Skip to main content
PLOS ONE logoLink to PLOS ONE
. 2021 Jul 16;16(7):e0253927. doi: 10.1371/journal.pone.0253927

Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda

Thomas H A Samuels 1,2,*, Priya B Shete 3,4, Chris Ojok 3,5, Talemwa Nalugwa 3, Katherine Farr 3,4, Stavia Turyahabwe 3,6, Achilles Katamba 3,6,7, Adithya Cattamanchi 3,4, David A J Moore 1,2,3
Editor: Eleanor Ochodo8
PMCID: PMC8284677  PMID: 34270582

Abstract

Introduction

Catastrophic costs incurred by tuberculosis (TB) patients have received considerable attention, however little is known about costs and pathways to care after a negative TB evaluation.

Materials and methods

We conducted a cross-sectional study of 70 patients with a negative TB evaluation at four community health centres in rural and peri-urban Uganda. Patients were traced 9 months post-evaluation using contact information from TB registers. We collected information on healthcare visits and implemented locally-validated costing questionnaires to assess the financial impact of their symptoms post-evaluation.

Results

Of 70 participants, 57 (81%) were traced and 53 completed the survey. 31/53 (58%) surveyed participants returned to healthcare facilities post-evaluation, making a median of 2 visits each (interquartile range [IQR] 1–3). 11.3% (95%CI 4.3–23.0%) of surveyed patients and 16.1% (95%CI 5.5–33.7%) of those returning to healthcare facilities incurred catastrophic costs (i.e., spent >20% annual household income). Indirect costs related to lost work represented 80% (IQR 32–100%) of total participant costs.

Conclusions

Patients with TB symptoms who experience financial catastrophe after negative TB evaluation may represent a larger absolute number of patients than those suffering from costs due to TB. They may not be captured by existing definitions of non-TB catastrophic health expenditure.

Introduction

Whilst the incidence and mortality of tuberculosis (TB) are declining globally, they are not declining fast enough to meet the ambitious targets set out in the World Health Organization’s (WHO) END TB strategy [1]. This strategy highlights the need for bold social policies and research in addition to patient-centred care in order to eliminate TB. To this end, there has been increased interest in the diagnostic journey of TB patients and their financial costs as they represent potential opportunities for novel interventions and programmatic development (1,2).

The severe economic implications of a TB diagnosis in lower and middle income countries have been well described [2, 3]. The proportion of patients incurring catastrophic costs (defined as >20% annual household income (AHI)) whilst obtaining a TB diagnosis and treatment serves as a measure of the financial burden of TB. Eliminating catastrophic costs for TB affected households is one of the three key targets in the END TB strategy [1, 4, 5]. However, much less attention has been paid to those who test negative during TB evaluation. These patients represent the vast majority of those embarking upon the TB diagnostic journey. Even in high TB-burden settings such as Uganda, 80–90% of patients with chronic cough will have a negative evaluation for TB [68]. Though they likely do not have the disease, persistent symptoms may lead patients to seek alternative diagnoses and therapies even after their negative TB evaluation. It is currently unclear to what extent these patients are at risk of incurring punitive costs in the pursuit of such a solution.

Studies of TB patients suggest that costs due to lost work represent a considerable proportion of their total financial burden [4] leading the END TB strategy to include lost income and non-medical cost in the calculation of ‘catastrophic costs’ in TB patients [9]. By contrast, financial risk in non-TB patients with similar respiratory symptomatology only considers out-of-pocket medical costs, termed by WHO as ‘catastrophic health expenditure’ [10]. It is not known to what extent non-TB patients suffer from non-medical and indirect costs that may not be captured under this current definition.

Previous studies have shown TB-negative individuals are likely to incur catastrophic costs prior to testing when their TB status is unknown [11]. However, to our knowledge, the financial burden accumulated after a negative TB evaluation has not been evaluated. We sought to characterise the number and type of healthcare providers visited by patients after a negative TB evaluation in Uganda and to estimate both the direct and indirect costs they incurred in following these pathways of care.

Materials and methods

Ethics statement

Ethical approval was granted by institutional review boards at the London School of Hygiene and Tropical Medicine (London, UK; MSc Ethics Ref: 15360), Makerere College of Health Sciences (Kampala, Uganda; REC Ref 2016–037) and University of California San Francisco (San Francisco, California, USA; ref:221338 IRB# 15–17296). Written consent was obtained for all in person interviews. Oral consent was taken and recorded for all telephone interviews.

Study setting

This exploratory cross-sectional study was carried out in four geographically-distinct areas of Uganda, two peri-urban and two rural, all within 150km of Kampala. Study sites were selected from those participating in XPEL TB trial, a cluster randomized trial to evaluate the effectiveness and implementation of onsite GeneXpert testing at community health centres [12]. One community-level TB microscopy centre was selected at random per a priori-defined area from those participating in the trial. Each of these centres uses sputum smear microscopy as the primary method of diagnosis for TB, tests more than 150 patients a year and refers sputum samples to a district or regional facility for Xpert MTB/Rif testing as part of the Uganda national TB program Xpert referral network.

