Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil.

The present study aimed to investigate the epidemiological situation of leprosy (Hansen's Disease), in a hyperendemic metropolis in the Central-West region of Brazil. We studied trends over eleven years, both in the detection of the disease and in disabilities, analyzing disparities and/or differences regarding gender and age. This is an ecological time series study conducted in Cuiabá, capital of the state of Mato Grosso. The population consisted of patients diagnosed with leprosy between the years 2008 and 2018. The time series of leprosy cases was used, stratifying it according to gender (male and female), disability grade (G0D, G1D, G2D, and not evaluated) and age. The calendar adjustment technique was applied. For modeling the trends, the Seasonal-Trend decomposition procedure based on Loess (STL) was used. We identified 9.739 diagnosed cases, in which 58.37% were male and 87.55% aged between 15 and 59 years. Regarding detection according to gender, there was a decrease among women and an increase in men. The study shows an increasing trend in disabilities in both genders, which may be related to the delay in diagnosis. There was also an increasing number of cases that were not assessed for disability at the time of diagnosis, which denotes the quality of the services.

Introduction

Leprosy, also called Hansen’s Disease, is a chronic infectious disease caused by Mycobacterium leprae, which affects Schwann cells, causing their destruction, affecting the skin, and resulting in severe neuropathies, which can lead to physical disabilities [1]. In the past 30 years, the World Health Organization (WHO) has sought measures to eliminate leprosy, and although its indicators have been decreasing over the years, the goal of elimination (prevalence <1 case per 10.000 inhabitants) has not yet been reached and currently seems to be more distant than imagined [2,3].

According to WHO 2020 Weekly epidemiological record Global leprosy, India, Brazil and Indonesia reported >10,000 new cases in 2019, classifying them as the three most highly endemic countries [4]. In 2019, Brazil had a detection rate of 13.23 per 100.000 inhabitants [5,6].

WHO stated in the “Towards zero leprosy Global leprosy (Hansen’s Disease) strategy 2021–2030” [1], that the main actions to control the disease should be directed towards leprosy prevention upscaling alongside integrated active case detection, leprosy disease management and its complications and prevent new disability and combat stigma and ensure human rights are respected. Interruption of transmission and elimination of disease are at the core of their strategy document, as well as of the WHO “Guidelines for the Diagnosis, Treatment and Prevention of Leprosy” [1,7].

Brazil is a country of continental proportions, which makes leprosy control a major challenge. It is divided into five macro-regions, of which the Central-West is one of the most problematic regions in terms of the burden of the disease. A study carried out in that region showed that in the trienniums of 2001–2003 and 2010–2012, there was a reduction in the disease; however, there are geographical areas where leprosy control has not advanced and these locations are far from elimination [8].

The official reports from Brazil indicate the reduction of leprosy in general, but there is evidence that there is gender inequity in access to health services [9]. Another issue refers to age, as there is evidence that the population aging process is changing the profile of the leprosy morbidity profile, given the number of people falling ill in a context of poverty and inequality, with older adults having more difficulty in accessing health services and tending to have a more unfavorable prognosis [10]. This needs to be better addressed from the perspective of health surveillance.

Also, regarding the inequality related to age, it is known that when there is a delay in diagnosis, children who had contact with index cases also become ill, which is an important gap to be filled [11]. Accordingly, the elimination of leprosy involves comprehending the determinants, according to a gender and age equity perspective. It is also understood that gender and age inequity should not be analyzed only from the perspective of detection, but also in terms of disability, as the WHO recognizes the disability grade indicator as the most sensitive measure of the real leprosy situation in a community [1].

There are hypotheses that there are gender differences, and that older adults and children are more severely affected by the disease, with regard to disabilities [10,11]. These aspects need to be studied in order to define public health policies and plan strategic actions in priority areas, as well as to advance equity. There are several tools that could be used to test these hypotheses; among them, one of the more sensitive tools is the time series. Its use is justified in the field of public health, as it can show the trend of the disease in vulnerable groups and verify how much success has been achieved in terms of the goal of elimination and reduction of injustices and/or inequity [12].

This study aimed to investigate the epidemiological situation of leprosy and trends in the detection of cases and disabilities, and to evidence disparities and/or differences regarding gender and age in a hyperendemic metropolis in Central-West Brazil.

Materials and methods

Ethics statement

The study was approved by the Ethics Committee of the University of São Paulo, School of Nursing (EERP/USP) under CAAE: 30394720.3.0000.5393. The investigation was exempted from signing consent forms, as it used secondary data, considering that the data were analyzed in an aggregated manner, without individual identification. Anonymized data was sent as Supporting Information to the Journal available to ensure reproducibility.

Study design and setting

This ecological time series study was carried out in Cuiabá [13], capital of the state of Mato Grosso, located in the Central-West region of Brazil (Fig 1). The metropolis has an area of 3.266,538 km2, with an estimated population of 607.153 inhabitants and demographic density of around 185.87 inhabitants per km2 in 2018 [14].

Fig 1

Location of Cuiabá—Mato Grosso.

(A) Brazil; (B) State of Mato Grosso; (C) City of Cuiabá. Source: Instituto Brasileiro de Geografia e Estatística (IBGE)–All maps are in public domain. (https://portaldemapas.ibge.gov.br/)

In relation to socioeconomic indicators, Cuiabá has an illiteracy rate of 4.56% for women and 4.79% for men, a life expectancy at birth of 75 years of age, and a Human Development Index (HDI) of 0.785. It also has a Gini index of 0.59, an indicator that measures how equitably a resource is distributed in a population; the nearest to 0 is the population with lowest inequality, and closest to 1 is the most unequal [15].

Regarding basic sanitation, 53.52% of Cuiabá’s territory has a sewage network and 98.12% a water supply [16,17]. It also has 63 primary health units, distributed throughout 4 administrative regions North, South, East and West.[18,19]. It should be highlighted that the municipality provides the following referral services for procedures of greater technological complexity as well as for leprosy,: “CERMAC—Centro Estadual Regional de Média e Alta Complexidade” (dermatology surveillance services), “Hospital Metropolitano” (hospital care for leprosy surgery services), “Hospital Universitário Júlio Muller” (hospital care for ophthalmology referral), “CRIDAC CER III—Centro de Reabilitação Integral Dom Aquino Corrêa” (center specialized in rehabilitation and regional outpatient and hospital referrals) [20,21].

