 95% CI = 117–528 parasites/μL) than in twice-treated communities (74 parasites/μL, 95% CI = 41–202 parasites/μL, P = 0.03). Mass distribution of azithromycin reduced malaria parasitemia 4–5 months after the intervention. The results suggest that drugs with antimalaria activity can have long-lasting impacts on malaria during periods of low transmission.
PMCID: PMC4015576  PMID: 24615132
17.  Control of Trachoma from Achham District, Nepal: A Cross-Sectional Study from the Nepal National Trachoma Program 
PLoS Neglected Tropical Diseases  2016;10(2):e0004462.
The WHO seeks to control trachoma as a public health problem in endemic areas. Achham District in western Nepal was found to have TF (trachoma follicular) above 20% in a 2006 government survey, triggering 3 annual mass drug administrations finishing in 2010. Here we assess the level of control that has been achieved using surveillance for clinical disease, ocular chlamydia trachomatis infection, and serology for antibodies against chlamydia trachomatis protein antigens.
We conducted a cross-sectional survey of children aged 1–9 years in communities in Achham District in early 2014 including clinical examination validated with photographs, conjunctival samples for Chlamydia trachomatis (Amplicor PCR), and serological testing for antibodies against chlamydia trachomatis protein antigens pgp3 and CT694 using the Luminex platform.
In 24 randomly selected communities, the prevalence of trachoma (TF and/or TI) in 1–9 year olds was 3/1124 (0.3%, 95% CI 0.1 to 0.8%), and the prevalence of ocular chlamydia trachomatis infection was 0/1124 (0%, 95% CI 0 to 0.3%). In 18 communities selected because they had the highest prevalence of trachoma in a previous survey, the prevalence of TF and/or TI was 7/716 (1.0%, 95% CI 0.4 to 2.0%) and the prevalence of ocular chlamydia trachomatis infection was 0/716 (0%, 95% CI 0 to 0.5%). In 3 communities selected for serological testing, the prevalence of trachoma was 0/68 (0%, 95% CI 0 to 5.3%), the prevalence of ocular chlamydia trachomatis infection was 0/68 (0%, 95% CI 0 to 0.5%), the prevalence of antibodies against chlamydia trachomatis protein antigen pgp3 was 1/68 (1.5%, 95% CI 0.04% to 7.9%), and the prevalence of antibodies against chlamydia trachomatis protein antigen CT694 was 0/68 (0%, 95% CI 0 to 5.3%).
This previously highly endemic district in Nepal has little evidence of recent clinical disease, chlamydia trachomatis infection, or serological evidence of trachoma, suggesting that epidemiological control has been achieved.
Author Summary
Trachoma is the most common cause of blindness from a bacterial infection in the world. It is caused by the bacterium Chlamydia trachomatis. The WHO (World Health Organization) seeks to control this disease worldwide using SAFE which includes mass antibiotic administrations (MDA) with azithromycin. The Nepal National Trachoma Program was started in 2002 with the goal of controlling trachoma as a public health problem. We did a survey in Achham District in early 2014 and found the prevalence of clinical signs of trachoma, chlamydia trachomatis infection and antibodies against chlamydia trachomatis were all below 1% in 1–9 year olds. Trachoma has been controlled and is no longer a public health problem in Achham district Nepal.
PMCID: PMC4752456  PMID: 26871898
18.  Importance of Including Borderline Cases in Trachoma Grader Certification 
We assessed trachoma grading agreement among field graders using photographs that included the complete spectrum of disease and compared it with cases where there was consensus among experienced graders. Trained photographers took photographs of children's conjunctiva during a clinical trial in Ethiopia. We calculated κ-agreement statistics using a complete set of 60 cases and then recalculated the κ using a consensus set where cases were limited to those cases with agreement among experienced graders. When the complete set of 60 cases was used, agreement was moderate (κ = 0.61, 95% confidence interval [95% CI] = 0.56–0.67). When the consensus set was used, agreement improved significantly (κ = 0.75, 95% CI = 0.68–0.80). The κ of the consensus set was higher than the complete set by 0.14 (95% CI = 0.12–0.16) (P < 0.001). If testing sets remove difficult-to-grade cases, agreement in trachoma grading may be higher than actually seen in population-based trachoma surveys.
PMCID: PMC4155563  PMID: 25002297
19.  Association Between In Vitro Susceptibility to Natamycin and Voriconazole and Clinical Outcomes in Fungal Keratitis 
Ophthalmology  2014;121(8):1495-1500.e1.