Participants

Potential participants were identified from TB laboratory registers routinely kept at the four centres. Adult patients (≥18 years) who could consent and had a negative TB test result at these centres in quarter three and four of 2017 were eligible for inclusion. Individuals with a positive TB test result or who started treatment for TB within 2 weeks of their original evaluation were excluded. A convenience sample of 70 eligible individuals was taken. Preference was shown for individuals with recorded mobile telephone information, but in all other respects sampling was random. Participants were traced approximately 9 months after their negative test (Fig 1). Once traced, participants were given information about the study purpose and procedures and then asked to provide informed consent. If contacted by telephone, participants were read a standardised information and consent script and asked to consent over the phone–this was recorded as an audio data file.

Fig 1. Participant tracing procedure.

Fig 1

NOK = next of kin; VHT = village health team.

Surveys

All traced participants found to be alive were surveyed in participants’ local languages. Participants found to have died had the approximate date and reported cause of death recorded. Information was collected for up to ten healthcare facility visits made after a participant’s negative TB evaluation. This included the number and type of facility and time taken to visit. Cost data was collected for the post-evaluation period using locally-validated questionnaires adapted from the WHO patient costs survey for TB [9]. The adapted tool is presented in the Supplementary information. Costs incurred prior to and during TB evaluation were not evaluated. Participants were asked to estimate the cost of each component part of their visit (e.g., travel expenses, medication) including the value of any lost income. Total direct (out-of-pocket costs, split into medical e.g., medication, and non-medical e.g., transport) and indirect (lost income) costs were calculated. Total indirect costs per participant were calculated by taking a fraction of reported annual personal income based on the reported number of days of work lost due to symptoms post-TB evaluation. Dissavings were defined as the sum of reported borrowing, selling of assets and taking-out of loans. Cost data were collected in Ugandan Shillings (USh) and reported in both United States Dollars ($) and as a proportion of pre-morbid annual household income. During the data collection period the median nominal exchange rate was 3,680USh to $1USD; this was used calculate and report results in USD.

Data analysis

Patient characteristics, costs and healthcare-seeking behaviours were described using proportions with 95% confidence intervals for dichotomous outcomes and medians with inter-quartile ranges for non-parametric continuous outcomes. Wilcoxon Rank Sum tests were used to assess statistical differences in time and cost data between dichotomous variables. Univariate and multivariable sub-analyses were conducted using logistic and linear regression for binary and continuous dependent variables respectively. All data were analysed in STATA (version 15, StataCorp USA).

Ethical approval was granted by institutional review boards at the London School of Hygiene and Tropical Medicine (London, UK), Makerere College of Health Sciences (Kampala, Uganda) and University of California San Francisco (San Francisco, California, USA).

Results

Participants

Tracing was successful in 57/70 individuals (81%). Four traced individuals had died. Of the remaining 53, all consented to being surveyed. Surveys were administered a median of 10 months following negative TB evaluation (range 8–14 months). The 13 untraced individuals were younger than the 57 traced participants (mean difference -14.5 years 95%CI -23.3 - -5.7). No other statistically significant difference was found between these groups.

The 53 surveyed participants had a median age of 40 (IQR 32–51), 28 (53%) were female (Table 1). Thirty-three were traced by phone (62%). Median AHI (mAHI) was $1,174 (IQR $489–$3,261). Eighty-seven percent (n = 46) visited another healthcare facility before presenting for TB evaluation, making a median of 3 visits (IQR 2–5) pre-evaluation.

Table 1. Characteristics of surveyed participants.

Patient characteristics Number/median
(percentage/IQR)
Age (years) 40 (32–51)
Sex Male 25 (47)
Female 28 (53)
HIV status Positive 27 (51)
Negative 24 (45)
Unknown 2 (4)
Living Environment Rural 29 (55)
Urban-/Peri-urban 24 (45)
Mobile phone ownership Yes 35 (66)
No 18 (34)
Tracing method Mobile phone 33 (62)
Address 20 (38)
Test type used in the initial negative TB evaluation Smear Microscopy 47 (89)
Xpert MTB/Rif 6 (11)
Awareness of negative TB test result Aware 38 (72)
Not aware 15 (28)

Total number of surveyed participants = 53

Most participants were evaluated for TB with smear microscopy (n = 47, 89%); the remainder were evaluated with Xpert MTB/Rif. Twenty-eight percent were not aware of the result of their evaluation. Six participants (11.3%; 95%CI 4–23%) reported being diagnosed with TB more than 2 weeks after their negative index evaluation and had subsequently been started on anti-tuberculous therapy.

Pathways to care

Symptoms persisted for a median of 4 weeks post-evaluation (IQR 3–13) in surveyed individuals (n = 53), causing a median loss of 7 days of work (IQR 1–30). Twenty-two participants made no further visit to any health facility post-evaluation. The remaining 31 participants (58%) made a total of 83 visits to healthcare post-evaluation, a median of 2 visits each (IQR 1–3) (Fig 2). Fig 3 shows a flowchart detailing pathways to care.

Fig 2. The distribution of healthcare facility visits made by study participants after TB evaluation.