The municipality presents a detection rate of 45.30 cases for every 100.000 inhabitants, classifying it as hyperendemic for leprosy according to “Sistema de Informação de Agravos de Notificação–SINAN” (Notifiable Disease Information System) 2018, which classifies hyperendemic cities with a detection greater than 40 cases for every 100.000 people [22,23]. In children under 15 years of age, in 2018 the detection rate was 7.9/100.000 inhabitants, placing the metropolis in the very high category for children [22].

Study population and information sources

Leprosy cases registered in the SINAN from 2008 to 2018 of residents of the city of Cuiabá were included. The SINAN is the Brazilian information system responsible for recording and processing information on mandatory notifiable diseases such as leprosy throughout Brazil, providing bulletins and reports of morbidity and constituting one of the main surveillance systems in the country.

According to the Brazil Practice Guide for Leprosy, the cases are diagnosed if the person presents a defined skin area with altered or complete loss of sensitivity with or without compromised nerve, or nerves with neural thickening, and/or positive bacterial index (via skin smear). The bacterial index is not the defining factor but important for clinical and epidemiological evaluation [24].

The selected variables were date of notification of the case, gender (male, female), age, education (no schooling, incomplete elementary education, complete elementary education, incomplete high school education, complete high school education, incomplete higher education and complete higher education), WHO operational classification (paucibacillary [pb], multibacillary [mb]), clinical form based on Madrid classification (indeterminate, tuberculoid, borderline and lepromatous) and assessment of disability grade in the diagnosis (Grade 0 disability [G0D], Grade 1 disability [G1D], Grade 2 disability [G2D], and not evaluated) [25]. Below, in the Table 1 is shown the disability grade characteristics.

Table 1

Disability grade and his characteristics.

Grade	Characteristics
0 [G0D]	No problem with eyes, hands or feet’s due to leprosy
1 [G1D]	Reduction or loss of eye sensitivityReduction or loss of sensation in hands and/or feet (does not feel 2g or pen touch)
2 [G2D]	Eyes: lagophthalmos and/or ectropion; trichiasis, central corneal opacity; acuityvisual less than 0.1 or not counting fingers at 6m.Hands: trophic injuries and/or traumatic injuries, claws; resorption, hand downFeet: trophic and/or traumatic injuries, claw hand deformity, resorption, foot dropped, contracture of ankle

Source: Ministério da saúde, Guia prático sobre a Hanseníase–Secretaria de Vigilância em Saúde–Departamento de Vigilância e Doenças Transmissíveis—Brasília—DF 2017 [24], based on WHO disability grading for leprosy (https://apps.who.int/iris/handle/10665/42060).

Access to the SINAN database was obtained from the Health Surveillance Service of the Regional Health Management of Cuiabá [“Serviço de Vigilância Sanitária da Gerência Regional de Saúde de Cuiabá”] in November 2019.

Statistical analysis

Initially, the variables of interest were standardized, with data relating to age, gender, and education considered in the sociodemographic dimension and operational classification, clinical form, and disability grade at diagnosis in the clinical-epidemiological dimension. Descriptive analysis of the sociodemographic and clinical-epidemiological variables was performed.

Next, the time series of leprosy cases were constructed according to the total number of cases [26,27], gender (male and female), and disability grade (G0D, G1D, G2D, and not evaluated).

For the construction of the time series, the general rates of detection and those stratified by gender were calculated, considering the total population of the municipality (for general detection rate) and the populations of men and women (for rates stratified according to gender) as the denominator, all with a multiplication factor per 100,.000 inhabitants.

After the construction of the time series, according to detection in general by gender, age, and disability grade, the evolutions of the trends were calculated using the Seasonal-Trend decomposition procedure based on Loess (STL) [28]. This methodology is based on the classic decomposition of time series that disaggregates the total series into three additive components (trend, seasonality or error), allowing each of these components to be separately estimated and identifying the source of variability of the series in a more concise way than through a global analysis of the series. The STL has a simple design that consists of a sequence of applications of the Loess, allowing analysis of the properties of the procedure and quick calculations [29].

One of the advantages of this methodology is that it is quite robust regarding the existence of outliers. ‘Trend’ refers to the general direction in which the variables of the time series develop, according to a time interval, presenting a pattern of increase/decrease of the variable over a certain period. ‘Seasonality’ is reflected in identical patterns that a time series seems follow and that occur regularly at fixed periods of time. Finally, ‘noise’ is the fluctuations that occur over the time of the series, visualized as irregular and random movements perceptible only with the removal of the other components [30].

Having estimated the three components of the time series, only the trend was selected to characterize the trend of the variables of interest over time. Subsequently, the Average Monthly Percentage Change (AMPC) was calculated for the trends in the general detection rates by gender and cases with disability grade identifying the mean percentages and how much the trends increased or decreased over the study period. Finally, the trends of the disability rates in various groups were also analyzed. All analyses were performed using the R Studio version 3.5.2 statistical software.

Results

A total of 9,739 leprosy cases were reported between 2008 and 2018. As shown in Table 2, the majority of cases were male (58.37%), with a predominant age of 15 to 59 years (87.55%). The predominant level of education was incomplete elementary school (43.96%).

Table 2

Clinical and social epidemiological characteristics of the cases diagnosed with leprosy, in an endemic municipality in Central-West Brazil (2008–2018).

Variables	Frequency (n = 9739)	%
Gender
Male	5685	58.37
Female	4052	41.60
Not classified/incomplete	2	0.03
Age
<15 years	514	5.28
15 to 59 years	8527	87.55
60 years or more	698	7.17
Education
No schooling	738	7.58
Incomplete elementary education	4279	43.96
Complete elementary education	821	8.43
Incomplete High School Education	736	7.55
Complete high school education	1621	16.64
Incomplete higher education	262	2.70
Complete higher education	552	5.65
Not classified/incomplete	650	6.67
Not applicable	80	0.82
Operational classification
Paucibacillary	2582	26.51
Multibacillary	7095	72.85
Not classified/incomplete	62	0.64
Clinical form
Indeterminate	1118	11,48
Tuberculoid	1456	14,95
Borderline	5535	56,83
Lepromatous	1422	14,60
Not classified/incomplete	208	2,14
Disability grade at diagnosis
Grade 0	3914	40.19
Grade 1	2074	21.30
Grade 2	785	8.06
Not classified/incomplete	2966	30.45

Regarding the clinical variables, there was predominance in operational classification of multibacillary cases (72.85%), and for the clinical form by borderline cases (56.83%). The disability grade at diagnosis showed that 40.19% had G0D, followed by 30.45% that were not evaluated, 21.3% with G1D and 8.06% with G2D.