To assess the association between minimum inhibitory concentration (MIC) and clinical outcomes in a fungal keratitis clinical trial.
Experimental study using data from a randomized comparative trial.
Of the 323 patients enrolled in the trial, we were able to obtain MIC values from 221 patients with monocular fungal keratitis.
The Mycotic Ulcer Treatment Trial I (MUTT I) was a randomized, double-masked clinical trial comparing clinical outcomes of monotherapy with topical natamycin versus voriconazole for the treatment of fungal keratitis. Speciation and determination of MIC to natamycin and voriconazole were performed according to Clinical and Laboratory Standards Institute guidelines. The relationship between MIC and clinical outcome was assessed.
Main Outcome Measures
The primary outcome was 3-month best spectacle-corrected visual acuity. Secondary outcomes included 3-month infiltrate/scar size, corneal perforation and/or therapeutic penetrating keratoplasty (TPK), and time to re-epithelialization.
A 2-fold increase in MIC was associated with a larger 3-month infiltrate/scar size (0.21 mm, 95% confidence interval [CI] 0.10–0.31, P <0.001) and increased odds of perforation (odds ratio [OR] 1.32, 95% CI 1.04–1.69, P=0.02). No correlation was found between MIC and 3-month visual acuity. For natamycin-treated cases, an association was found between higher natamycin MIC with larger 3-month infiltrate/scar size (0.29 mm, 95% CI 0.15–0.43, P<0.001) and increased perforations (OR 2.41, 95% CI 1.46–3.97, P<0.001). Among voriconazole-treated cases, the voriconazole MIC did not correlate with any of the measured outcomes in the study.
Decreased susceptibility to natamycin was associated with increased infiltrate/scar size and increased odds of perforation. There was no association between susceptibility to voriconazole and outcome.
PMCID: PMC4122634  PMID: 24746358
21.  The Global Trachoma Mapping Project: Methodology of a 34-Country Population-Based Study 
Ophthalmic Epidemiology  2015;22(3):214-225.
Purpose: To complete the baseline trachoma map worldwide by conducting population-based surveys in an estimated 1238 suspected endemic districts of 34 countries.
Methods: A series of national and sub-national projects owned, managed and staffed by ministries of health, conduct house-to-house cluster random sample surveys in evaluation units, which generally correspond to “health district” size: populations of 100,000–250,000 people. In each evaluation unit, we invite all residents aged 1 year and older from h households in each of c clusters to be examined for clinical signs of trachoma, where h is the number of households that can be seen by 1 team in 1 day, and the product h × c is calculated to facilitate recruitment of 1019 children aged 1–9 years. In addition to individual-level demographic and clinical data, household-level water, sanitation and hygiene data are entered into the purpose-built LINKS application on Android smartphones, transmitted to the Cloud, and cleaned, analyzed and ministry-of-health-approved via a secure web-based portal. The main outcome measures are the evaluation unit-level prevalence of follicular trachoma in children aged 1–9 years, prevalence of trachomatous trichiasis in adults aged 15 + years, percentage of households using safe methods for disposal of human feces, and percentage of households with proximate access to water for personal hygiene purposes.
Results: In the first year of fieldwork, 347 field teams commenced work in 21 projects in 7 countries.
Conclusion: With an approach that is innovative in design and scale, we aim to complete baseline mapping of trachoma throughout the world in 2015.
PMCID: PMC4687001  PMID: 26158580
Blindness; mHealth; prevalence study; trachoma; trichiasis
22.  Quantitative analyses and modelling to support achievement of the 2020 goals for nine neglected tropical diseases 
Parasites & Vectors  2015;8:630.
Quantitative analysis and mathematical models are useful tools in informing strategies to control or eliminate disease. Currently, there is an urgent need to develop these tools to inform policy to achieve the 2020 goals for neglected tropical diseases (NTDs). In this paper we give an overview of a collection of novel model-based analyses which aim to address key questions on the dynamics of transmission and control of nine NTDs: Chagas disease, visceral leishmaniasis, human African trypanosomiasis, leprosy, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. Several common themes resonate throughout these analyses, including: the importance of epidemiological setting on the success of interventions; targeting groups who are at highest risk of infection or re-infection; and reaching populations who are not accessing interventions and may act as a reservoir for infection,. The results also highlight the challenge of maintaining elimination ‘as a public health problem’ when true elimination is not reached. The models elucidate the factors that may be contributing most to persistence of disease and discuss the requirements for eventually achieving true elimination, if that is possible. Overall this collection presents new analyses to inform current control initiatives. These papers form a base from which further development of the models and more rigorous validation against a variety of datasets can help to give more detailed advice. At the moment, the models’ predictions are being considered as the world prepares for a final push towards control or elimination of neglected tropical diseases by 2020.