Fig 2

Fig 3. Patient pathways to care after TB evaluation.

Fig 3

Flowchart showing patient pathways to care after TB evaluation. To the right of each facility visit, coloured boxes represent the types of facilities participants visited (see Key). Numbers within the boxes represent the number of participants visiting that type of facility. Blank boxes indicate that facility type was not visited. If a participant visited a further facility, their next visit is recorded at the next step of the flow chart. If a participant did not visit a further facility, they exit the flow chart to the left of their current facility visit. CHW = Community Health Worker.

Participants spent a median of 20 minutes travelling (IQR 10–60) and 2 hours visiting (IQR 1.25–5) per facility visit. The most commonly visited facilities were private clinics or hospitals, constituting 36% of all visits made. Local pharmacies (22%) and level III or IV government health centres (23%) were also commonly visited.

Costs of healthcare seeking behaviour post-evaluation

Participants (n = 53) incurred a median of $16.46 total costs post-TB evaluation (IQR $7.07-$93.33). Direct and indirect costs represented 20% (IQR 0–68%) and 80% (IQR 32–100%) of total costs respectively. Participants lost a median of $13.17 in indirect costs (IQR $1.05-$65.84). For those who accessed healthcare post-evaluation (n = 31), direct costs were a median of $8.97 (IQR $3.40-$30.57). Out-of-pocket medical costs represented 68% (IQR 59–86%) of total direct costs.

The median cost of a facility visit was $10.19 (IQR $4.35-$28.53) (Table 2). Of the 83 visits made, medical costs occurred in 62 visits and non-medical costs in 72 visits. Purchase of medicines was the most frequent medical cost, occurring in 56 (67%) visits. In 38 visits these costs represented the only medical cost. Radiology was the most expensive type of medical cost with a median cost of $6.79. However, it was only accessed in 6 of 83 (7%) visits. Travel costs were the most common type of non-medical direct cost, incurred in 64 of 83 (77%) visits. Food costs were incurred in 32/83 visits and represented a median of 33% (IQR 24–68%) of non-medical costs when they occurred. The fraction of total direct participant expenditure represented by different cost categories is presented in Fig 4.

Table 2. Participant costs per facility visit.

Total cost per facility visit (IQR) Direct cost per facility visit (IQR) Direct medical costs per facility visit (IQR) Direct non-medical costs per facility visit (IQR) Indirect cost per facility visit (IQR)
Median cost 10.19 6.79 4.35 1.36 2.72
($ USD) (4.35–28.53) (2.58–16.30) (0–11.41) (0.54–4.07) (0–13.59)
Median cost as a percentage of mAHI (%) 0.9% 0.6% 0.4% 0.1% 0.2%
(0.4–2.4) (0.2–1.4) (0–1.0) (0.04–0.3) (0–1.2)

Costs per facility visit in absolute terms and as a percentage of median annual household income; n = 83. USD = United States Dollar, mAHI = median annual household income, IQR = interquartile range.

Fig 4. Distribution of direct costs during facility visits by study participants.

Fig 4

Direct costs incurred in 83 facility visits by the 31 study participants who returned to healthcare after TB evaluation. Slices represent the percentage of overall direct costs incurred by study participants by cost category (percentages labelled). The number of visits in which the specified cost category was accessed is also shown on the slices in brackets. The inner legend shows the median and inter-quartile range (in brackets) spent in that cost category, when accessed.

In total, 11% (95%CI 4.3–23.0%) of study participants spent >20% of AHI post-TB evaluation, incurring catastrophic costs. This amounted to 16.1% (95%CI 5.5–33.7%) of the 31 patients who accessed healthcare post-evaluation. Total financial losses were not significantly greater in those who attended healthcare post-evaluation, although they trended towards being so (median $40.61 [attended] vs $13.64 [did not attend]; p = 0.09). All participants suffering catastrophic costs experienced symptoms for more than 6 weeks post-evaluation.

Of surveyed individuals (n = 53), 66% (95%CI 51.7–78.5%) suffered dissavings post-evaluation. They incurred a median loss of $32.61 (IQR $10.87-$206.52), equivalent to 1.8% of AHI. Borrowing money was the most common form of dissaving (21/53) whilst selling assets incurred the largest median loss ($70.65, IQR $21.74-$353.26). Dissavings were significantly more common amongst participants who attended care post-evaluation (p = 0.04). However, the magnitude of dissaving did not vary between those who attended care post-evaluation and those who did not (p = 0.6). Catastrophic costs trended towards being more common in those that incurred dissavings (p = 0.07).

Discussion

Patients with chronic cough whose evaluation for TB is negative, although considered to be ‘completed’ from the perspective of National TB Programmes, remain patients with ongoing symptoms sufficiently troubling as to prompt further healthcare-seeking. More than 10% of individuals experienced financial catastrophe after negative TB evaluation without even considering costs incurred prior to or during TB evaluation. In TB patients these pre-diagnostic costs represent 48–53% of total expenditure [4]. Spending of this magnitude is sufficiently prevalent to warrant the attention of primary healthcare programs.