According to the results, for the detection rates (S1 Fig) there was a decreasing trend in the general detection rate and for the reported female cases, and an increasing trend for male cases (0.01%).

Fig 2 presents the main changes in the structure of the time series of the total detection rate of leprosy cases. Three changes of structure are verified in the series; the first occurred in November 2011, in which the series shows a marked decrease until the year 2013. The second change in structure occurred in August 2013, with an increase in the time series, presenting the highest values in the years 2014 and 2015, with a detection rate of more than 20 cases per 100.000 inhabitants. From October 2015 onwards, the last change in structure occurred, with a decrease and later stability in the detection rate values until the end of the series.

Fig 2

Changes in the structure of the time series for the general leprosy detection rate, Cuiabá, Mato Grosso, Brazil (2008–2018).

(A) Time series; (B) Trend; (C) Change of structure; (D) Point of structural change.

Considering disability grade in the general population (S2 Fig), no disability (G0D) was the only grade with a decreasing trend, while G1D (0.56%), G2D (0.38%), and unevaluated cases (0.28%) showed increasing tendencies.

The increasing or decreasing of the trends is shown by the Table 3 below.

Table 3

Mean percentage variation in the rates of detection of leprosy and disability grade at the time of diagnosis of cases, in an endemic municipality in Central-West Brazil (2008–2018).

Variables	Average Monthly Percentage Change (AMPC) (%)	Trend*
LEPROSY DETECTION
General population	- 0.11	Decreasing
Gender
Male	0.01	Increasing
Female	- 0.26	Decreasing
Age group (years)
<15	-0.99	Decreasing
15–29	-0.49	Decreasing
30–59	0.07	Increasing
≥60	-0.0028	Decreasing
DISABILITIES
Disability grade in patients with leprosy
Grade 0	-0.57	Decreasing
Grade 1	0.56	Increasing
Grade 2	0.38	Increasing
Not evaluated	0.28	Increasing
Disability grade in male patients
Grade 0	-0.44	Decreasing
Grade 1	0.35	Increasing
Grade 2	0.67	Increasing
Not evaluated	0.22	Increasing
Disability grade in female patients
Grade 0	-0.7	Decreasing
Grade 1	1.24	Increasing
Grade 2	-6.09	Decreasing
Not evaluated	0.45	Increasing
Disability grade in children <15 with leprosy
Grade 0	-0.26	Decreasing
Grade 1	1.02	Increasing
Grade 2	9.86	Increasing
Not evaluated	-0.42	Decreasing
Disability grade in patients aged 15 to 29 years
Grade 0	-0.56	Decreasing
Grade 1	0.98	Increasing
Grade 2	0.04	Increasing
Not evaluated	-0.91	Decreasing
Disability grade in patients aged 30 to 59 years
Grade 0	-0.47	Decreasing
Grade 1	0.74	Increasing
Grade 2	-0.62	Decreasing
Not evaluated	0.63	Increasing
Disability grade in patients aged ≥60 years
Grade 0	-0.40	Decreasing
Grade 1	0.73	Increasing
Grade 2	0.67	Increasing
Not evaluated	0.21	Increasing

* Considered the mean, which is influenced by changes and/or extreme variations.

Source: authors.

When stratifying disability grade according to gender (S3 Fig) there was a decreasing trend for no disability (G0D) in males (-0.44%) and females (-0.70%), and a decrease in G2D in females (-6.09%). The other disability grade showed increasing trends throughout the series.

In S4 Fig shows the disability grade according to age groups. For all age groups, the rates of new diagnosis with no disability (G0D) are decreasing. Regarding G1D, all age groups showed an increasing trend. For G2D, only the 30–59 years age group presented a decreasing trend (-0.62), with the other groups showing increasing trends. Finally, regarding those not evaluated for disability grade, children aged under 15 years (-0.42) and the group aged 15 to 29 years (-0.91) showed decreasing trends, while the other groups (30–59 years and ≥60 years) presented increasing trends.

Discussion

The present study aimed to investigate the epidemiological situation of leprosy, its trend over the years, and whether there were trends, both in the detection of the disease and in disabilities, analyzing disparities and/or differences regarding gender and age in a hyperendemic metropolis in the Central-West region of Brazil.

The study showed that leprosy has been declining in the research area; however, when analyzed according to gender, age and disabilities, we observed that the leprosy affects men, children under 15 years and elderly people unequally, with an increase in disabilities, raising the hypothesis that late diagnosis and underreporting may be occurring, revealing a possible weakness of the health services in Cuiabá [31-33].

A current ally to fight leprosy is leprosy chemoprophylaxis. According to the WHO guidelines, single-dose rifampicin (SDR) as post-exposure prophylaxis (PEP) can be used in children and adults [1]. In a randomized controlled trial, SDR given to leprosy contacts provided a reduction in leprosy risk of 57% in 2 years and 30% in 5–6 years [34]. As leprosy is a highly stigmatized disease, revealing the identity of the index patient when implementing this preventive therapy for contacts should be handled with care and only after gaining consent, especially when this takes place outside the patient’s family.

The result that men are more affected than women has also been found in other studies [35,36]. This can be related to several factors, such as being less concerned about their own health and difficulties for men to access public health services [37-39]. Currently, there are few health policies aimed at this population to meet their needs [40]. Barriers related to the difficulty of access to health services, the incompatibility between the hours of operation of health units and the workday, and the belief of being less susceptible to the disease in comparison with women may contribute to this greater burden of leprosy in the male population [41].

Most of the cases had incomplete elementary education, an indicator of low schooling, which may be related to the social aspect and living conditions. Low levels of education hinder access to better jobs and better economic conditions [42-43].

The predominance of multibacillary cases, with the most severe clinical forms (especially borderline and lepromatous cases), may suggest the occurrence of active transmission of the disease and, consequently, greater potential to incapacitate the affected individuals [44].

In relation to children under 15 years of age, when analyzing the disability grade, there were growing trends in the number of G1D and G2D in this age group, which may indicate that the municipality faces difficulties in the early diagnosis of the disease and ongoing transmission. A study by Xavier et al. (2014) with children under 15 years of age indicated that the early exposure to the pathogen in this age group suggests a late diagnosis and prolonged exposure [45]. The fact that there are any G2D in children is concerning, as it falls far short of the WHO goal for zero disability in children [1,45]. In addition, people who are affected by multibacillary forms of the disease have a greater chance of developing health problems… Leprosy is highly disabling when not properly treated in this population, which can influence academic school performance (and future occupation) and cause problems related to social limitations, discrimination, self-esteem, and stigma experienced by the affected person, especially because this is a period of growth and physical and emotional development [45,46].