PMCID: PMC4674954  PMID: 26652272
Modelling; Elimination; Neglected tropical diseases; Transmission; Chagas disease; Visceral leishmaniasis; Kala-azar; Human African trypanosomiasis; Leprosy; Soil-transmitted helminths; Schistosomiasis; Lymphatic filariasis; Onchocerciasis; Trachoma; Mass drug administration; Preventive chemotherapy
23.  Spatial heterogeneity in projected leprosy trends in India 
Parasites & Vectors  2015;8:542.
Leprosy is caused by infection with Mycobacterium leprae and is characterized by peripheral nerve damage and skin lesions. The disease is classified into paucibacillary (PB) and multibacillary (MB) leprosy. The 2012 London Declaration formulated the following targets for leprosy control: (1) global interruption of transmission or elimination by 2020, and (2) reduction of grade-2 disabilities in newly detected cases to below 1 per million population at a global level by 2020. Leprosy is treatable, but diagnosis, access to treatment and treatment adherence (all necessary to curtail transmission) represent major challenges. Globally, new case detection rates for leprosy have remained fairly stable in the past decade, with India responsible for more than half of cases reported annually.
We analyzed publicly available data from the Indian Ministry of Health and Family Welfare, and fit linear mixed-effects regression models to leprosy case detection trends reported at the district level. We assessed correlation of the new district-level case detection rate for leprosy with several state-level regressors: TB incidence, BCG coverage, fraction of cases exhibiting grade 2 disability at diagnosis, fraction of cases in children, and fraction multibacillary.
Our analyses suggest an endemic disease in very slow decline, with substantial spatial heterogeneity at both district and state levels. Enhanced active case finding was associated with a higher case detection rate.
Trend analysis of reported new detection rates from India does not support a thesis of rapid progress in leprosy control.
PMCID: PMC4618538  PMID: 26490137
Leprosy; Mycobacterium leprae; India; Linear mixed effects regression
24.  Short-term forecasting of the prevalence of clinical trachoma: utility of including delayed recovery and tests for infection 
Parasites & Vectors  2015;8:535.
The World Health Organization aims to control blinding trachoma by 2020. Decisions on whether to start and stop mass treatments and when to declare that control has been achieved are currently based on clinical examination data generated in population-based surveys. Thresholds are based on the district-level prevalence of trachomatous inflammation–follicular (TF) in children aged 1–9 years. Forecasts of which districts may and may not meet TF control goals by the 2020 target date could affect resource allocation in the next few years.
We constructed a hidden Markov model fit to the prevalence of two clinical signs of trachoma and PCR data in 24 communities from the recent PRET-Niger trial. The prevalence of TF in children in each community at 36 months was forecast given data from earlier time points. Forecasts were scored by the likelihood of the observed results. We assessed whether use of TF with additional TI and PCR data rather than just the use of TF alone improves forecasts, and separately whether incorporating a delay in TF recovery is beneficial.
Including TI and PCR data did not significantly improve forecasts of TF. Forecasts of TF prevalence at 36 months by the model with the delay in TF recovery were significantly better than forecasts by the model without the delay in TF recovery (p = 0.003). A zero-inflated truncated normal observation model was better than a truncated normal observation model, and better than a sensitivity-specificity observation model.
The results in this study suggest that future studies could consider using just TF data for forecasting, and should include a delay in TF recovery.
Trial registration NCT00792922
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-015-1115-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4618840  PMID: 26489933
Trachoma; Model; Mass drug administration; Forecast; Prediction
25.  Evaluating Subcriticality during the Ebola Epidemic in West Africa 
PLoS ONE  2015;10(10):e0140651.
The 2014–2015 Ebola outbreak is the largest and most widespread to date. In order to estimate ongoing transmission in the affected countries, we estimated the weekly average number of secondary cases caused by one individual infected with Ebola throughout the infectious period for each affected West African country using a stochastic hidden Markov model fitted to case data from the World Health Organization. If the average number of infections caused by one Ebola infection is less than 1.0, the epidemic is subcritical and cannot sustain itself. The epidemics in Liberia and Sierra Leone have approached subcriticality at some point during the epidemic; the epidemic in Guinea is ongoing with no evidence that it is subcritical. Response efforts to control the epidemic should continue in order to eliminate Ebola cases in West Africa.
PMCID: PMC4618845  PMID: 26484544

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