Despite a negative evaluation for TB, many individuals continue to search for diagnostic and therapeutic solutions. Although a significant minority did not visit any further facility, more than half did so, some many times over. These results are consistent with the likely range of aetiologies of chronic cough in this setting [13]. The sickest and hardest to diagnose patients may repeatedly access care without resolution, whilst those with self-limiting infectious illnesses require little, if any, further medical attention. However, a lack of accurate diagnostic data means this interpretation warrants further study. Visits to the private sector predominated, contributing 61% of all post-evaluation healthcare episodes. This is consistent with other studies of pathways to care in high-TB burden settings [14, 15].

Many participants experienced significant financial burden from their symptoms post-evaluation, and 11% financial catastrophe. Although this study did not include pre-evaluation costs, the authors and others have previously documented the potential for these costs to be financially catastrophic [4, 11]. Our study shows that for some, these costs do not stop after a negative test for TB. Taken together, the proportion of individuals with non-tuberculous chronic cough experiencing financial catastrophe during their diagnostic journey is likely higher than reported here. TB-negative individuals represent the majority of patients undergoing evaluation for TB. At a community level they could constitute as large a total financial burden as those with the disease. This cost burden likely reflects not only unwell and difficult-to-diagnose individuals who repeatedly access care but also the high indirect cost of seeking healthcare in this environment relative to income. The high burden of indirect costs in this study mirrors those found to occur in TB-affected households, which are characterised by lost income, inability to work and job loss [4, 1619]. The fact that 28% of participants did not return to receive the results of their TB test is further suggestion that accessing healthcare in this environment is prohibitively expensive for some. The cost of accessing healthcare in lower- and middle-income countries is known to be financially challenging for many and often leads to dissaving and other coping strategies not traditionally assessed in financial risk protection research [20].

There were several limitations to this study. Firstly, the methodology predisposes costing information to recall bias. Steps were taken to mitigate this by making survey questions as unambiguous as possible. Nevertheless, cost findings need to be interpreted with a degree of caution. Second, the study’s cross-sectional design does not allow for definitive conclusions to be drawn on causality between observed associations. Last, this study did not include costs incurred prior to evaluation, which limits the extent to which firm conclusions can be drawn regarding the total cost incurred by participants during their illness. Despite these limitations, this study focuses on a patient group that has been comparatively neglected by international health research and presents important insights into the financial implications of their health issues. The generalisability of our findings could be seen as a limitation as we purposefully did not institute complex sampling procedures to make our subjects completely representative of the population they are derived from. However, the aim of the study was to describe the situation in these areas of Uganda in order to illustrate issues that could be widespread, rather than to derive specific generalisable conclusions. Of note, rates of phone ownership in study participants are consistent with those of the general population in Uganda [21, 22].

The move towards universal health coverage (UHC), advocated by the WHO as a possible solution to catastrophic health expenditure, may help patients surmount the financial barriers to medical costs for non-TB illnesses. However, UHC-related interventions by themselves will likely not be sufficient to mitigate financial catastrophe for patients as medical costs are only one driver of total patient cost [4, 18, 23]. Parallel social protection initiatives to prevent or reduce non-medical and indirect costs are likely to be essential as these costs make up a significant proportion of patient expenditure. These initiatives have been proven to mitigate such costs in TB patients [24]. Furthermore, under the current definition of catastrophic health expenditure advocated by the WHO, these non-medical and indirect costs are excluded when assessing the financial stress on non-TB patients [10]. A definition of financial catastrophe that accounts for the important financial burdens that non-direct medical costs and indirect costs create would support identification of affected patients and allow health programs to better select and target interventions.

Conclusions

Far from avoiding the catastrophic costs incurred by many of their TB-positive counterparts, some individuals continue to experience financial catastrophe after negative TB evaluation. They may represent a larger economic burden at a community level than those suffering from similar costs due to TB and may not be captured by existing definitions of non-TB catastrophic health expenditure. A prospective longitudinal study with recruitment at the point of TB evaluation would allow more accurate cost estimation, capture of final diagnoses and allow exploration of alternative definitions of financial catastrophe and their relationship to outcomes. Furthermore, such a study could be designed to prospectively compare the costs after both a positive and negative TB evaluation from the same population. Meanwhile, more attention needs to be paid to encouraging TB-negative patients to return to the clinic that tested them to coordinate further investigative efforts.

Supporting information

S1 Table. Multivariable logistic regression of factors associated with increased odds of attending healthcare facilities after negative TB evaluation.

n = 51 for analysis (due to n = 51 known HIV status). OR = odds ratio; TB = tuberculosis. All variables found to be associated with accessing healthcare post-evaluation with a significance level of p≤0.1 in the univariate analysis were included in the multivariable analysis along with age and sex. A longer duration of symptoms after TB evaluation was associated with increased odds of attending healthcare facilities post-evaluation. Subjects living in rural settings and those with HIV infection had lower odds. Four or more healthcare attendances prior to TB evaluation trended towards association with increased odds of attendance post-evaluation but was non-significant.