In the state of Mato Grosso in 2015, the National Campaign for Leprosy, Geohelminthiasis and Trachoma [“Campanha Nacional de Hanseníase, Verminoses, Tracoma e Esquistossomose”] was initiated, which mobilized local health services to execute actions related to the active search for cases, focusing on schoolchildren aged 5 to 14 years. The campaign was carried out in approximately 915 schools in 65 municipalities (including Cuiabá), to examine and treat more than 291.200 students and their possible contacts [21]. It is estimated that the campaign may have had an impact in the region studied, reflecting the peak of detection verified in the study for this age group. No further policies were encountered in public archives to influence the detection of leprosy in the region during the time period.

Regarding the age group of 15 to 29 years, despite presenting a decreasing trend in the case detection rate, it should be noted that G1D and G2D ended the series with increasing trends. These results can be strong indications of late diagnosis and the existence of underreported of cases [42,47], since the decrease in the detection rate of new cases is not accompanied by the decrease of cases with disability grade. This constitutes a warning about possible difficulties of health services in detecting patients early and conducting adequate active case finding activities [48].

The group aged 30 to 59 years ended the time series with an increasing trend in the detection rate of new cases, as well as in G1D. This age group is composed of the economically active population, where the disabilities and incapacities caused by leprosy affect the work and social life environments, causing not only economic losses for the individual and his or her community but also psychological losses [9,49,50].

The older adult age group (aged 60 years or more) had a decreasing trend in the rate of detection of new cases and increasing values in G1D and G2D. As stated, the antagonism between the decrease in the detection rate and the increase in disabilities is a strong indication of difficulties in the active search for cases and the possibility of underreporting [47].

The issue of not evaluating cases for disability showed an increasing trend over the study period. The assessment of physical disability at the time of diagnosis is a priority action for newly diagnosed leprosy cases, and the fact that ‘non-evaluation’ presents an increasing trend may raise discussions regarding the management of leprosy cases in the research setting. According to the Ministry of Health quality control, at least 75.00% of new cases at the time of diagnosis need to be evaluated for the disability grade and registered into SINAN [23,24]. In the Official Epidemiologic Bulletin of Cuiabá of the years 2017, 2018 and 2019 health units evaluated a mean of 56.24% G2D registration of new cases at the time of diagnosis, below expectations [22]. The authors of this study emphasize that a 100% of disability grade assessment and registration at time of diagnosis, as well as for disease progression evaluation, should be pursued.

These findings lead us to suppose that the assessment and registration of leprosy patients at health care level or in the national surveillance system had not been carried out systematically, with the number of unevaluated cases often showing a lack of adherence, unpreparedness, and a lack of standardized protocols that guide the classification and registration, of both the clinical leprosy form and its disability grade.

Leprosy affects men and women, age groups and social classes in different ways, it emerges from inequality and produces more inequality among the affected populations. In addition to this discussion, it can also be defined as neglected, both by public policies and health authorities, with regards to incorporating it into priority investment actions, considering that it affects the most marginalized populations and those in situations of extreme vulnerability [51-53].

If there is a clear intention to overcome leprosy, investments in health care and different methodological approaches must be considered, in both research, health service delivery and the surveillance system of health systems and territories. The elimination of leprosy involves comprehending the differences in gender issues and life stages in the health territories, and the elaboration of intervention projects aimed to target risk groups must be sufficiently supported by scientific and operational evidence.

Guiding public policies based on this evidence is essential for advancing equity and eliminating leprosy. Actions are needed to support health care providers to correctly evaluate disabilities. Active case finding activities can result into higher patient detection rates, and in addition, the search and follow-up of patient contacts must also be promoted. As mentioned, SDR-PEP could be studied by policy makers and/or health care managers, to be implemented in their context based on the WHO’s recommendations and the effectiveness and feasibility as reported in the literature [1,7, 34,54,55].

A limitation of this study is that the database used is secondary, so it may contain inconsistent information regarding quantity and quality with presence of data that were potentially ignored or incomplete, data regarding the operational classification and clinical leprosy registration form were, in some cases, not filled completely. Another limitation involved STL, which is only a visual resource for showing findings and does not having a "measure" of increase or decrease. AMPC is based on a percentage, which is why it does not contain a p-value or 95% confidence interval. In the data, we encountered some operational classification with incompatibility with clinical form, such as ‘indeterminate’ being classified as ‘multibacillary’ cases, thus having to add ‘not classified/incomplete’ on operational classification. Not all clinical forms were filled in the databank contrary to the operational classification, causing disparities. The number of children with G2D in the trends is small and thus might not be able to show a clear trend. The interpretation of these data cannot be understood at the individuals’ level.

In conclusion, the present study highlights the need to prioritize leprosy active case finding activities to foster early detection, to improve the care for this disease, as well as to develop strategies for leprosy prevention and health care strengthening.

STROBE Statement—checklist of items that should be included in reports of observational studies.

(DOCX)

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Minimal anonymized data set.

(XLSX)

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Trends in total detection rates, in the general population, by gender and age groups per 100.000 inhabitants in Cuiabá (2008–2018).

(Black line) Time series; (Red line) Trend.

(TIF)

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Trends in the gross number of cases of disability grade at Diagnosis (DPD) in patients diagnosed with leprosy in the period from 2008 to 2018 in Cuiabá.

(Black line) Time series; (Red line) Trend.

(TIF)

Click here for additional data file.

Trends in the gross number of cases of disability grade at Diagnosis (DPD) by gender in patients diagnosed with leprosy in the period from 2008 to 2018 in Cuiabá.

(Black line) Time series; (Red line) Trend.

(TIF)

Click here for additional data file.

Trends in the gross number of cases of disability grade at Diagnosis (DPD) by age group in patients diagnosed with leprosy in the period from 2008 to 2018 in Cuiabá.

(Black line) Time series; (Red line) Trend.

(TIF)

Click here for additional data file.

15 Apr 2021

Dear Mr Martoreli Júnior,

Thank you very much for submitting your manuscript "Inequality of gender, age and disabilities due to leprosy and trend in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: methods are well explained and appropriate for this study

Reviewer #2: Information on the objectives of the study is clear, ethical approval was obtained. See full comments below in the Methods section.

Reviewer #3: The objectives of the study are clearly articulated with a clear testable hypothesis stated.

The study design is appropriate to address the stated objectives.

The population is clearly described and appropriate for the hypothesis being tested.

Since all the population is included in the study, there is no sample size issue.

The statistical analysis is corrected for supporting the conclusions.

But: (1) Please include the diagnosis criterion of leprosy for better under standing. (2) Please clarify the mobile population for analysis since it could be a confounding factor for the result. (3) Is there any policy change for leprosy which could influence the detection of leprosy. (4) The method of Seasonal-Trend decomposition procedure based on Loess (STL) can be described more clearly for better understanding by readers.

Reviewer #4: This is an interesting exercise made possible by the comprehensive SINAN database in Brazil. The authors have given much emphasis to the statistical analysis of trends. I believe the statistical approach is generally valid and the analysis well-performed, but there are some unclarities:

1) Please provide the definition used in Brazil for hyper endemic. For international use, consider to just state 'highly endemic' and use this term as well in the title, instead of 'hyper endemic'.

2) There is quite some 'fog' in relation to disability grade, its registration and the way it was dealt with in the analysis. Lines 152-154 are unclear; e.g. what does 'below expectations' mean. Also the sentence in lines 188-190 is unclear. What total number? And how does this translate in the results? There I see a breakdown by disability grade and 'not registered'. With the great uncertainty with regard to the indicator disability grade, why do you not just take 'grade 0' and 'joint grade 1 and 2' in the trend analysis, and ignore the 'not evaluated'?

3) I think very important information is missing necessary for interpreting trends, namely operational changes in the leprosy control program, or for that matter the health system in general. The total leprosy detection over the ten years is rather spiky. It comes down between 2008 and 2012, increases and decreases steeply between 2012 and 2016, and then increases again to reach possibly a plateau. The health system (or other operational changes) during this time need to be described in some detail in the methods section under a separate heading. This is essential context to understand and interprete the trends.

Reviewer #5: There is too much background information in the methods – make this more concise, especially the parts about the “study design and research scenario”. Also, in English, we generally don’t say “Research scenario”. I would say “Study Design and Setting”.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: well presented and relevant information provided

Reviewer #2: The result section is clearly written. I would suggest to use not only colours, but also a different line appearance in the table to make them more clear for readers who are printing the tables in black/white. Please also see my comments below on the Results section.

Reviewer #3: The analysis presented matches the analysis plan.

The results are clearly and completely presented.

But: A standardized population need to be provided and calulated for the age and gender groups.

Reviewer #4: With regard to the case characteristics (table 1) there is some unclarity about operational classification and clinical form. PB (26.67%) seems to be the sum of I and TT clinical forms (26.88%), but not just the same. In the sentence starting on line 237 it states: "... there was a predominance of multibacillary cases (73.33%), followed by borderline cases (57.00%)". But borderline cases are part of MB...

With regard to presentation of trends, I would first like to see the figure 'Detection total' separately with under the time line some bars or arrows indicating important operational changes in time. See for instance the figure A in the following article for inspiration https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(20)30065-4. In that way the overall trend is placed in context of the most important operational factors influencing the trend.

Table 2 summarizes the main findings of the trend figures 2-5. You could therefore consider to place all these figures in an appendix.

In table 2, make sure to give the full name of the abbreviation AMPC. Furthermore, as reader I need help to understand the importance of the figures under AMPC. Under the heading Trend you state Increasing or Decreasing. But is there a way to indicate a measure of increase or decrease, for instance through a p-value? And how do you establish the importance of a trend. When is the trend such, that you want to highlight it as an important result and discuss its implications. And when is it just some irrelevant 'noise'.

Reviewer #5: 1. I don’t think G0D (as opposed to G1D and G2D for grade 1 and grade2) is an accepted acronym for “no disability” and it’s confusing to say that G0D is decreasing – G0D in effect is “NO disability”. I would use a different way of describing it because if you read it quickly you may think that some disability is decreasing whereas what you are saying is that people presenting without disability is actually decreasing among many groups which is very concerning.

For all “G0D”, I would substitute “No disability”

2. I know that Asian descent for race translates to “amarelo” in Portuguese, but many English language readers would find “Yellow” offensive, so I would change that to Asian descent.

3. Lines 237-238: You wouldn’t really say “followed by borderline cases”, since they are part of two different categories, just state these separately.

Figures overall seem ok, but would change the G0D label as per above.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #2: In the discussion, I am missing the role of leprosy prevention as post-exposure chemoprophylaxis with a single dose of rifampicin (SDR-PEP) for contacts of leprosy contacts, in combination with contact screening / active case finding. This is a very important strategy for decreasing the number of new cases / case detection delay / disability etc. For example in Brazil, a current research project is ongoing studying advanced chemoprophylaxis regimen (PEP++). But the evidence from e.g. COLEP & LPEP regarding SDR-PEP is clear and it is also included in the WHO Leprosy Guidelines for the Diagnosis, Treatment and Prevention of Leprosy. You could add this as reconmendation.

Including 1 study limitation may be a bit limited.

Reviewer #3: The conclusions are supported by the data presented.

The limitations of the study are addressed.

Public health relevance is addressed.

The authors need to discuss in more detail to help readers understanding the result.

Reviewer #4: To start with, cut the discussion by at least 50%. It is far too long and therefore unclear. In the discussion state first what you consider the really most important findings of your study. Which trends are really relevant in terms of being unexpected, undesired and amendable to health care interventions?

After stating the most important findings, only then start with some explanation and interpretation. Make clear that you are discussing everything against the Brazilian background. You use the term 'global' at a certain point, but I understand it to mean Brazil as a whole and not the world. Here it is also important to take into account the operational factors, that you have now incorporated in the new figure 1.

Much of the disparities are due to delayed detection, which may apply more strongly to e.g. women and people in the working age. This is also related to stigma. Try to bring that together in the discussion more comprehensively, instead of just going along the different groups (gender, age and disability) in order of appearance in analysis.

Whereas the general discussion text should be much shorter, the paragraph on strengths and weaknesses should be a more detailed.

Finally, the conclusion is very general. Can you make it a bit more specific, based on your findings? Just one or two sentences more.

Reviewer #5: 1. Line 288 Again, do not say “grade 0 disabilities” are decreasing. That’s misleading. Grade 0 means there is no disability, so you shouldn’t describe it like that. You should say that the rates of new diagnosis without disability is decreasing.

2. Gender differences – I think you are missing discussion of a potentially big reason for differences in gender that has been proposed – that women are not seeking care for their leprosy, possibly due to more PB in women than men so underrecognition or possibly due to stigma (reference: Factors preventing early case detection for women affected by leprosy: a review of the literature. Price VG.Glob Health Action. 2017 Jan-Dec;10(sup2):1360550. doi: 10.1080/16549716.2017.1360550.PMID: 28853325 )

3. The discussion is too long – you should summarize the different age time series more succinctly and in 1-2 paragraphs and not just repeat your results.

4. There is no discussion on the limitations of this study – one big thing, which you can tell from the figures, is that the number of children with grade 2 disability is actually quite small so it may not be able to tell a clear trend. However, the fact that there are any G2D in children is concerning, and at odds with the WHO goals for zero disability in children < 15 (you should mention these goals in the discussion).

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #2: ABSTRACT:

32-35: First sentence in abstract is quite long, change this into 2 sentences to increase readability.

35-36: Second sentence in abstract is incorrect. Start the sentence with e.g. “This is a …”

45-46: In the abstract it is stated “Regarding detection according to gender, there was a decrease among women”, but “by evidencing a increasing trend of leprosy cases among women” (47-48). This seems contradictive, please make some changes. It should also be ”aN increasing trend”.

INTRODUCTION:

60: In introduction, I would advise to change “which lead to physical disabilities” into “which can lead to physical disabilities”.

61: Please remove “skin contact” in “skin contact or other means cannot be excluded”, the evidence for skin contact is low (i.e. using a tattoo needle in a leprosy patch and next tattooing another person with the same needle is risky, but not normal skin contact and rare of course) and stating it like this can sound stigmatizing for some people.

65: Reference numbers should be placed before/after (depending on reference style) punctuation marks. In this case: before a comma (,) or full stop/period (.), not in the middle of a sentence. Please move [2,3] to after “imagined”.

67: “In 2016, according to WGHO data, 143 countries…” -> This data is a bit outdates, especially because your data reflected in the time series study is ranging from 2008-2018. Please use WHO data from 2018 (or even 2019) here.

72: It seems like you are referring to both North and South America, so it should be continentS.

77: “preventing cases with grade of disability” should be “preventing cases with disabilities”.

79: Please remove the capital at “The Plan” -> “The plan” or even better, change it to “The strategy”.

89: Place a comma after “2010-2012”.

102-107: This is also the case because you cannot count ‘undetected cases’.

105: “disabilitie” should be “disability”.

111: the word “public” is missing: “define public policies” -> “define public health policies”.

113: the word “tools” is missing: “more sensitive is the time series” -> “more sensitive tools is the time series”.

METHODS

129: when including such an exact number as 3,266,538 km2, I would suggest to remove the word “approximately”.

138: Explain shortly what Gini index is.

140. full stop is missing after “[17,18]”

140-141: capital usage is incorrect, please check. I would suggest to remove most of the capitals used in this sentence.

145-146: same point regarding the capitals, I would suggest to remove most of the capitals used in this sentence.

153-154: which expectations are meant here? Where does 75.00% come from?

STUDY POPULATION AND INFORMATION SOURCES

164: I do understand why you included this (race/skin color), and the explanation on this in the discussion is very clear and correct. But when people are reading this in the Methods section, it is a bit in your face. Registering this data should be avoided or happen very carefully from an ethical perspective, as it may sound like ethical profiling / offensive / discriminatory to some people. The colors as outlined here (“white, black, yellow, mixed, and indigenous”) is not ethical preferred. Starting with white is tricky (also now with Black Lives Matter), alphabetical order would be better. I would include information that people had to register their own race (instead of the health professionals / researchers registering it, because it is hard to judge whether someone is mixed or black for example). I would remove it completely from the article. If you want to leave it in, I would suggest to more clearly explain also in the Methods section that this is registered in the national leprosy system and that this is outdated or not found to be ethical anymore and why this data can still be important and change/remove this listing of skin tones.

181/189/192/212/214/215: Grade of Disability is sometimes written with capitals and sometimes without, I would suggest to write it without capitals. I also prefer “disability grade” over “grade of disability”.

202-206: I would use “” or ‘’ for the words you are defining: ‘Trend’, ‘Seasonality’, ‘noise’.

RESULTS:

229 & Table & 321: see comments above about “race/skin color”

235 & 262: Delete “Source: Authors”. If there is no other source included, it is clear it is from the authors.

238/240/241-242/245/Table 2/260/262/264/268/268/271/274/354/372: See comment above: “Grade of Disability” -> “disability grade”.

243: full stop missing after “Fig”.

Table 2: “General Population”-> “General population”.

Fig. 2/3/4/5: It may be nice to use strips/dots for one of the lines in the graphs (e.g. the red one) besides a color difference, so people who print it black & white can still see the color difference.

279 & 339 & 434: I would suggest a different word here, as “behavior“ is more suitable for humans/animals, go for e.g. “trend” here instead.

280 & 289: “and or” should be “and/or”.

297: remove “the” before “: disability”.

299: Remove “The” before “literature”.

300: Maybe add reference here, as “literature” sounds like plural.

308: Possibly remove “various”.

310: you could replace “published works” by simply staying “studies”.

311: what is meant here by “risky situations”? It this referring to getting infected? As prolonged contact is needed, I would not call this “risky situations” (also sounds a bit stigmatizing), or is it referring to possible damage to the hands because of work related accidents or so? I would delete “risky situations” or rephrase and explain it.

313-314: at least 2 references seem to be missing, as you are talking about evidence from the 90ies and current policies.

343: add the word “the” between “regarding” and “detection”.

343 & 354: add “years of age” after “15”.

348-349: word repetition “carry out”, if you like, change for executed/organized…

357 & 377: reference location not correct (should be at end of sentence or before comma).

357-360: what do you mean here by the statement that “early exposure” leads to disabilities? Because of the length of the exposure/infection period (although, they were still children at time of diagnosis, so it cannot be decades for example) or is it because their bodies were still developing biologically at that age. Or both?

362: I would change “academic performance” into “school performance”, as “academic” often refers to university level.

383: delete commas around “as well as”.

384: “incapacity” –> “incapacities”.

400: change the word “scenario” into “setting”.

400: you may like to add “registration at health care level/national surveillance system”.

402: you may like to add “lack of adherence”.

408: “a way of” sounds a bit informal, you could replace it for “a method of”.

421-422: change “does not behave in a homogenous way” into “disease trend is not homogenous”.

427: what is meant by “promotion actions”? Awareness raising? Self care? Please explain.

431 & 432: I don’t think “State” should be capitalized here.

432: “State protection” has a double definition (also a negative one), I would replace it for “state support”.

434: 432-435: references are missing, as you are referring to multiple studies and WHO reports.

435: delete “which is true”, as you need to have verified all these studies/data to know for sure.

435: a decrease in new cases can also be caused by a lack of active case finding activities, and this, is not always a ‘positive’ finding.

445: usually, multiple limitations (at least 2) are named.

Say something on post-exposure prophylaxis (PEP) as prevention strategy for leprosy (see my comment above) in the discussion section.

REFERENCES:

Reference 1 (457) and reference 5 are the same, though 2 difference websites are used. Please replace reference 1 with number 5 (2018 WHO is the correct reference for the WHO Leprosy Guidelines).

Reviewer #4: The first paragraph of the introduction is rather outdated. Please use 2019 WHO data and also refer to the latest WHO strategic document for leprosy.

Reviewer #5: The paper needs some work before publication, especially in its length, which I think can be shortened, and in the English / writing in certain places. I found a few typos as well. It needs a thorough review for English language editing, spelling, typos before publication. I also didn't see cover letter or summary which was unusual.

--------------------

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Reviewer #1: Yes: Carlos Franco-Paredes

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: I enjoyed reading this and reviewing this manuscript. It is a master piece in social sciences in medicine and it reveals the fallacy of the academic imperlalism by the "experts" drinking latte in European countries dictaing polices in coutnries where leprosy is a major public health concern. This publication is a clear demonstration of the poor decision meaking of public health organizations. The only thing that the elimination campign of leprosy did, was the elimination of attention to major chronic infectious disease that causes severe disability. It was an honor to review this paper.

Reviewer #2: Very nice article and an important topic. Please make some editorial changes (see full comments), and pay extra attention to capital usage. Also, be careful with the section on race/skin color (especially in the Methods section) as this is a sensitive topic. See if you can add another limitation and add chemoprophylaxis for leprosy in your recommendations. Also please do check the reference list again and add a few extra references in the text (see comments).

Reviewer #5: This study is a straightforward analysis of epidemiologic data on leprosy from the SINAN data base and uses a time series analysis that really studies the trends over time of the 3 key epidemiologic indicators for leprosy: 1. New case detection rate, 2. Pediatric cases, 3. New grade 2 disability. Using a hyperendemic city is a really nice way to not only show concerning trends in this area, but to model ways that we can study other geographic areas. These findings are very important because it shows that the decreasing incidence does not tell the whole study and that different age / sex can be impacted differently and may need different control strategies. The paper needs some work before publication, especially in its length, which I think can be shortened, and in the English / writing in certain places.

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16 Jun 2021

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

9 Jul 2021

Dear Mr Martoreli Júnior,

Thank you very much for submitting your manuscript "Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations. Please pay particular attention to reviewer's 2 comments and make sure that their concerns are addressed appropriately.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Alberto Novaes Ramos Jr

Associate Editor

PLOS Neglected Tropical Diseases

Hélène Carabin

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: OK

Reviewer #2: TITLE:

- "hyperendemic" is written with space in the rest of the manuscript, but without in the title

INTRODUCTION:

- Most changes made were appreciated.

- See my suggested changes and comments in the text file attached.

- Please include the latest version oif the WHO Global Leprosy Strategy (2021-2030).

- I would delete: "Also, regarding the inequality related to age, it is known that when there is a delay in diagnosis, children that who had contact with index cases can also become ill [1112], which is an important gap to be filled."

METHODS:

- Most changes made were appreciated.

- See my suggested changes and comments in the text file attached.

- You could think of adding a definition table with an overview of the disability grades (what is G0D, G1D, G2D)

- Capital usage still not fully correct

- This sentence is unclear: "Regarding the disability gradethe grade of disability, health units evaluated a mean of 56.24% of new cases with a disability at the time of diagnosis, below expectations, which was listsed as should be at least 75.00% according to SINAN [235, 26]."

- I donnot understand this sentence because of the level of English, you can maybe also delete it: "For the construction of time series of the cases with disability grade we considered all the number of cases with disability grade (G0D, G1D, G2D, and not evaluated)."

- This is also quite vague, could it be deleted? "... even for a very long time series and large amounts of trend and seasonal smoothing, a very small amount of trend smoothing, and seasonal components that are not distorted by aberrant behavior in the data ability to decompose time series with missing values"

- This should not be in the methods section, but in the discussion (is already included there). Also, the word 'dubious' is too strong/incorrect: "Finally, we mention that the notification forms are filled out by third parties, so dubious data may be provided."

Reviewer #3: The objectives of the study are clearly articulated with a clear testable hypothesis stated. The study is design appropriate to address the stated objectives. The population is clearly described and appropriate for the hypothesis being tested. The sample size is sufficient to ensure adequate power to address the hypothesis being tested.

Reviewer #4: See attachment

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: OK

Reviewer #2: - Changes made were appreciated.

- 'ignored' is too strong in table 1, go for: 'not classified / incorrect / incomplete' instead

Reviewer #3: The analysis presented matches the analysis plan. The results are clearly and completely presented.

Reviewer #4: See attachment

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: OK

Reviewer #2: DISCUSSION:

- Most changes made were appreciated.

- See my suggested changes and comments in the text file attached.

- Improvements can be made regarding: item order in the discussion, repetition, level of English.

- I would suggest to delete this, as it seems less relevant (not clearly explained how this affects the leprosy programme) and the discussion word count is too high: "In the state of Mato Grosso, in 2015, the “National Campaign for Leprosy, Geohelminthiasis and Trachoma” was initiated, which mobilized local health services to execute carry out actions related to the active search for cases, focusing on schoolchildren, aged from 5 to 14 years. The campaign was carried out in approximately 915 schools in 65 municipalities (including Cuiabá), to examine and treat more than 291..200 thousand students and possibly their possible contacts [242]. It is estimated that the campaign may have had an impact in the region studied, reflecting the peak of detection verified in the study for this age group. No further policies were encountered in public archives to influence the detection of leprosy in the region duringh the time period."

CONCLUSION:

- See my suggested changes and comments in the text file attached.

Reviewer #3: The conclusions are supported by the data presented. The limitations of the study are clearly described.

Reviewer #4: See attachment

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: OK

Reviewer #2: revision needed

Reviewer #3: (No Response)

Reviewer #4: I have made some edits to the text (attached, visible with track changes). That is easier for me than repeating everything in this form one by one.

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: OK

Reviewer #2: Improvements were made and are much appreciated. Nevertheless, the manuscript still need to be revised. Especially the discussion needs attention, the text order should be changed and repetition should be avoided. Both the introduction and discussion section can be shorter and more to the point. The newly written text segments need improvents regarding the level of English.

Reviewer #3: (No Response)

Reviewer #4: The paper has improved well after a thorough revision. There are still some small issues that I have addressed directly in the revised manuscript with track changes visible. This is not intended as a full language edit, but just to improve on some relatively important matters with regard to language and explanation.

--------------------

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Reviewer #1: Yes: Carlos Franco-Paredes MD

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

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Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Submitted filename: Revised Manuscript with Track Changes_corrJHR.docx

Click here for additional data file.

6 Aug 2021

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

27 Aug 2021

Dear Mr Martoreli Júnior,

Thank you very much for submitting your manuscript "Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Alberto Novaes Ramos Jr

Associate Editor

PLOS Neglected Tropical Diseases

Hélène Carabin

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: yes

Reviewer #2: - The changes made after last round were a great imporvement.

- The methods section can still be shortened, see if you can delete some sentences, this will make it easier to read.

- I suggested in the Word document to move a text section from the 'Methods' to the 'Discussion'.

- Please look at my other suggested changes (tracked changes & yellow marked) and comments in the Word file.

Reviewer #4: (No Response)

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: yes

Reviewer #2: - The changes made after last round were a great imporvement.

- Please look at my other suggested changes (tracked changes & yellow marked) and comments in the Word file.

Reviewer #4: (No Response)

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: yes

Reviewer #2: - The changes made after last round were a great imporvement.

- Please look at my other suggested changes (tracked changes & yellow marked) and comments in the Word file. These were especially focused on the level or English.

Reviewer #4: (No Response)

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: no

Reviewer #2: Minor revision, mainly editorial, English language and references. Especially the methods section can be shortened. See my suggestions & comments in the Word file.

Reviewer #4: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: yes

Reviewer #2: - The changes made after last round were a great imporvement.

- If possible, further shorten the 'Methods'-section.

- Describe where the raw data can be found for reproducibility reasons (see my comment/addition in 'Ethics'-section).

- Please look at my other suggested changes (tracked changes & yellow marked) and comments in the Word file.

- Please check the references, some are incorrect in the text and inconsistent in the reference list.

Reviewer #4: I am happy with all revisions made.

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Carlos Franco-Paredes

Reviewer #2: No

Reviewer #4: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Submitted filename: Revised Article with Changes Highlighted_reviewers comments+changes v3.docx

Click here for additional data file.

28 Sep 2021

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

21 Oct 2021

Dear Mr Martoreli Júnior,

We are pleased to inform you that your manuscript 'Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases. However, Reviewer 2 still had a few more recommendations to improve the manuscript a little more. Please make sure to address the comments from Reviewer 2 when preparing your mansucript for publication.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Alberto Novaes Ramos Jr

Associate Editor

PLOS Neglected Tropical Diseases

Hélène Carabin

Deputy Editor

PLOS Neglected Tropical Diseases

***********************************************************

Make the minor changes indicated by the reviewer:

"The manuscript has improved a lot and is, in my opinion, almost ready to be published. Some relatively minor final comments:

- Please check punctuation marks and paces use throughout the manuscript. Examples: remove comma in sentence 51; parenthesis in sentence 143 should be placed after 'referrals' instead of 'rehabilitation'; remove full stop in sentence 317; remove space in sentence 325 & 397.

- In table 'Table 1 - Disability grade and his characteristics', the word 'claw' at hands & feet at G2D can be seen as stigmatizing language. Better is 'contractures' or 'claw hand deformity'

- The reference for 'WHO disability grading for leprosy' (part of Table 1) is: https://apps.who.int/iris/handle/10665/42060

- The level of English could be improved at sentence 291-2: 'care should be taken to reveal the identity of the index patient when implementing this preventive therapy in contacts, especially outside the patient's family.'. I would like to propose to change that into: 'revealing the identity of the index patient when implementing this preventive therapy for contacts should be handled with care and only after gaining consent, especially when this takes place outside the patient's family'.

- In sentence 397, the English could be improved by removing 'between the sum of them'."

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Adequate

Reviewer #2: (No Response)

Reviewer #3: The objectives of the study were articulated with a clear testable hypothesis stated. The study design is appropriate to address the stated objectives. The population is described and appropriate for the hypothesis being tested. The sample size is sufficient to ensure adequate power to address the hypothesis being tested. There are concerns about ethical or regulatory requirements being met.

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Presented well

Reviewer #2: (No Response)

Reviewer #3: The analysis presented matches the analysis plan. The results are clearly and completely presented.

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Relevant and concordant to previous sections

Reviewer #2: (No Response)

Reviewer #3: The conclusions are supported by the data presented. The limitations of analysis are described.

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: Accept

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: (No Response)

Reviewer #2: The manuscript has improved a lot and is, in my opionion, almost ready to be published. Some relatively minor final comments:

- Please check punctuation marks and paces use througout the manuscript. Examples: remove comma in sentence 51; parenthesis in sentence 143 should be placed after 'referrals' instead of 'rehabilitation'; remove full stop in sentence 317; remove space in sentence 325 & 397.

- In table 'Table 1 - Disability grade and his characteristics', the word 'claw' at hands & feet at G2D can be seen as stigmatizing language. Better is 'contractures' or 'claw hand deformity'

- The reference for 'WHO disability grading for leprosy' (part of Table 1) is: https://apps.who.int/iris/handle/10665/42060

- The level of English could be improved at sentence 291-2: 'care should be taken to reveal the identity of the index patient when implementing this preventive therapy in contacts, especially outside the patient's family.'. I would like to propose to change that into: 'revealing the identity of the index patient when implementing this preventive therapy for contacts should be handeled with care and only after gaining consent, especially when this takes place outside the patient's family'.

- In sentence 397, the English could be improved by removing 'between the sum of them'.

Reviewer #3: (No Response)

**********

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

11 Nov 2021

Dear Mr Martoreli Júnior,

We are delighted to inform you that your manuscript, "Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases