A refined and updated health impact assessment of the Global Programme to Eliminate Lymphatic Filariasis (2000-2020).

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease (NTD). In 2000 the World Health Organization (WHO) established the Global Programme to Eliminate Lymphatic Filariasis (GPELF). A key component of this programme is mass drug administration (MDA). Between 2000 and 2020, the GPELF has delivered over 8.6 billion treatments to at-risk populations. The last impact assessment of the programme evaluated the treatments provided between 2000-2014. The goal of this analysis is to provide an updated health impact assessment of the programme, based on the numbers treated between 2000-2020. METHODS: We updated and refined a previously established model that estimates the number of clinical manifestations and disability-adjusted life years (DALYs) averted by the treatments provided by the GPELF. The model comprises three different population cohorts that can benefit from MDA provided (those protected from acquiring infection, those with subclinical morbidity prevented from progressing and those with clinical disease alleviated). The treatment numbers were updated for all participating countries using data from the WHO. In addition, data relating to the estimated number of individuals initially at risk of LF infection were updated where possible. Finally, the DALY calculations were refined to use updated disability weights. RESULTS: Using the updated model and corresponding treatment data, we projected that the total benefit cohort of the GPELF (2000-2020) would consist of approximately 58.5 million individuals and the programme would avert 44.3 million chronic LF cases. Over the lifetime of the benefit cohorts, this corresponded to 244 million DALYs being averted. CONCLUSION: This study indicates that substantial health benefits have resulted from the first 20 years of the GPELF. It is important to note that the GPELF would have both additional benefits not quantified by the DALY burden metric as well as benefits on other co-endemic diseases (such as soil-transmitted helminths, onchocerciasis and scabies)-making the total health benefit underestimated. As with the past impact assessments, these results further justify the value and importance of continued investment in the GPELF.

Baseline Mapping of Neglected Tropical Diseases in Africa: The Accelerated WHO/AFRO Mapping Project.

Mapping is a prerequisite for effective implementation of interventions against neglected tropical diseases (NTDs). Before the accelerated World Health Organization (WHO)/Regional Office for Africa (AFRO) NTD Mapping Project was initiated in 2014, mapping efforts in many countries were frequently carried out in an ad hoc and nonstandardized fashion. In 2013, there were at least 2,200 different districts (of the 4,851 districts in the WHO African region) that still required mapping, and in many of these districts, more than one disease needed to be mapped. During its 3-year duration from January 2014 through the end of 2016, the project carried out mapping surveys for one or more NTDs in at least 2,500 districts in 37 African countries. At the end of 2016, most (90%) of the 4,851 districts had completed the WHO-required mapping surveys for the five targeted Preventive Chemotherapy (PC)-NTDs, and the impact of this accelerated WHO/AFRO NTD Mapping Project proved to be much greater than just the detailed mapping results themselves. Indeed, the AFRO Mapping Project dramatically energized and empowered national NTD programs, attracted donor support for expanding these programs, and developed both a robust NTD mapping database and data portal. By clarifying the prevalence and burden of NTDs, the project provided not only the metrics and technical framework for guiding and tracking program implementation and success but also the research opportunities for developing improved diagnostic and epidemiologic sampling tools for all 5 PC-NTDs-lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiasis, and trachoma.

Setting the stage for a Global Programme to Eliminate Lymphatic Filariasis: the first 125 years (1875-2000).

The development of the World Health Organization's Global Programme to Eliminate Lymphatic Filariasis (GPELF) can be interpreted through many different lenses-e.g. one focusing on the health or economic plight of affected individuals and populations, another tracking the individuals and organizations responsible for building the programme or, as in this review, one identifying each of the critical requirements and specific hurdles that need to be addressed in order to successfully construct the programme. For almost 75 y after the life cycle of LF was first described, the principal tool for countering it was vector control. Discovery that diethylcarbamazine (and later ivermectin and albendazole) could effectively treat affected and at-risk populations, along with the availability of a simple, field-based diagnostic test to monitor programme progress, provided the essential tools for LF elimination. Recognition of this potential by the global health community (including the World Health Assembly) led two pharmaceutical companies (GlaxoSmithKline and Merck) to make enormous, unprecedented donations of albendazole and ivermectin to achieve this goal. Additional resource support from the public and private sectors and from health ministries in the 80 LF-endemic countries led to the creation of a Global Alliance to Eliminate LF, which launched the GPELF in 2000, just 125 y after the LF life cycle was first described.

Evolution of the monitoring and evaluation strategies to support the World Health Organization's Global Programme to Eliminate Lymphatic Filariasis.

The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was established with the ambitious goal of eliminating LF as a public health problem. The remarkable success of the GPELF over the past 2 decades in carrying out its principal strategy of scaling up and scaling down mass drug administration has relied first on the development of a rigorous monitoring and evaluation (M&E) framework and then the willingness of the World Health Organization and its community of partners to modify this framework in response to the practical experiences of national programmes. This flexibility was facilitated by the strong partnership that developed among researchers, LF programme managers and donors willing to support the necessary research agenda. This brief review summarizes the historical evolution of the GPELF M&E strategies and highlights current research needed to achieve the elimination goal.

The Health and Economic Burdens of Lymphatic Filariasis Prior to Mass Drug Administration Programs.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the goal of eliminating lymphatic filariasis (LF) as a public health problem by 2020. Despite considerable progress, the current prevalence is around 60% of the 2000 figure, with the deadline looming a year away. Consequently, there is a continued need for investment in both the mass drug administration (MDA) and morbidity management programs, and this paper aims to demonstrate that need by estimating the health and economic burdens of LF prior to MDA programs starting in GPELF areas. METHODS: A previously developed model was used to estimate the numbers of individuals infected and individuals with symptomatic disease, along with the attributable number of disability-adjusted life years (DALYs). The economic burden was calculated by quantifying the costs incurred by the health-care system in managing clinical cases, the patients' out-of-pocket costs, and their productivity costs. RESULTS: Prior to the MDA program, approximately 129 million people were infected with LF, of which 43 million had clinical disease, corresponding to a DALY burden of 5.25 million. The average annual economic burden per chronic case was US $115, the majority of which resulted from productivity costs. The total economic burden of LF was estimated at US $5.8 billion annually. CONCLUSIONS: These results demonstrate the magnitude of the LF burden and highlight the continued need to support the GPELF. Patients with clinical disease bore the majority of the economic burden, but will not benefit much from the current MDA program, which is aimed at reducing transmission. This assessment further highlights the need to scale up morbidity management programs.

The Elimination of Neglected Tropical Diseases: A Case Study Exemplifying How Foreign Assistance Funding Can Be Catalytic in Reducing the Burden of Major Global Health Conditions.

In 2006, following direct advocacy and published rationale, the US Agency for International Development (USAID) established a neglected tropical diseases (NTDs) program to support the scale-up of integrated platforms to target the elimination and control of 5 NTDs-lymphatic filariasis, trachoma, onchocerciasis, schistosomiasis, and soil-transmitted helminthiasis. By 2017, more than 2.3 billion NTD treatments had been delivered to at-risk populations in 25 countries, leveraging $19 billion in donated drugs-approximately $26 dollars in donated medicine per $1 spent by USAID. As a result, most of the supported countries are on track to achieve their elimination goals (for lymphatic filariasis and trachoma) by 2020 or 2021 and their control goals soon thereafter. Though "small" when compared to other global health initiatives, this investment proved to be catalytic, and indeed highlights how foreign assistance funding can be transformative, in reducing the burden of major global health conditions such as NTDs.

Transitioning from river blindness control to elimination: steps toward stopping treatment.

The transition from onchocerciasis control to elimination requires country programmes to rethink their approach to a variety of activities as they move from addressing morbidity to addressing transmission of the parasite. Although the 2016 WHO guidelines provide extensive recommendations, it was beyond the scope of the document to provide guidance on all aspects of the transition. This paper will discuss some of the important issues that programmes are grappling with as they transition to elimination and provide some potential approaches that programmes can use to address them. Although there are some data to support some aspects of the suggested approaches, operational research will be needed to generate data to support these approaches further and to determine how programmes could best tailor them to their own unique epidemiological challenges. Good communication between the national programmes and the broader global programme will facilitate the clear articulation of programmatic challenges and the development of the evidence to support programme decision-making.

Onchocerciasis: shifting the target from control to elimination requires a new first-step-elimination mapping.

The meaning of 'mapping' in relation to onchocerciasis has changed at least three times over the past 50 years as the programmatic goals and the assessment tools have changed. With the current goal being global elimination of Onchocerca volvulus (OV), all areas where OV might currently be transmitted and where mass drug administration (MDA) with ivermectin treatment has not been delivered previously must now be identified by careful, detailed 'elimination mapping' as either OV endemic or not, so that appropriate programmatic targets can be established. New tools and strategies for such elimination mapping have become available, though ongoing studies must still be completed to define agreed upon optimal diagnostic evaluation units, sampling strategies and serologic tools. With detailed guidance and technical support from the World Health Organization and with implementation and financial support from their global partners, the OV-endemic countries of Africa can soon complete their elimination mapping and then continue with MDA programmes to progressively achieve the same success in OV elimination as that already achieved by the growing list of formerly OV-endemic countries in the Americas.

Initiating NTD programs targeting schistosomiasis and soil-transmitted helminthiasis in two provinces of the Democratic Republic of the Congo: Establishment of baseline prevalence for mass drug administration.

BACKGROUND: Schistosomiasis (SCH) and soil-transmitted helminthiasis (STH) are widely distributed in the Democratic Republic of the Congo (DRC) and constitute a serious public health problem. As recommended by the World Health Organization (WHO), before launching mass chemotherapy to control these diseases, parasitological surveys were conducted in sentinel sites in six health zones (HZs) in Bandundu and Maniema provinces. Baseline prevalence and intensity of infection for SCH and STH were determined to establish the appropriate treatment plan using Praziquantel (PZQ) and Albendazole (ALB). METHODS: Parasitological surveys were conducted from April to May 2015 in twenty-six selected sampling units (schools) for baseline mapping in six HZs: Fifty school children (25 females and 25 males) aged 9-15 years were randomly selected per sampling unit. A total of 1300 samples (urine and stool) were examined using haematuria dipsticks, parasite-egg filtration and the point-of-care Circulating Cathodic Antigen (POC-CCA) assay for urine samples and the Kato-Katz technique for stool specimens. RESULTS: Three species of schistosomes (S. mansoni, S. haematobium and S. intercalatum) and three groups of STH (hookworm, Ascaris and Trichuris) were detected at variable prevalence and intensity among the schools, the HZs and the provinces. In Bandundu, no SCH was detected by either Kato-Katz or the POC-CCA technique, despite a high prevalence of STH with 68% and 80% at Kiri and Pendjua HZs, respectively. In Maniema, intestinal schistosomiasis was detected by both Kato-Katz and POC-CCA with an average prevalence by Kato-Katz of 32.8% and by POC-CCA of 42.1%. Comparative studies confirmed the greater sensitivity (and operational feasibility) of the POC-CCA test on urine compared to Kato-Katz examination of stool for diagnosing intestinal schistosomiasis even in areas of comparatively light infections. STH was widely distributed and present in all HZs with a mean prevalence (95% CI) of 59.62% (46.00-65.00%). The prevalence of hookworm, roundworm and whipworm were 51.62% (32.40%-71.50%), 15.77% (0.50%-39.60%) and 13.46 (0.50%-33.20%), respectively. CONCLUSION: This study provided the evidence base for implementing programs targeting SCH and STH in these Health Zones. Observations also reinforce the operational value and feasibility of the POC-CCA test to detect S. mansoni and, for the first time, S. intercalatum infections in a routine NTD program setting.

The health and economic benefits of the global programme to eliminate lymphatic filariasis (2000-2014).

BACKGROUND: Lymphatic filariasis (LF), also known as elephantiasis, is a neglected tropical disease (NTD) targeted for elimination through a Global Programme to Eliminate LF (GPELF). Between 2000 and 2014, the GPELF has delivered 5.6 billion treatments to over 763 million people. Updating the estimated health and economic benefits of this significant achievement is important in justifying the resources and investment needed for eliminating LF. METHOD: We combined previously established models to estimate the number of clinical manifestations and disability-adjusted life years (DALYs) averted from three benefit cohorts (those protected from acquiring infection, those with subclinical morbidity prevented from progressing and those with clinical disease alleviated). The economic savings associated with this disease prevention was then analysed in the context of prevented medical expenses incurred by LF clinical patients, potential income loss through lost-labour, and prevented costs to the health system to care for affected individuals. The indirect cost estimates were calculated using the human capital approach. A combination of four wage sources was used to estimate the fair market value of time for an agricultural worker with LF infection (to ensure a conservative estimate, the lowest wage value was used). RESULTS: We projected that due to the first 15 years of the GPELF 36 million clinical cases and 175 (116-250) million DALYs will potentially be averted. It was estimated that due to this notable health impact, US$100.5 billion will potentially be saved over the lifetimes of the benefit cohorts. This total amount results from summing the medical expenses incurred by LF patients (US$3 billion), potential income loss (US$94 billion), and costs to the health system (US$3.5 billion) that were projected to be prevented. The results were subjected to sensitivity analysis and were most sensitive to the assumed percentage of work hours lost for those suffering from chronic disease (changing the total economic benefit between US$69.30-150.7 billion). CONCLUSIONS: Despite the limitations of any such analysis, this study identifies substantial health and economic benefits that have resulted from the first 15 years of the GPELF, and it highlights the value and importance of continued investment in the GPELF.

RRR for NNN-a rapid research response for the Neglected Tropical Disease NGDO Network: a novel framework to challenges faced by the global programs targeting neglected tropical diseases.

While global programs targeting the control or elimination of five of the neglected tropical diseases (NTDs)-lymphatic filariasis, onchocerciasis, soil-transmitted helminthiasis, schistosomiasis and trachoma-are well underway, they still face many operational challenges. Because of the urgency of 2020 program targets, the Bill & Melinda Gates Foundation and the U.S. Agency for International Development devised a novel rapid research response (RRR) framework to engage national programs, researchers, implementers and WHO in a Coalition for Operational Research on NTDs. After 2 years, this effort has succeeded as an important basis for the research response to programmatic challenges facing NTD programs.

Progress and impact of 13 years of the global programme to eliminate lymphatic filariasis on reducing the burden of filarial disease.

BACKGROUND: A Global Programme to Eliminate Lymphatic Filariasis was launched in 2000, with mass drug administration (MDA) as the core strategy of the programme. After completing 13 years of operations through 2012 and with MDA in place in 55 of 73 endemic countries, the impact of the MDA programme on microfilaraemia, hydrocele and lymphedema is in need of being assessed. METHODOLOGY/PRINCIPAL FINDINGS: During 2000-2012, the MDA programme made remarkable achievements - a total of 6.37 billion treatments were offered and an estimated 4.45 billion treatments were consumed by the population living in endemic areas. Using a model based on empirical observations of the effects of treatment on clinical manifestations, it is estimated that 96.71 million LF cases, including 79.20 million microfilaria carriers, 18.73 million hydrocele cases and a minimum of 5.49 million lymphedema cases have been prevented or cured during this period. Consequently, the global prevalence of LF is calculated to have fallen by 59%, from 3.55% to 1.47%. The fall was highest for microfilaraemia prevalence (68%), followed by 49% in hydrocele prevalence and 25% in lymphedema prevalence. It is estimated that, currently, i.e. after 13 years of the MDA programme, there are still an estimated 67.88 million LF cases that include 36.45 million microfilaria carriers, 19.43 million hydrocele cases and 16.68 million lymphedema cases. CONCLUSIONS/SIGNIFICANCE: The MDA programme has resulted in significant reduction of the LF burden. Extension of MDA to all at-risk countries and to all regions within those countries where MDA has not yet reached 100% geographic coverage is imperative to further reduce the number of microfilaraemia and chronic disease cases and to reach the global target of interrupting transmission of LF by 2020.

Assessing progress in reducing the at-risk population after 13 years of the global programme to eliminate lymphatic filariasis.

BACKGROUND: In 1997, the World Health Assembly adopted Resolution 50.29, committing to the elimination of lymphatic filariasis (LF) as a public health problem, subsequently targeted for 2020. The initial estimates were that 1.2 billion people were at-risk for LF infection globally. Now, 13 years after the Global Programme to Eliminate Lymphatic Filariasis (GPELF) began implementing mass drug administration (MDA) against LF in 2000-during which over 4.4 billion treatments have been distributed in 56 endemic countries-it is most appropriate to estimate the impact that the MDA has had on reducing the population at risk of LF. METHODOLOGY/PRINCIPAL FINDINGS: To assess GPELF progress in reducing the population at-risk for LF, we developed a model based on defining reductions in risk of infection among cohorts of treated populations following each round of MDA. The model estimates that the number of people currently at risk of infection decreased by 46% to 789 million through 2012. CONCLUSIONS/SIGNIFICANCE: Important progress has been made in the global efforts to eliminate LF, but significant scale-up is required over the next 8 years to reach the 2020 elimination goal.

Transmission assessment surveys (TAS) to define endpoints for lymphatic filariasis mass drug administration: a multicenter evaluation.

BACKGROUND: Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. METHODOLOGY: The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6-7 year olds or 1(st)-2(nd) graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. PRINCIPAL FINDINGS/CONCLUSIONS: In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance requires further investigation.

Predictive vs. empiric assessment of schistosomiasis: implications for treatment projections in Ghana.

BACKGROUND: Mapping the distribution of schistosomiasis is essential to determine where control programs should operate, but because it is impractical to assess infection prevalence in every potentially endemic community, model-based geostatistics (MBG) is increasingly being used to predict prevalence and determine intervention strategies. METHODOLOGY/PRINCIPAL FINDINGS: To assess the accuracy of MBG predictions for Schistosoma haematobium infection in Ghana, school surveys were evaluated at 79 sites to yield empiric prevalence values that could be compared with values derived from recently published MBG predictions. Based on these findings schools were categorized according to WHO guidelines so that practical implications of any differences could be determined. Using the mean predicted values alone, 21 of the 25 empirically determined 'high-risk' schools requiring yearly praziquantel would have been undertreated and almost 20% of the remaining schools would have been treated despite empirically-determined absence of infection - translating into 28% of the children in the 79 schools being undertreated and 12% receiving treatment in the absence of any demonstrated need. CONCLUSIONS/SIGNIFICANCE: Using the current predictive map for Ghana as a spatial decision support tool by aggregating prevalence estimates to the district level was clearly not adequate for guiding the national program, but the alternative of assessing each school in potentially endemic areas of Ghana or elsewhere is not at all feasible; modelling must be a tool complementary to empiric assessments. Thus for practical usefulness, predictive risk mapping should not be thought of as a one-time exercise but must, as in the current study, be an iterative process that incorporates empiric testing and model refining to create updated versions that meet the needs of disease control operational managers.

Antibody to the filarial antigen Wb123 reflects reduced transmission and decreased exposure in children born following single mass drug administration (MDA).

BACKGROUND: Antibody (Ab) to the Wuchereria bancrofti (Wb) infective larval (L3) antigen Wb123, using a Luciferase Immunoprecipitation System (LIPS) assay, has been shown to be a species-specific, early marker of infection developed for potential use as a surveillance tool following transmission interruption post mass drug administration. To examine its usefulness in a single filarial-endemic island assessed at two time points with markedly different levels of transmission, Ab to Wb123 was measured in sera collected from subjects from Mauke, Cook Islands in 1975 (no previous treatment) and 1992 (5 years after a one time island-wide treatment with diethylcarbamazine [DEC]). FINDINGS: Between 1975 and 1992, Wb transmission decreased dramatically as evidenced by reduced prevalences of microfilariae (31% vs. 5%) and circulating Ag (CAg, 49% vs. 16%). Age specific prevalence analysis showed a dramatic reduction in Wb123 Ab positivity from 54% (25/46) in 1975 to 8% (3/38) in 1992 in children 1-5 years (p<0.0001), reflecting the effects of single-dose treatment five years earlier. By 1992, Wb123 Ab prevalence in children 6-10 years had fallen from 75% (42/56) in 1975 to 42% (33/79) consistent with a lower cumulative transmission potential. In the whole population, Wb123 seropositivity decreased from 86% to 60% between 1975 and 1992. In CAg+ subjects the levels of Wb123 Ab were indistinguishable between the 2 time points but differed in those who were CAg- (p<0.0001). In paired sample analysis, individuals who were CAg+ in 1975 but became CAg- in 1992 had significantly lower Ab levels in 1992 (p<0.0001), with 9/40 (23%) becoming seronegative for Wb123. CONCLUSIONS: The relationship between reduction in Wb123 Ab prevalence and the reduction of transmission, seen most clearly in young children, strongly advocates for the continuing assessment and rapid development of Wb123 as a surveillance tool to detect potential transmission of bancroftian filariasis in treated endemic areas.

Integrated implementation of programs targeting neglected tropical diseases through preventive chemotherapy: identifying best practices to roll out programs at national scale.

In 2006 the U.S. Agency for International Development (USAID) established the Neglected Tropical Disease (NTD) Control Program to support national governments in developing successful, cost-efficient NTD programs that integrate disease-specific programs into coordinated national initiatives, in accord with the World Health Organization recommendations. A 3-stage "roll-out package" has been developed for effectively integrating and scaling up such programs to full-national scale. Stage-1 lays the groundwork-identifying NTD leadership within the Ministry of Health, conducting a national Situation Analysis, formulating a multiyear Plan of Action, and undertaking a funding gap analysis. Stage-2 focuses on scaling up the integrated NTD program-convening national stakeholder meetings, developing annual work plans, carrying out disease mapping, and establishing monitoring and evaluation activities. Stage-3 aims at ensuring effective management-identifying clear roles and responsibilities for partners, and creating a central coordinating mechanism. Assessment and reassessment of these complex NTD programs that target literally billions of people are essential to establish "best practice" strategies for long-term public health success.

A multicenter evaluation of diagnostic tools to define endpoints for programs to eliminate bancroftian filariasis.

Successful mass drug administration (MDA) campaigns have brought several countries near the point of Lymphatic Filariasis (LF) elimination. A diagnostic tool is needed to determine when the prevalence levels have decreased to a point that MDA campaigns can be discontinued without the threat of recrudescence. A six-country study was conducted assessing the performance of seven diagnostic tests, including tests for microfilariae (blood smear, PCR), parasite antigen (ICT, Og4C3) and antifilarial antibody (Bm14, PanLF, Urine SXP). One community survey and one school survey were performed in each country. A total of 8,513 people from the six countries participated in the study, 6,443 through community surveys and 2,070 through school surveys. Specimens from these participants were used to conduct 49,585 diagnostic tests. Each test was seen to have both positive and negative attributes, but overall, the ICT test was found to be 76% sensitive at detecting microfilaremia and 93% specific at identifying individuals negative for both microfilariae and antifilarial antibody; the Og4C3 test was 87% sensitive and 95% specific. We conclude, however, that the ICT should be the primary tool recommended for decision-making about stopping MDAs. As a point-of-care diagnostic, the ICT is relatively inexpensive, requires no laboratory equipment, has satisfactory sensitivity and specificity and can be processed in 10 minutes-qualities consistent with programmatic use. Og4C3 provides a satisfactory laboratory-based diagnostic alternative.