(PDF)

S2 Table. Univariate logistic regression analysis comparing the unadjusted odds of attending healthcare facilities by study participants after negative TB evaluation.

n = 51 for analysis (due to n = 51 known HIV status). OR = odds ratio; TB = tuberculosis; NTLP = National Tuberculosis and Leprosy Program. Variables that demonstrated an association with a significance level of p≤0.1 were taken through to multivariable analysis along with age and sex.

(PDF)

S3 Table. Univariate linear regression analysis comparing the unadjusted total cost incurred by participants after negative TB evaluation.

n = 51 for analysis (due to n = 51 known HIV status). TB = tuberculosis; USh = Ugandan Shillings; NTLP = National Tuberculosis and Leprosy Program.

(PDF)

S1 File. Modified costing tool.

This tool was adapted from a validated costing tool used in previous work by our group [11]. No questions related to financial expenditure were added or subtracted from the original costing tool. Additional questions were added to aid in discriminating different pathways to care used by study participants.

(PDF)

S2 File. Raw data for analysis.

(XLSX)

Acknowledgments

The authors would particularly like to thank Damalie Nakkonde for her work in the field collecting and screening the data and assisting in translation of questionnaires.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

DJAM received a grant from the UK Medical Research Council (grant number MR/M017362/1; https://mrc.ukri.org/). AC received a grant from the National Heart, Lung, and Blood Institute (grant number R01HL130192 https://www.nhlbi.nih.gov/). THAS received funding from the Masters Trust Fund at the London School of Hygiene and Tropical Medicine (Project Code ITCR 082010; www.lshtm.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.WHO | WHO End TB Strategy [Internet]. WHO. World Health Organization; 2015. [cited 2018 Mar 28]. Available from: http://www.who.int/tb/post2015_strategy/en/ [Google Scholar]
  • 2.Kemp JR, Mann G, Simwaka BN, Salaniponi FM, Squire SB. Can Malawi’s poor afford free tuberculosis services? Patient and household costs associated with a tuberculosis diagnosis in Lilongwe. Bull World Health Organ. 2007. Aug;85(8):580–5. doi: 10.2471/blt.06.033167 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Laurence Y V., Griffiths UK, Vassall A. Costs to Health Services and the Patient of Treating Tuberculosis: A Systematic Literature Review. Pharmacoeconomics. 2015. Sep 5;33(9):939–55. doi: 10.1007/s40273-015-0279-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Tanimura T, Jaramillo E, Weil D, Raviglione M, Lonnroth K. Financial burden for tuberculosis patients in low- and middle-income countries: a systematic review. Eur Respir J. 2014. Jun 1;43(6):1763–75. doi: 10.1183/09031936.00193413 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Cmj M, Sudihr Annan ZR, Van E, Ke Xu by. Distribution of health payments and catastrophic expenditures Methodology. World Heal Organ. 2005; [Google Scholar]
  • 6.Hanrahan CF, Haguma P, Ochom E, Kinera I, Cobelens F, Cattamanchi A, et al. Implementation of Xpert MTB/RIF in Uganda: Missed Opportunities to Improve Diagnosis of Tuberculosis. Open forum Infect Dis. 2016. Mar;3(2):ofw068. doi: 10.1093/ofid/ofw068 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Shete PB, Nalugwa T, Farr K, Ojok C, Nantale M, Howlett P, et al. Feasibility of a streamlined tuberculosis diagnosis & treatment initiation strategy. Int J Tuberc Lung Dis. 2017;21(7):746–52. doi: 10.5588/ijtld.16.0699 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Sekandi JN, Neuhauser D, Smyth K, Whalen CC. Active case finding of undetected tuberculosis among chronic coughers in a slum setting in Kampala, Uganda. Int J Tuberc Lung Dis. 2009. Apr;13(4):508–13. [PMC free article] [PubMed] [Google Scholar]
  • 9.World Health Organization (WHO). Tuberculosis patient cost survey: a handbook. 2017. 95 p. [Google Scholar]
  • 10.WHO. World Heath Report: health systems financing—the path to universal coverage. Geneva: World Health O. 2010. [DOI] [PMC free article] [PubMed]
  • 11.Shete PB, Haguma P, Miller CR, Ochom E, Ayakaka I, Davis JL, et al. Pathways and costs of care for patients with tuberculosis symptoms in rural Uganda. Int J Tuberc Lung Dis. 2015. Aug 1;19(8):912–7. doi: 10.5588/ijtld.14.0166 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Reza TF, Nalugwa T, Farr K, Nantale M, Oyuku D, Nakaweesa A, et al. Study protocol: A cluster randomized trial to evaluate the effectiveness and implementation of onsite GeneXpert testing at community health centers in Uganda (XPEL-TB). Implement Sci. 2020. Apr 21;15(1):1–11. doi: 10.1186/s13012-020-00983-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Munyati SS, Dhoba T, Makanza ED, Mungofa S, Wellington M, Mutsvangwa J, et al. Chronic Cough in Primary Health Care Attendees, Harare, Zimbabwe: Diagnosis and Impact of HIV Infection. Clin Infect Dis. 2005. Jun 15;40(12):1818–27. doi: 10.1086/429912 [DOI] [PubMed] [Google Scholar]
  • 14.Kapoor SK, Raman AV, Sachdeva KS, Satyanarayana S. How Did the TB Patients Reach DOTS Services in Delhi? A Study of Patient Treatment Seeking Behavior. Neyrolles O, editor. PLoS One. 2012. Aug 6;7(8):e42458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Asres A, Jerene D, Deressa W. Pre- and post-diagnosis costs of tuberculosis to patients on Directly Observed Treatment Short course in districts of southwestern Ethiopia: a longitudinal study. J Health Popul Nutr. 2018. May 21;37(1):15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Ukwaja KN, Alobu I, lgwenyi C, Hopewell PC. The High Cost of Free Tuberculosis Services: Patient and Household Costs Associated with Tuberculosis Care in Ebonyi State, Nigeria. Hill PC, editor. PLoS One. 2013. Aug 27;8(8):e73134. doi: 10.1371/journal.pone.0073134 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Mudzengi D, Sweeney S, Hippner P, Kufa T, Fielding K, Grant AD, et al. The patient costs of care for those with TB and HIV: a cross-sectional study from South Africa. Health Policy Plan. 2017. Nov 1;32(suppl_4):iv48–56. doi: 10.1093/heapol/czw183 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Pedrazzoli D, Siroka A, Boccia D, Bonsu F, Nartey K, Houben R, et al. How affordable is TB care? Findings from a nationwide TB patient cost survey in Ghana. Trop Med Int Heal. 2018. Aug 1;23(8):870–8. doi: 10.1111/tmi.13085 [DOI] [PubMed] [Google Scholar]
  • 19.Foster N, Vassall A, Cleary S, Cunnama L, Churchyard G, Sinanovic E. The economic burden of TB diagnosis and treatment in South Africa. Soc Sci Med. 2015. Apr 1;130:42–50. doi: 10.1016/j.socscimed.2015.01.046 [DOI] [PubMed] [Google Scholar]
  • 20.Murphy A, Mcgowan C, Mckee M, Suhrcke M, Hanson K. Coping with healthcare costs for chronic illness in low-income and middle-income countries: a systematic literature review Coping with healthcare costs for chronic illness in low-income and middle-income countries: a systematic literature review. BMJ Global. BMJ Glob Heal. 2019;4:1475. doi: 10.1136/bmjgh-2019-001475 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Wanyama JN, Nabaggala Sarah M, Kiragga A, Owarwo NC, Seera M, Nakiyingi W, et al. High mobile phone ownership but low internet access and use among young adults attending an urban HIV clinic in Uganda. Vulnerable Child Youth Stud. 2018. Jul 3;13(3):207–20. [Google Scholar]
  • 22.Pearson AL, Mack E, Namanya J. Mobile phones and mental well-being: Initial evidence suggesting the importance of staying connected to family in rural, remote communities in Uganda. PLoS One. 2017;12(1). doi: 10.1371/journal.pone.0169819 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Lönnroth K, Glaziou P, Weil D, Floyd K, Uplekar M, Raviglione M. Beyond UHC: Monitoring Health and Social Protection Coverage in the Context of Tuberculosis Care and Prevention. PLoS Med. 2014. Sep 22;11(9):e1001693. doi: 10.1371/journal.pmed.1001693 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Wingfield T, Tovar MA, Huff D, Boccia D, Montoya R, Ramos E, et al. The economic effects of supporting tuberculosis-affected households in Peru. Eur Respir J. 2016;48(5):1396–410. doi: 10.1183/13993003.00066-2016 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Eleanor Ochodo

11 May 2021

PONE-D-21-07641

Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda

PLOS ONE

Dear Thomas Henry Ashleigh Samuels, 

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We ask you to address the minor comments raised by the peer-reviewers including comments on sampling and handling data for example. Please submit your revised manuscript by 10 June 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Eleanor Ochodo, M.D., PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. 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.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Summary of the research

The authors set out to characterize the number and type of health care providers visited by patients after a negative TB evaluation. In addition, they sought to estimate both the direct and indirect costs these patents incurred in following these pathways of care. From the participants they surveyed, the authors found that those with negative TB evaluation experience both direct and indirect costs which could be more than what those with positive TB evaluation experience. The findings showed that indirect costs accounted for most of the costs incurred. They found that more than half of the participants surveyed visited health facilities especially private ones after negative TB evaluation with some of them experiencing catastrophic costs especially those with persistent symptoms. These findings show that once someone has negative TB evaluation, that should not be the end of having contact with the person but subsequent follow up on them would be beneficial to enable them to establish the diagnosis and may help minimize the costs. The findings have also highlighted a new area which has received very little focus yet an important area to help achieve universal health coverage in low- and middle-income settings.

Strengths and limitations of the study

The manuscript is well written, easy to follow, and the findings presented clearly. The Participant tracing, the survey and ethical issues have been described clearly. The authors have acknowledged their drawbacks in sampling of the participants, recall bias, study design and generalizability of the findings. They have also highlighted they were not able to do pre-evaluation costs.

