In a Letter to the Editor, Eberhard et al. question the validity of our model of skin snip sensitivity and argue against the use of skin snips to evaluate onchocerciasis elimination by mass drug administration. Here we discuss their arguments and compare model predictions with observed data to assess the validity of our model

Attah, Simon K

Basáñez, Maria-Gloria

Bottomley, Christian

Isham, Valerie

Kuesel, Annette C

Lustigman, Sara

Opoku, Nicholas O

Vivas-Martínez, Sarai

Walker, Martin

Parasites & Vectors

Bottomley, C

Isham, V

Vivas-Martínez, S

Kuesel, AC

Attah, SK

Opoku, NO

Lustigman, S

Walker, M

Basáñez, MG

Spiral - Imperial College Digital Repository

LETTER TO THE EDITOR Open AccessResponse to the Letter to the Editor byEberhard et al.Christian Bottomley1*, Valerie Isham2, Sarai Vivas-Martínez3, Annette C. Kuesel4, Simon K. Attah5,Nicholas O. Opoku6, Sara Lustigman7, Martin Walker8,9† and Maria-Gloria Basáñez8†AbstractIn a Letter to the Editor, Eberhard et al. question the validity of our model of skin snip sensitivity and argue againstthe use of skin snips to evaluate onchocerciasis elimination by mass drug administration. Here we discuss theirarguments and compare model predictions with observed data to assess the validity of our model.Letter to the EditorIn our recent paper in Parasites & Vectors [1], we pre-sented a model of the number of microfilariae (mf) perskin snip, which we used to predict the sensitivity of skinsnips as a test for detecting patent Onchocerca volvulusinfection when a treatment programme, based on massdrug administration (MDA) with ivermectin, is close toachieving elimination. We concluded that our modelsupports the recommendation of the African Programmefor Onchocerciasis Control (APOC) to conduct skin snipsurveys 3–5 years post-MDA, and that sensitivitycould be improved by taking four skin snips ratherthan two. Based on the findings from our model, weargued that skin snips are useful, when used togetherwith entomological and serological data, for evaluatingprogrammes of MDA.In a Letter to the Editor, Eberhard and colleagues [2]suggest that our model of skin snip sensitivity is misspe-cified, and argue that skin snips should not be used forevaluating onchocerciasis elimination by mass drug ad-ministration because they have poor sensitivity and indi-viduals are often reluctant to be skin-snipped.Eberhard et al. begin their critique by suggesting ourmodel is misspecified. In particular, they question ourassumption that the number of mf per skin snip followsa negative binomial distribution (conditional on adult fe-male worm burden) and suggest that a zero-inflated dis-tribution might be more appropriate. As we discussed inour paper, there are good theoretical reasons for choos-ing this model, and it fits the data well. Specifically, itdoes not underestimate the proportion of skin snips withzero mf (Fig. 1), as the authors suggest it might. We be-lieve a zero-inflated model is therefore unnecessary.The authors then present two arguments against theuse of skin snips for evaluating programmes of MDA.Their first argument is that skin snip sensitivity is knownto be low. But they present an estimate of sensitivity(20%) without reference to either time after treatment ornumber of skin snips. By itself, this figure is uninforma-tive since, as we have shown, sensitivity ranges from zeroto c.100%, depending on the number of skin snips takenand when they are taken after treatment. For two skinsnips, our model predicts low sensitivity (≤ 31%) oneyear after treatment, which is consistent with data pre-sented by Thiele et al. [3].Their second argument is that skin snips are not usefulbecause people are sometimes reluctant to be skin-snipped; they cite as evidence the low rates of participa-tion in the Mali/Senegal study [4, 5] (c.70% participated inthe first survey conducted after the last round of MDAand c.50% in the fourth skin snip survey 3–4 years later).We acknowledged this limitation in our paper when wesaid that, “communities are increasingly reluctant to par-ticipate in skin snipping, so a compromise must be foundbetween what is feasible and the ideal” and that “strategiesand surveillance should be implemented using tests thatare less invasive than the skin snip method.” Nonetheless,we believe skin snip data from the Mali/Senegal study areuseful since they were used successfully to model the like-lihood of elimination and recrudescence [6], and the* Correspondence: christian.bottomley@lshtm.ac.uk†Equal contributors1MRC Tropical Epidemiology Group, London School of Hygiene and TropicalMedicine, Keppel Street, London WC1E 7HT, UKFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Bottomley et al. Parasites & Vectors  (2017) 10:240 DOI 10.1186/s13071-017-2125-5model predictions are now supported by Ov16 serologicaldata from Senegal indicating that elimination may nothave been sustained in the River Gambia focus [7].Eberhard et al. conclude that “country program man-agers must be made aware of the extreme lack ofusefulness of skin snips in assessing the elimination ofOnchocerca volvulus”. However, the recommendation ofthe World Health Organization (WHO) that skin snipmicroscopy should not be used to demonstrate interrup-tion of transmission [8] is only a “conditional recom-mendation, low certainty of evidence”. Equally, programmanagers should be made aware of the limitations ofOv16 serology, particularly of the current rapid diagnostictests. The WHO recommendation to use Ov16 serologyin < 10-year olds to confirm transmission interruption is a“strong recommendation”, but also based on “low cer-tainty of evidence”, and it may need to be adapted in thefuture. For example, the WHO guidelines provide a singlethreshold of Ov16 seropositivity (<0.1%); however, recentmodelling suggests that it may be more appropriate to usethresholds that depend on pre-MDA endemicity [9, 10].Clearly, more research is needed to achieve ‘high certaintyof evidence-based recommendations’. Our study con-tributes to this endeavour.Authors’ contributionsAll authors read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Ethics approval and consent to participateNot applicable.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1MRC Tropical Epidemiology Group, London School of Hygiene and TropicalMedicine, Keppel Street, London WC1E 7HT, UK. 2Department of StatisticalScience, University College London, Gower Street, London WC1E 6BT, UK.3Cátedra de Salud Pública. Facultad de Medicina (Escuela Luis Razetti),Universidad Central de Venezuela, Caracas, Venezuela. 4UNICEF/UNDP/WorldBank/WHO, Special Programme for Research and Training in TropicalDiseases, World Health Organization, Geneva, Switzerland. 5Department ofMicrobiology, University of Ghana Medical School, Accra, Ghana. 6Universityof Health and Allied Sciences Research Centre (UHASRC) Hohoe, VoltaRegion, Ghana. 7Laboratory of Molecular Parasitology, Lindsley F. KimballResearch Institute, New York Blood Center, 310 E 67th St, New York NY10065,USA. 8London Centre for Neglected Tropical Disease Research, Departmentof Infectious Disease Epidemiology, School of Public Health, Faculty ofMedicine (St Mary’s campus), Norfolk Place, London W2 1PG, UK.9Department of Pathobiology and Population Sciences and London Centrefor Neglected Tropical Disease Research, Royal Veterinary College,Hawkshead Lane, Hatfield, Hertfordshire AL9 7TA, UK.Received: 28 March 2017 Accepted: 30 March 2017References1. Bottomley C, Isham V, Vivas-Martínez S, Kuesel AC, Attah SK, Opoku NO,Lustigman S, Walker M, Basáñez MG. Modelling neglected tropical diseasesdiagnostics: the sensitivity of skin snips for Onchocerca volvulus in nearelimination and surveillance settings. Parasit Vectors. 2016;9:343.2. Eberhard ML, Cupp EW, Katholi CR, Richards FO, Unnasch TR. Skin snipshave no role in programmatic evaluations for onchocerciasis elimination:a reply to Bottomley et al. Parasit Vectors. 2017;10:154.3. Thiele EA, Cama VA, Lakwo T, Mekasha S, Abanyie F, Sleshi M, et al.Detection of Onchocerca volvulus in skin snips by microscopy and real-timepolymerase chain reaction: Implications for monitoring and evaluationactivities. Am J Trop Med Hyg. 2016;94:906–11.4. Diawara L, Traoré MO, Badji A, Bissan Y, Doumbia K, Goita SF, et al.Feasibility of onchocerciasis elimination with ivermectin treatment inendemic foci in Africa: first evidence from studies in Mali and Senegal. PLoSNegl Trop Dis. 2009;3(7):e497.5. Traore MO, Sarr MD, Badji A, Bissan Y, Diawara L, Doumbia K, et al. Proof-of-principle of onchocerciasis elimination with ivermectin treatment in endemicfoci in Africa: Final results of a study in Mali and Senegal. PLoS Negl Trop Dis.2012;6(9):e1825.6. Walker M, Stolk WA, Dixon MA, Bottomley C, Diawara L, Traoré MO, et al.Modelling the elimination of river blindness using long-term epidemiologicaland programmatic data from Mali and Senegal. Epidemics. 2017;18:4–15.7. Wilson NO, Badara Ly A, Cama VA, Cantey PT, Cohn D, Diawara L, et al.Evaluation of lymphatic filariasis and onchocerciasis in three Senegalesedistricts treated for onchocerciasis with ivermectin. PLoS Negl Trop Dis.2016;10(12):e0005198.8. Onchocerciasis. Guidelines for Stopping Mass Drug Administration andVerifying Elimination of Human Onchocerciasis. Criteria and Procedures. WorldHealth Organization; 2016. p. 55. Available: http://apps.who.int/iris/bitstream/10665/204180/1/9789241510011_eng.pdf?ua=1. (Accessed 27 Apr 2017).9. Stolk WA, Walker M, Coffeng LE, Basáñez MG, de Vlas SJ. Required durationof mass ivermectin treatment for onchocerciasis elimination in Africa: acomparative modelling analysis. Parasit Vectors. 2015;8:552.10. Lont YL, Coffeng LE, de Vlas SJ, Golden A, de Los Santos, T, Domingo GJ, et al.Modelling anti-Ov16 IgG4 antibody prevalence as an indicator for evaluationand decision making in onchocerciasis elimination programmes. PLoS NeglTrop Dis. 2017;11(1):e0005314.Fig. 1 Proportion of iliac skin snips with zero microfilariae versusmodel predictions for study communities in Guatemala, Venezuela,Cameroon and GhanaBottomley et al. Parasites & Vectors  (2017) 10:240 Page 2 of 2

English

Response to the Letter to the Editor by Eberhard et al.

Abstract In a Letter to the Editor, Eberhard et al. question the validity of our model of skin snip sensitivity and argue against the use of skin snips to evaluate onchocerciasis elimination by mass drug administration. Here we discuss their arguments and compare model predictions with observed data to assess the validity of our model

Christian Bottomley

Valerie Isham

Sarai Vivas-Martínez

Annette C. Kuesel

Simon K. Attah

Nicholas O. Opoku

Sara Lustigman

Martin Walker

Maria-Gloria Basáñez

Directory of Open Access Journals

Crossref

Vivas-Martinez, S

Kuesel, A C

Attah, S K

Opoku, N O

Basáñez, M-G

RVC Research Online

Response to the Letter to the Editor by Eberhard et al

In a Letter to the Editor, Eberhard et al. question the validity of our model of skin snip sensitivity and argue against

the use of skin snips to evaluate onchocerciasis elimination by mass drug administration. Here we discuss their

arguments and compare model predictions with observed data to assess the validity of our model

Basanez, M-G

UCL Discovery

LSHTM Research Online

Bottomley, C; Isham, V; Vivas-Martnez, S; Kuesel, AC; Attah, SK;Opoku, NO; Lustigman, S; Walker, M; Basez, MG (2017) Responseto the Letter to the Editor by Eberhard et al. Parasit Vectors, 10(1). p. 240. ISSN 1756-3305 DOI: 10.1186/s13071-017-2125-5Downloaded from: http://researchonline.lshtm.ac.uk/4259200/DOI: 10.1186/s13071-017-2125-5Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: http://creativecommons.org/licenses/by/2.5/LETTER TO THE EDITOR Open AccessResponse to the Letter to the Editor byEberhard et al.Christian Bottomley1*, Valerie Isham2, Sarai Vivas-Martínez3, Annette C. Kuesel4, Simon K. Attah5,Nicholas O. Opoku6, Sara Lustigman7, Martin Walker8,9† and Maria-Gloria Basáñez8†AbstractIn a Letter to the Editor, Eberhard et al. question the validity of our model of skin snip sensitivity and argue againstthe use of skin snips to evaluate onchocerciasis elimination by mass drug administration. Here we discuss theirarguments and compare model predictions with observed data to assess the validity of our model.Letter to the EditorIn our recent paper in Parasites & Vectors [1], we pre-sented a model of the number of microfilariae (mf) perskin snip, which we used to predict the sensitivity of skinsnips as a test for detecting patent Onchocerca volvulusinfection when a treatment programme, based on massdrug administration (MDA) with ivermectin, is close toachieving elimination. We concluded that our modelsupports the recommendation of the African Programmefor Onchocerciasis Control (APOC) to conduct skin snipsurveys 3–5 years post-MDA, and that sensitivitycould be improved by taking four skin snips ratherthan two. Based on the findings from our model, weargued that skin snips are useful, when used togetherwith entomological and serological data, for evaluatingprogrammes of MDA.In a Letter to the Editor, Eberhard and colleagues [2]suggest that our model of skin snip sensitivity is misspe-cified, and argue that skin snips should not be used forevaluating onchocerciasis elimination by mass drug ad-ministration because they have poor sensitivity and indi-viduals are often reluctant to be skin-snipped.Eberhard et al. begin their critique by suggesting ourmodel is misspecified. In particular, they question ourassumption that the number of mf per skin snip followsa negative binomial distribution (conditional on adult fe-male worm burden) and suggest that a zero-inflated dis-tribution might be more appropriate. As we discussed inour paper, there are good theoretical reasons for choos-ing this model, and it fits the data well. Specifically, itdoes not underestimate the proportion of skin snips withzero mf (Fig. 1), as the authors suggest it might. We be-lieve a zero-inflated model is therefore unnecessary.The authors then present two arguments against theuse of skin snips for evaluating programmes of MDA.Their first argument is that skin snip sensitivity is knownto be low. But they present an estimate of sensitivity(20%) without reference to either time after treatment ornumber of skin snips. By itself, this figure is uninforma-tive since, as we have shown, sensitivity ranges from zeroto c.100%, depending on the number of skin snips takenand when they are taken after treatment. For two skinsnips, our model predicts low sensitivity (≤ 31%) oneyear after treatment, which is consistent with data pre-sented by Thiele et al. [3].Their second argument is that skin snips are not usefulbecause people are sometimes reluctant to be skin-snipped; they cite as evidence the low rates of participa-tion in the Mali/Senegal study [4, 5] (c.70% participated inthe first survey conducted after the last round of MDAand c.50% in the fourth skin snip survey 3–4 years later).We acknowledged this limitation in our paper when wesaid that, “communities are increasingly reluctant to par-ticipate in skin snipping, so a compromise must be foundbetween what is feasible and the ideal” and that “strategiesand surveillance should be implemented using tests thatare less invasive than the skin snip method.” Nonetheless,we believe skin snip data from the Mali/Senegal study areuseful since they were used successfully to model the like-lihood of elimination and recrudescence [6], and the* Correspondence: christian.bottomley@lshtm.ac.uk†Equal contributors1MRC Tropical Epidemiology Group, London School of Hygiene and TropicalMedicine, Keppel Street, London WC1E 7HT, UKFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Bottomley et al. Parasites & Vectors  (2017) 10:240 DOI 10.1186/s13071-017-2125-5model predictions are now supported by Ov16 serologicaldata from Senegal indicating that elimination may nothave been sustained in the River Gambia focus [7].Eberhard et al. conclude that “country program man-agers must be made aware of the extreme lack ofusefulness of skin snips in assessing the elimination ofOnchocerca volvulus”. However, the recommendation ofthe World Health Organization (WHO) that skin snipmicroscopy should not be used to demonstrate interrup-tion of transmission [8] is only a “conditional recom-mendation, low certainty of evidence”. Equally, programmanagers should be made aware of the limitations ofOv16 serology, particularly of the current rapid diagnostictests. The WHO recommendation to use Ov16 serologyin < 10-year olds to confirm transmission interruption is a“strong recommendation”, but also based on “low cer-tainty of evidence”, and it may need to be adapted in thefuture. For example, the WHO guidelines provide a singlethreshold of Ov16 seropositivity (<0.1%); however, recentmodelling suggests that it may be more appropriate to usethresholds that depend on pre-MDA endemicity [9, 10].Clearly, more research is needed to achieve ‘high certaintyof evidence-based recommendations’. Our study con-tributes to this endeavour.Authors’ contributionsAll authors read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Ethics approval and consent to participateNot applicable.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1MRC Tropical Epidemiology Group, London School of Hygiene and TropicalMedicine, Keppel Street, London WC1E 7HT, UK. 2Department of StatisticalScience, University College London, Gower Street, London WC1E 6BT, UK.3Cátedra de Salud Pública. Facultad de Medicina (Escuela Luis Razetti),Universidad Central de Venezuela, Caracas, Venezuela. 4UNICEF/UNDP/WorldBank/WHO, Special Programme for Research and Training in TropicalDiseases, World Health Organization, Geneva, Switzerland. 5Department ofMicrobiology, University of Ghana Medical School, Accra, Ghana. 6Universityof Health and Allied Sciences Research Centre (UHASRC) Hohoe, VoltaRegion, Ghana. 7Laboratory of Molecular Parasitology, Lindsley F. KimballResearch Institute, New York Blood Center, 310 E 67th St, New York NY10065,USA. 8London Centre for Neglected Tropical Disease Research, Departmentof Infectious Disease Epidemiology, School of Public Health, Faculty ofMedicine (St Mary’s campus), Norfolk Place, London W2 1PG, UK.9Department of Pathobiology and Population Sciences and London Centrefor Neglected Tropical Disease Research, Royal Veterinary College,Hawkshead Lane, Hatfield, Hertfordshire AL9 7TA, UK.Received: 28 March 2017 Accepted: 30 March 2017References1. Bottomley C, Isham V, Vivas-Martínez S, Kuesel AC, Attah SK, Opoku NO,Lustigman S, Walker M, Basáñez MG. Modelling neglected tropical diseasesdiagnostics: the sensitivity of skin snips for Onchocerca volvulus in nearelimination and surveillance settings. Parasit Vectors. 2016;9:343.2. Eberhard ML, Cupp EW, Katholi CR, Richards FO, Unnasch TR. Skin snipshave no role in programmatic evaluations for onchocerciasis elimination:a reply to Bottomley et al. Parasit Vectors. 2017;10:154.3. Thiele EA, Cama VA, Lakwo T, Mekasha S, Abanyie F, Sleshi M, et al.Detection of Onchocerca volvulus in skin snips by microscopy and real-timepolymerase chain reaction: Implications for monitoring and evaluationactivities. Am J Trop Med Hyg. 2016;94:906–11.4. Diawara L, Traoré MO, Badji A, Bissan Y, Doumbia K, Goita SF, et al.Feasibility of onchocerciasis elimination with ivermectin treatment inendemic foci in Africa: first evidence from studies in Mali and Senegal. PLoSNegl Trop Dis. 2009;3(7):e497.5. Traore MO, Sarr MD, Badji A, Bissan Y, Diawara L, Doumbia K, et al. Proof-of-principle of onchocerciasis elimination with ivermectin treatment in endemicfoci in Africa: Final results of a study in Mali and Senegal. PLoS Negl Trop Dis.2012;6(9):e1825.6. Walker M, Stolk WA, Dixon MA, Bottomley C, Diawara L, Traoré MO, et al.Modelling the elimination of river blindness using long-term epidemiologicaland programmatic data from Mali and Senegal. Epidemics. 2017;18:4–15.7. Wilson NO, Badara Ly A, Cama VA, Cantey PT, Cohn D, Diawara L, et al.Evaluation of lymphatic filariasis and onchocerciasis in three Senegalesedistricts treated for onchocerciasis with ivermectin. PLoS Negl Trop Dis.2016;10(12):e0005198.8. Onchocerciasis. Guidelines for Stopping Mass Drug Administration andVerifying Elimination of Human Onchocerciasis. Criteria and Procedures. WorldHealth Organization; 2016. p. 55. Available: http://apps.who.int/iris/bitstream/10665/204180/1/9789241510011_eng.pdf?ua=1. (Accessed 27 Apr 2017).9. Stolk WA, Walker M, Coffeng LE, Basáñez MG, de Vlas SJ. Required durationof mass ivermectin treatment for onchocerciasis elimination in Africa: acomparative modelling analysis. Parasit Vectors. 2015;8:552.10. Lont YL, Coffeng LE, de Vlas SJ, Golden A, de Los Santos, T, Domingo GJ, et al.Modelling anti-Ov16 IgG4 antibody prevalence as an indicator for evaluationand decision making in onchocerciasis elimination programmes. PLoS NeglTrop Dis. 2017;11(1):e0005314.Fig. 1 Proportion of iliac skin snips with zero microfilariae versusmodel predictions for study communities in Guatemala, Venezuela,Cameroon and GhanaBottomley et al. Parasites & Vectors  (2017) 10:240 Page 2 of 2

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