Just some minor comments as much as the authors did a convenience sampling for the participants, it is not clear how the four facilities were selected from four geographical areas of Uganda given that there are other facilities in those areas. In addition, for the six participants who reported being diagnosed with TB more than two weeks after their negative index evaluation and were on anti-tuberculous therapy, how was their data handled. More so, two of their references appear to be incomplete.

Examples and Evidence

Major Issues

No major issues

Minor issues

1. In line 87-88,” One community-level TB microscopy Centre was selected per area” can this be described further how the selection was done for instance random, systematically, convenience etc.

2. In figure 1, is it possible to key in the numbers in the participant tracing procedure to show how you ended up with the numbers you surveyed.

In the same figure please give the key for the abbreviations ‘NOK’ and ‘VHT’

3. In Table 1, please state the denominator for the proportions calculated and the units for age.

4. In line 158-160, the six participants who later turned to be positive and were on anti-TB drugs, how did you handle their data?

(i) Were they part of the 31 who visited health care post-evaluation?

(ii) If they were part of the 31, won’t their costs be different from the others who were not on anti-TB drugs?

5. In figure 4, in line 208-209 you have stated what the slices represented, which data did you use to calculate the proportions? One can easily get mixed up with proportions described in line 194 to 199.

6. In line 330, reference 7 and line 372, reference 21 they appear to be incomplete. Are they journal articles? not clear what type of references they are.

7. One of the discussion points, given that majority of those that visited health facilities, visited private health facilities could it explain the high direct medical costs per facility.

8. A suggestion in your recommendations in the conclusion: It would be helpful to do a comparative study between the costs encountered by those having positive TB evaluation and negative TB evaluation in the same population to know the magnitude in both groups.

Reviewer #2: 1. Authors have mentioned it in the limitation, but collecting information on cost incurred over past 9-10 months may have serious recall issues. Have authors tried to access some documents to verify at least the resource use?

2. I would like see more details of indirect cost estimation. How was it estimated if someone was not employed? Was it just by asking how much income they lost for healthcare faculty visit?

3. Figure 2 may not be required and can be explained in text only.

**********

6. 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: Yes: Rakesh Kumar

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Jul 16;16(7):e0253927. doi: 10.1371/journal.pone.0253927.r002

Author response to Decision Letter 0


28 May 2021

For ease of reference, the specific reviewer and editor comments and our associated replies are detailed in a table format in the document uploaded as a response to the reviewers. For ease of access, these are listed here too.

We will address reviewers points below sequentially as raised.

Reviewer 1:

Comment: Line 87-88: One community-level TB microscopy Centre was selected per area” can this be described further how the selection was done for instance random, systematically, convenience etc.

Response: The centres were selected from amongst those used in a trial to assess the efficacy of on-site GeneXpert testing in local community health centres in Uganda - https://doi.org/10.1186/s13012-020-00988-y

One centre was selected at random from each of the four pre-defined areas from those participating in the above trial. These areas were selected a priori to illustrate a wider variety of patient experience.

We have amended the methods section to make this clearer

Comment: In figure 1, is it possible to key in the numbers in the participant tracing procedure to show how you ended up with the numbers you surveyed.

In the same figure please give the key for the abbreviations ‘NOK’ and ‘VHT’

Response: Unfortunately, we do not have any more granular data than whether participants were traced by phone, in person, or not at all. This data is available from Table 1. We agree with the authors points about the abbreviations and have amended the legend of the figure.

Comment: In Table 1, please state the denominator for the proportions calculated and the units for age.

Response: We agree and have made the changes suggested by the reviewer.

Comment: In line 158-160, the six participants who later turned to be positive and were on anti-TB drugs, how did you handle their data?

(i) Were they part of the 31 who visited health care post-evaluation?

(ii) If they were part of the 31, won’t their costs be different from the others who were not on anti-TB drugs?

Response: In response to the reviewer:

1) They were part of the 31.

2) If diagnosed with TB, the subsequent healthcare visits after the visit in which that diagnosis was made were not included in this analysis as for our purposes, they constituted a completed healthcare pathway. TB medication itself is free in Uganda as it is provided by the state, but analysis beyond the point of diagnosis would have included further costs from clinic visits etc. that went beyond the scope of the study.

Comment: In figure 4, in line 208-209 you have stated what the slices represented, which data did you use to calculate the proportions? One can easily get mixed up with proportions described in line 194 to 199.

Response: In figure 4, all direct costs incurred by participants were summed, and then broken down by the type of expenditure as shown. The fraction of overall total costs represented by each type of expenditure was then calculated and is presented as the pie chart in figure 4.

We agree with the reviewer that the reference to Figure 4 in the main text is misleading in this regard as it refers to different data. We have corrected this.

Comment: In line 330, reference 7 and line 372, reference 21 they appear to be incomplete. Are they journal articles? not clear what type of references they are.

Response: It appears our referencing software had not fully completed these two references. We have corrected the issue and thank the reviewer for bringing this to our attention.

Comment: Discussion - One of the discussion points, given that majority of those that visited health facilities, visited private health facilities could it explain the high direct medical costs per facility.

Response: The reviewer makes an excellent point. In data that we have not reported in the manuscript, we found that visits to private facilities had a higher median cost than state facilities (59,000Ush for private facilities vs. 37,000Ush for a district hospital and 27,000Ush for a local health centre). However, perhaps due to the small number of participants in the study, this difference was not statistically significant. Other studies done similar populations tend to support this point.

This is unlikely to only factor at play, however. In Ugandan state-funded health facilities, medical services beyond a simple consultation, such as radiographs and medications, are often not free at the point of use and health insurance is non-existent. The reported direct medical costs are therefore likely due to more than just the type of facility attended and likely reflect the generally high out-of-pocket expenditure required in this health system.

We chose not to include these points within the discussion as there were other things we wished to explore in more detail.

Comment: Conclusions - A suggestion in your recommendations in the conclusion: It would be helpful to do a comparative study between the costs encountered by those having positive TB evaluation and negative TB evaluation in the same population to know the magnitude in both groups.

Response: We completely agree with the reviewer and have added this suggestion to the conclusion.

Reviewer 2:

Comment: Authors have mentioned it in the limitation but collecting information on cost incurred over past 9-10 months may have serious recall issues. Have authors tried to access some documents to verify at least the resource use?

Response: We agree with the reviewer that these sorts of documents would assist in validating some of the cost results to some extent. Unfortunately, in the vast majority of cases very few such documents exist, and we were not able to collect any within the limits of the study. Ideally, further prospective research needs to occur to validate cost data, as we suggest in the conclusion.

Comment: I would like see more details of indirect cost estimation. How was it estimated if someone was not employed? Was it just by asking how much income they lost for healthcare faculty visit?

Response: Indirect cost estimation was calculated as the fraction of annual reported income lost based on the number of days of work reported lost due to symptoms after TB evaluation/number of total work-days per annum. Separate data was collected asking participants how much lost income occurred due to individual healthcare visits. This was not added to the total calculated above but reported separately as per the results section. If a participant was not employed (almost always due to subsistence farming being their primary economic activity), they were asked to estimate the cost of their lost time. We also attempted to capture the economic costs to these participants by reporting dissavings in the results.

We have amended the methods to further detail how indirect cost data was calculated

Comment: Figure 2 may not be required and can be explained in text only.

Response: We agree with the reviewer that Figure 2 can be explained in text alone. However, we feel that the simplicity and clarity of the figure is a strength. Given that it remains within the overall figure limit of the paper, we would ideally prefer to keep it in the manuscript.

Attachment

Submitted filename: Response to the reviewers WWIE v1.0 20210511.docx

Decision Letter 1

Eleanor Ochodo

16 Jun 2021

Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda

PONE-D-21-07641R1

Dear Thomas Samuels,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Eleanor Ochodo

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have responded to the comments of the reviewer and made the necessary changes in the manuscript. The manuscript has been written well and the research is scientifically sound. The analysis has been done well and the findings have been presented clearly in text ,figures and tables. The authors have drawn their conclusions from their findings.

Reviewer #2: (No Response)

**********

7. 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: Yes: Rakesh Kumar

Acceptance letter

Eleanor Ochodo

7 Jul 2021

PONE-D-21-07641R1

Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda.

Dear Dr. Samuels:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Eleanor Ochodo

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Multivariable logistic regression of factors associated with increased odds of attending healthcare facilities after negative TB evaluation.

    n = 51 for analysis (due to n = 51 known HIV status). OR = odds ratio; TB = tuberculosis. All variables found to be associated with accessing healthcare post-evaluation with a significance level of p≤0.1 in the univariate analysis were included in the multivariable analysis along with age and sex. A longer duration of symptoms after TB evaluation was associated with increased odds of attending healthcare facilities post-evaluation. Subjects living in rural settings and those with HIV infection had lower odds. Four or more healthcare attendances prior to TB evaluation trended towards association with increased odds of attendance post-evaluation but was non-significant.

    (PDF)

    S2 Table. Univariate logistic regression analysis comparing the unadjusted odds of attending healthcare facilities by study participants after negative TB evaluation.

    n = 51 for analysis (due to n = 51 known HIV status). OR = odds ratio; TB = tuberculosis; NTLP = National Tuberculosis and Leprosy Program. Variables that demonstrated an association with a significance level of p≤0.1 were taken through to multivariable analysis along with age and sex.

    (PDF)

    S3 Table. Univariate linear regression analysis comparing the unadjusted total cost incurred by participants after negative TB evaluation.

    n = 51 for analysis (due to n = 51 known HIV status). TB = tuberculosis; USh = Ugandan Shillings; NTLP = National Tuberculosis and Leprosy Program.

    (PDF)

    S1 File. Modified costing tool.

    This tool was adapted from a validated costing tool used in previous work by our group [11]. No questions related to financial expenditure were added or subtracted from the original costing tool. Additional questions were added to aid in discriminating different pathways to care used by study participants.

    (PDF)

    S2 File. Raw data for analysis.

    (XLSX)

    Attachment

    Submitted filename: Response to the reviewers WWIE v1.0 20210511.docx

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.


    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES