Epidemiology of pre-cancerous cervical lesion and risk factors among adult women in Tigray, Ethiopia

Gerezgiher B Abera; Henock G Yebyo; Haftamu Hailekiros; Selam Niguse; Yibrah Berhe; Goitom Gigar; Tsehaye Asmelash; Gelila Goba

doi:10.1371/journal.pone.0280191

. 2023 Jan 6;18(1):e0280191. doi: 10.1371/journal.pone.0280191

Epidemiology of pre-cancerous cervical lesion and risk factors among adult women in Tigray, Ethiopia

Gerezgiher B Abera ^1,^*, Henock G Yebyo ², Haftamu Hailekiros ³, Selam Niguse ³, Yibrah Berhe ³, Goitom Gigar ⁴, Tsehaye Asmelash ⁵, Gelila Goba ⁶

Editor: Sebsibe Tadesse⁷

PMCID: PMC9821489 PMID: 36608041

Abstract

Background

Cervical cancer is a preventable disease if treated early, but remains the second leading cause of cancer-related mortality among women in low and middle-income countries. Data on epidemiology and risk factors in these settings are scarce. This study aimed to assess the prevalence of pre-cancerous cervical lesions and risk factors in Tigray region, Ethiopia.

Methods

A community-based, cross-sectional study was used and 900 participants were 30 recruited using multistage sampling and finally data from 883 were collected using an interviewer administered questionnaire and screening with visual inspection with ascetic acid. Data were collected using an interviewer administered questionnaire and screening with visual inspection with acetic acid from March 2016 to June 2017. Multinomial logistic regression analysis was conducted to estimate predictors.

Results

Seventy-nine (8.95%) women were positive for pre-cancer lesion and 35 (3.96%) were suspicious for cervical cancer. We used relative risk ratio (rrr) to estimate the strength of association. Divorced or widowed women had 2.5 and 4.7 times more risk of being positive and suspicious respectively, compared to single women (rrr = 2.5, 95% CI [1.13, 5.52]); (rrr = 4.69, 95% CI [1.00, 21.84]). The risk of having a suspicious result was 68% lower for women with primary education compared to those with no formal education (rrr = 0.32, 95% CI [1.00, 21.84]). History of sexually transmitted infection was associated with positive pre cancer lesion (rrr = 1.91, 95% CI [1.11, 3.27]) whereas, being farmer (rrr = 4.83, 95% CI [1.44, 16.13]), merchant (rrr = 4.85, 95% CI [1.52, 15.46]), bleeding between periods (rrr = 3.26, 95% CI [1.32, 8.04]) and pelvic or back pain (rrr = 2.79, 95% CI [1.18, 6.58]) were associated with suspicious for cancer.

Conclusion

About 8.9% and 3.96% of the women were positive for pre-cancerous cervical lesion and suspicious for cancer, respectively. The prevalence of pre-cancerous cervical lesion is high as compared to other regional prevalence in the country. Marital status, education, sexually transmitted infection, bleeding, and pelvic pain were risk factors of pre-cancerous cervical lesion’. This finding implies that the sexual exposure, having no permanent husband and being not educated attributes to the high prevalence of pre-cancerous cervical lesion and may aggravate the transmission of HPV.”

Introduction

Cervical cancer is a public health problem worldwide [1], primarily in low and middle-income countries, though data are scarce [2, 3]. The disease is fatal, but preventable if treated early [4]. The World Health Organization (WHO) indicates that cervical cancer kills an estimated 275,000 women every year and 500,000 new cases reported worldwide [1]. Cervical cancer is the second largest killer among cancer-related death of women in low-and-middle income countries (LMICs) [4]. Reports from different countries showed that the incidence of cervical cancer is high in developing countries and sexually transmitted infections (STIs), hormonal influences, genetics and participant factors (risk taking behavior, substance abuse, alcohol use) are risk factors for cervical cancer [5, 6]. In Sub-Saharan Africa, an estimated 57,000 cases of cervical cancer occurred in 2000, comprising 22.2% of all female cancers [7].

A study from India revealed that late-stages reporting of disease was common with a peak age of cervical cancer incidence from 55 to 59 years and early marriage, multiple sexual partners, multiple pregnancies, oral contraceptives, and lack of awareness were significant risk factors [8]. A study in Uganda showed that 99% of women had heard about cervical cancer and 63% believed that family planning was a cause of cervical cancer as well as 85% recognizing inter-menstrual bleeding as a symptom of cervical cancer [9]. Other studies have also revealed the burden and public health importance of cervical cancer in LMICs [10–13].

In Ethiopia, cervical cancer is the most common cause of cancer death among female cancers with an overall mortality of 70% [14]. A study in Ethiopia showed that the mean age at diagnosis with cervical cancer was 48 years [15]. In a community based cross-sectional survey conducted in Gondar, northwest Ethiopia (2010), only 31% of respondents were knowledgeable about risk factors, symptoms, treatment options, prevention and early detection measures for cervical cancer [16]. Studies from Addis Ababa, Adama and Jimma showed that women 40–49 years of age, having a history of STIs, having two or more lifetime sexual partners and contraceptive use were risk factors of the cervical pre-cancerous lesion [17–19]. Another institution based studies in Tigray revealed a prevalence of pre-cancerous cervical lesion of 6.7% and that STIs are predictors of the pre-cancerous cervical lesions [20, 21].

The Ethiopian Ministry of Health officially launched guideline for cervical cancer prevention and control in 2005, describes a “See and Treat approach” using visual inspection with acetic acid (VIA) screening and cryotherapy treatment for the reason of feasibility and affordability [22].

Although Ethiopia’s federal ministry of health (FMoH) has given priority for cervical cancer prevention and control, there is a scarcity of data related to pre-cancerous cervical lesions. Existing guidelines call for community based pre-cancerous cervical lesions epidemiology and risk factors [22]. Accordingly, this community-based research determines the prevalence and factors associated with pre-cancerous cervical lesions among adult women in Tigray, Ethiopia.

Materials and methods

Ethical consideration

The study protocol was evaluated and approved by the Research Ethics Review Committee of College of Health Sciences, Mekelle University Research and Community Service Committee (Registration number–ERC 0597/2015). Official cooperation letters were obtained from Mekelle University, Tigray Regional Health Bureau, and zonal health offices. Moreover, prior conducting the study, the purpose and objective of the study were described to the study participants and a written informed consent was obtained. The consent involves permission to disseminate the findings of the study through scientific workshop and publish in reputable journals. The study participants were told that they have full right to discontinue the study. Confidentiality and any special data security requirements were maintained and assured. The results of the screening that have a direct benefit to the health of the study participants were informed to physicians working in the nearby health facility.

Study setting and design

We conducted a community-based, cross-sectional study in Tigray, Northern Ethiopia. Data were collected from March 2016 to June 2017. The study was conducted in Tigray region, which has seven zones, 34 rural and 18 urban districts (‘Woredas’ in local name) and 763 sub-districts (‘Kebele/Tabia’ in local name). In 2017, the Tigray Region had one specialized hospital, 14 general hospitals, 22 primary hospitals, 214 health centers, and 712 health posts as well as more than 500 private health facilities.

Study population

Study participants

All adult women living in Tigray region for about six months or more were considered as a source population, and those who were voluntary and provided informed consent were study participants.

Eligibility criteria

All adult women, who were sexually active and voluntarily consented to participate were included in the study. Those with history of hysterectomy were excluded from the study.

Sample size and sampling technique

The sample size was calculated with the aim of estimating a precise population prevalence of pre-cancerous cervical lesions in the Tigray Region. As there is no baseline study of prevalence of pre-cancerious cervical lesion, we assumed a 0.5 probability of the disease, 0.05 probability of alpha testing, 80% power and design effect of 2 accounting for two-stage sampling. Previous studies, the response rate ranges from 77.1% to 98.2%, which implies a 1.8% to 2.9.9% contingency [23, 24]. We added 10% to the calculated sample size to account for non-responses, yielding a sample size of 846, which we rounded to 900 for convenience.

A multistage sampling was used to select the study subjects. Considering 40% of the 52 districts in the region, 21 of the districts which were distributed proportionally to zones were selected randomly. Since there are 315 sub-districts in the selected districts, 20% of the sub-districts (a total of 63 sub-districts) were selected randomly. Study participants were allocated proportionally to sub-districts based on the number of participants fulfilling the eligibility criteria in each sites. This was taken from the health extension workers registration book.

Recruitment process

A community mobilization exercise preceded the screening. This effort entailed training of Health Extension Workers (HEWs) from selected sub-districts. HEWs in turn oriented women in their communities. They also mobilized Women Development Army (WDA) leaders and members as well as sub-district leaders by providing brief orientations about cervical cancer as well as upcoming screening dates and locations. Grassroots mobilization was complimented by promotion on regional radio stations by the Tigray Regional Health Bureau (TRHB).

Following community mobilization, participants were invited for screening to a total of 17 primary and general hospitals in the sub districts which have cervical cancer screening cencers using visual inspection with acetic acid (VIA). As per the estimated number of expected participants, a key value of 4 was calculated. Every forth woman arriving at the hospitals following grassroots mobilization were selected and invited to participate in the study. Finally, those who fulfill the eligibility criteria were recruited as a study subject.

Data collection procedure

Women providing consent were interviewed using an interviewer administered questionnaire to obtain socio-demographic and risk-factors information, including health related behaviors and lifestyle, knowledge and attitude of cervical cancer screening, and clinical attributes.

Clinical testing was conducted by certified nurses trained by the TRHB according to the national cervical cancer prevention and control guidelines [25]. A VIA screening protocol was developed based on the national guideline. The protocol included private examination area, examination table, trained health professionals, adequate light source, sterile vaginal speculum, new examination or surgical gloves, large cotton swabs, diluted (3–5%) acetic acid, small bowl, containers with 0.5% chlorine solution, plastic bucket with a plastic bag and the steps as quality assurance system to maximize accuracy.

Pre-cancerous cervical lesion was screened using vaginal speculum examination during which providers applied diluted acetic acid to the cervix. The provider was supported by the guideline protocol of VIA screening and supervised by gynecologists available in the institutions and assigned supervisors as appropriate to assure the quality of data. Visual confirmation of color change by the naked eye was used to determine the presence or absence of lesion. The test was considered positive if a sharp, distinct, well-defined, dense (opaque/dull or oyster) Aceto-white area was present with raised margins touching the Squamo-columnar junction (SCJ). We assumed the test as negative if no or faint Aceto-white lesions and or smooth surface was present. The test was taken as suspicious for cervical cancer where clinically visible ulcerative, cauliflower like growth or ulcer, oozing, and/or bleeding on touch were observed.

The history of sexually transmited infection (STI) was determined if any one of the sign and symptoms (discharge, offensive secretion, itching, dysuria, lower abdominal pain, and fever) were present. The variable ‘history of cervical cancer screening’ was not included in our study, since most of our sites did not have the screening modality previously and we may get no participants with previous history of cervical cancer screening.

Data analysis

Data were analyzed using statistical analysis (STATA) version14. Data entry and clearance was done using descriptive analysis to check if any missing and inappropriate categories. Descriptive statistics were presented in texts and tables. The dependent variable was pre-cancerous cervical lesion’status, in which the screening result had three possible outcomes: Negative, Positive and Suspicious for VIA. A multinomial regression model was used to check the influence of socio-demographic, risk factors and reproductive health characteristics on pre-cancerous cervical lesion ‘status. Unadjusted multinomial regression was used to examine the separate bivariate relationship between each independent variables and the dependent variable. The variables with p-value < 0.05 in the unadjusted multinomial regression was considered as significant and used in the multivariable multinomial logistic regression. Relative risk ratios (rrr) were used to assess the multivariate association of the predictor variables with the dependent variable.

Results

Socio-demographic characteristics of the study participants

A total of 883 questionnaires were collected with complete information, equating to a response rate of 98.1%. More than half of the participants 496 (56.2%) came from urban districts. Mean age of participants was 35.69 years (standard deviation (SD) ±8.45, range 16–62). Among all respondents, 532 (60.2%) were married, 723 (81.9%) were Orthodox Christian, 286 (32.4%) had no formal education, 282 (31.9%) had no formal work, and 717 (81.2%) had zero to four children. Median income was Ethiopian Birr 1,500 and 515 (58.3%) women earned between Ethiopian Birr 0 and 2,000 per month [Table 1].

Table 1. Distribution of socio-demographic characteristics by pre-cancerous cervical lesion status among women of reproductive age in Tigray, (n = 883).

Socio-demographic Variables	Groups	VIA results			Total
		Negative	Positive	Suspicious	Total
		N (%)	N (%)	N (%)	N (%)
Residence	Rural	345(89.1)	28(7.2)	14(3.6)	387(43.8)
Residence	Urban	424(85.5)	51(10.3)	21(4.2)	496(56.2)
Age (yr)	15–30	257(86.5)	30(10.1)	10(3.4)	297 (33.6)
	31–45	416(87.6)	44(9.3)	15(3.2)	475 (53.8)
	> = 46	96(86.5)	5(4.5)	10(9.0)	111 (12.6)
Marital status	Single	208(92.0)	14(6.2)	4(1.8)	226(25.6)
	Married	472(88.7)	42(7.9)	18(3.4)	532(60.2)
	Divorced/Others	89(71.2)	23(18.4)	13(10.4)	125(14.2)
Religion	Orthodox	627(86.7)	64(8.9)	32(4.4)	723(81.9)
Religion	Muslim and others	142(88.8)	15(9.4)	3(1.9)	160(18.1)
Educational status	No formal education	240(83.9)	25(8.7)	21(7.3)	286(32.4)
	Primary education	325(89.0)	30(8.2)	10(2.7)	365(41.3)
	Secondary education	116(85.3)	17(12.5)	3(2.2)	136(15.4)
	Tertiary education	88(91.7)	7(7.3)	1(1.0)	96(10.9)
Occupation	Civil servant	209(93.3)	11(4.9)	4(1.8)	224(25.4)
	Farmer	141(81.5)	21(12.1)	11(6.4)	173(19.6)
	Merchant	172(84.3)	18(8.8)	14(6.9)	204(23.1)
	No formal work	247(87.6)	29(10.3)	6(2.1)	282(31.9)
Monthly income	0–2000	439(85.2)	51(9.9)	25(4.9)	515(58.3)
	2001–4000	158(86.3)	16(8.7)	9(4.9)	183(20.7)
	4001–6000	105(92.1)	8(7.0)	1(0.9)	114(12.9)
	6001–8000	16(88.9)	2(11.1)	0(0.0)	18(2.0)
	8001–10000	51(96.2)	2(3.8)	0(0.0)	53(6.0)
Parity	0–4 children	628(87.6)	67(9.3)	22(3.1)	717(81.2)
Parity	5–12 children	141(84.9)	12(7.2)	13(7.8)	166(18.79)

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Risk factors of cervical cancer

A total of 782 (88.6%) had visible SCJ. Among all the participants, 79 (8.9%) were positive for VIA, 35 (3.96%) were suspicious for cancer, and 769 (87.1%) were negative for pre-cancer lesions. Participants with positive result for VIA and suspicious for cervical cancer were linked to related medical centers for further investigation and management. Most VIA positive participants were treated with Cryotherapy in the same site, while those who are not cryothrerapy eligible and suspicious results were refered to centers having loop electro-excision procedure (LEEP) and pathology for further investigation and management. A total of 776 (87.9%) reported that their age at first sexual contact was less than 20 years. Of the total, 344 (39.0%) respondents had more than two sexual partners in their lifetime and 199 (22.5%) experienced STIs. Thirty-two (3.6%) were smokers and one-third of respondents consumed alcohol 255 (28.9%). Corticosteroids were used in 97 (11.0%) women and 199 (22.5%) where current contraceptive users. Seventy (7.9%) had a family history of CC. Out of these women, nine (12.9%) were VIA-positive. The variable HIV status was excluded from analysis, since it was filled incomplete, because some sites has no HIV testing clinic and filled as unknown, which could not be logically true to treat those sites with sites that have HIV clinic [Table 2].

Table 2. Distribution of risk factors by pre-cancerous cervical lesion status among women of reproductive age in Tigray, (n = 883).

Risk factors of cervical cancer		VIA results			Total
		Negative	Positive	Suspicious	N (%)
		N (%)	N (%)	N (%)	N (%)
Age at first sexual contact	≤ 20 years age	675(87.0)	66(8.5)	35(4.5)	776(87.9)
Age at first sexual contact	> 20 years age	94(87.9)	13(12.1)	0(0.0)	107(12.1)
Number of Sexual Partner	Only one	461(88.3)	45(8.6)	16(3.1)	522(59.1)
	Two or more	293(85.2)	33(9.6)	18(5.2)	344(39.0)
	No or unspecified	15(88.2)	1(5.9)	1(5.9)	17(1.9)
History of STI	Yes	156(78.4)	32(16.1)	11(5.5)	199(22.5)
History of STI	No	613(89.6)	47(6.9)	24(3.5)	684(77.5)
Active smoking	Yes	29(90.6)	2(6.2)	1(3.1)	32(3.6)
Active smoking	No	740(87.0)	77(9.0)	34(4.0)	851(96.4)
Alcohol consumption	Yes	232(91.0)	18(7.1)	5(2.0)	255(28.9)
Alcohol consumption	No	537(85.5)	61(9.7)	30(4.8)	628(71.1)
Chronic corticosteroids use	Yes	86(88.7)	8(8.2)	3(3.1)	97(11.0)
Chronic corticosteroids use	No	683(86.9)	71(9.0)	32(4.1)	786(89.0)
Current contraceptive use	Yes	169(84.9)	21(10.6)	9(4.5)	199(22.5)
Current contraceptive use	No	600(87.7)	58(8.5)	26(3.8)	684(77.5)
Family history of cervical cancer	Yes	60(85.7)	9(12.9)	1(1.4)	70(7.9)
Family history of cervical cancer	No	709(87.2)	70(8.6)	34(4.2)	813(92.1)

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NB: STI–sexually transmitted infection

Signs and symptoms of cervical cancer

From the study participants, 183 (20.7%) women experienced bleeding between menstruation, 94 (10.6%) experienced heavy menstruation, 176 (19.9%) experienced contact bleeding and 152 (17.2%) women experienced pain during sex. Pelvic or back pain was reported by 267 (30.2%) women [Table 3].

Table 3. Distribution of signs and symptoms by pre-cancerous cervical lesion status among women of reproductive age in Tigray, (n = 883).

Sign and symptoms and cervical cancer status		VIA results			N (%)
		Negative	Positive	Suspicious
		N (%)	N (%)	N (%)
Bleeding between menstruation	Yes	149(81.4)	16(8.7)	18(9.8)	183(20.7)
Bleeding between menstruation	No	620(88.6)	63(9.0)	17(2.4)	700(79.3)
Heavy menstruation	Yes	70(74.5)	12(12.8)	12(12.8)	94(10.6)
Heavy menstruation	No	699(88.6)	67(8.5)	23(2.9)	789(89.4)
Bleeding after menopause	Yes	78(77.2)	14(13.9)	9(8.9)	101(11.4)
Bleeding after menopause	No	691(88.4)	65(8.3)	26(3.3)	782(88.6)
Contact bleeding	Yes	143(81.2)	19(10.8)	14(8.0)	176(19.9)
Contact bleeding	No	626(88.5)	60(8.5)	21(3.0)	707(80.1)
Pain during sex	Yes	120(78.9)	23(15.1)	9(5.9)	152(17.2)
Pain during sex	No	649(88.8)	56(7.7)	26(3.6)	731(82.8)
Pelvic or back pain	Yes	213(79.8)	33(12.4)	21(7.9)	267(30.2)
Pelvic or back pain	No	556(90.3)	46(7.5)	14(2.3)	616(69.8)
Unusual vaginal discharge	Yes	239(79.9)	37(12.4)	23(7.7)	299(33.9)
Unusual vaginal discharge	No	530(90.8)	42(7.2)	12(2.1)	584(66.1)

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Factors associated with pre-cancerous cervical lesion

In the multinomial analysis “Negative result of the dependent variable was used as a base reference against the positive and suspicious results; hence the relative risk ratio (rrr) is relative to those who have negative results.

Multinomial bivariate analysis revealed that age, marital and education status, occupation, symptoms of cervical cancer, parity, STI history of partner, and lower abdominal pain were significantly associated with positive or suspicious results (p-value < 0.05). Other variables were not significantly associated with pre-cancerous cervical lesion’. The multivariate logistic regression analysis showed that marital and educational status, occupation, history of STIs, bleeding between menstruation, and pelvic or back pain were significantly associated with the presence of pre-cancerous cervical lesion’. Divorced or widowed women were 2.5 and 4.7 times more risk of being VIA-positive and suspicious respectively than single women (rrr = 2.50, 95% confidence interval (CI) [1.13, 5.52]); (rrr = 4.69, 95% CI [1.00, 21.84]). The risk of having lesions suspicious of cancer was 68% lower for women with primary education than those with no formal education (rrr = 0.32, 95% CI [1.00, 21.84]). The risk of being suspicious for cancer was 4.8 times higher among farmers (rrr = 4.83, 95% CI [1.44, 16.13]) and merchants (rrr = 4.85, 95% CI [1.52, 15.46]) than respondents with no formal work.

The risk of being VIA-positive was 90% higher for women with a history of STIs (rrr = 1.91, 95% CI [1.11, 3.27]) than their counter parts. The risk of being suspicious for cancer was 3.26 times higher for women who experienced bleeding between periods (rrr = 3.26, 95% CI [1.32, 8.04]) than their counter parts. Women with a history of pelvic or back pain were 2.7 times more likely to be suspicious for cancer (rrr = 2.79, 95% CI [1.18, 6.58]) [Table 4] than their counter parts.

Table 4. Bivariate and multivariable analysis of independent variables with pre-cancerous cervical lesion status among reproductive age women in Tigray, (n = 883).

Variables			VIA results
		Negative	Positive			Suspicious for cancer
		N(%)	N(%)	cRRR [95% CI]	aRRR [95% C.I.)	N(%)	cRRR [95% CI]	aRRR [95% C.I.)
Age	15–30	257(86.5)	30(10.1)	1	1	14(3.6)	1	1
	31–45	416(87.6)	44(9.3)	0.91 (0.56, 1.48)	0.50(0.17, 1.45)	21(4.2)	0.93(0.410, 2.09)	2.34(0.74, 7.36)
	> = 46	96(86.5)	5(4.5)	0.45(0.17, 1.18)	0.91(0.53, 1.55)	10(3.4)	2.68(1.08, 6.63) ^*	0.58(0.22, 1.55)
Marital status	Single	208(92.0)	14(6.2)	1	1	4(1.8)	1	1
	Married	472(88.7)	42(7.9)	1.32(0.71, 2.47)	0.94(0.46, 1.91)	18(3.4)	1.98(0.66, 5.93)	2.15(0.51, 8.97)
	Divorced/widowed	89(71.2)	23(18.4)	3.84(1.89, 7.80)^***	2.50(1.13, 5.52)^*	13(10.4)	7.59(2.41, 23.93)^***	4.69(1.00, 21.84)^*
Educational status	No formal education	240(83.9)	25(8.7)	1	1	21(7.3)	1	1
	Primary Education	325(89.0)	30(8.2)	0.89(0.51, 1.55)	0.78(0.41, 1.48)	10(2.7)	0.35(0.17, 0.76) ^***	0.32(0.11, 0.91)^*
	Secondary Education	116(85.3)	17(12.5)	1.41(0.73, 2.71)	1.15(0.54, 2.43)	3(2.2)	0.29(0.09, 1.01)	0.25(0.05, 1.09)
	Tertiary Education	88(91.7)	7(7.3)	0.76(0.32, 1.83)	0.84(0.29, 2.39)	1(1.0)	0.13(0.02, 0.98)^*	0.12(0.01, 1.41)
Occupation	Civil Servant	209(93.3)	11(4.9)	0.45(0.22, 0.92)^*	0.78(0.41, 1.48)	4(1.8)	0.78(0.22, 2.82)	2.67(0.48, 14.68)
	Farmer	141(81.5)	21(12.1)	1.26(0.69, 2.30)	1.15(0.54, 2.43)	11(6.4)	3.21(1.16, 8.87)^*	4.83(1.44, 16.13)^*
	Merchant	172(84.3)	18(8.8)	0.89(0.47, 1.65)	0.84(0.29, 2.39)	14(6.9)	3.35(1.26, 8.89)^*	4.85(1.52, 15.46)^**
	No formal work	247(87.6)	29(10.3)	1	1	6(2.1)	1	1
Parity	0–4 children	628(87.6)	67(9.3)	1	1	22(3.1)	1
Parity	5–12 children	141(84.9)	12(7.2)	0.79(0.42, 1.51)	0.85(0.40, 1.79)	13(7.8)	2.63(1.29, 5.35)^**	1.62(0.61, 4.25)
History of STI	Yes	156(78.4)	32(16.1)	2.67(1.65, 4.33)^***	1.91(1.11, 3.27)^*	11(5.5)	1.80(0.86, 3.75)	0.99(0.40, 2.42)
History of STI	No	613(89.6)	47(6.9)	1	1	24(3.5)	1	1
Blood between period	Yes	149(81.4)	16(8.7)	1.05(0.59, 1.88)	0.71(0.35, 1.45)	18(9.8)	4.40(2.21, 8.75)^***	3.26(1.32, 8.04)^*
Blood between period	No	620(88.6)	63(9.0)	1	1	17(2.4)	1	1
Heavy menstruation	Yes	70(74.5)	12(12.8)	1.78(0.92, 3.46)	1.23(0.55, 2.74)	12(12.8)	5.20(2.48, 10.9)^***	2.45(0.92, 6.52)
Heavy menstruation	No	699(88.6)	67(8.5)	1	1	23(2.9)	1	1
Bleeding after menopause	Yes	78(77.2)	14(13.9)	1.90 (1.02, 3.55)^*	1.25(0.57, 2.71)	9(8.9)	3.06 (1.38, 6.77) ^**	1.27(0.40, 3.99)
Bleeding after menopause	No	691(88.4)	65(8.3)	1	1	26(3.3)	1	1
Contact bleeding	Yes	143(81.2)	19(10.8)	1.38(0.80, 2.39)	0.85(.42, 1.69)	14(8.0)	2.91(1.44, 5.87)^**	0.81(0.30, 2.19)
Contact bleeding	No	626(88.5)	60(8.5)	1	1	21(3.0)	1	1
Pain during sex	Yes	120(78.9)	23(15.1)	2.22(1.31, 3.74)^**	1.39(0.70, 2.74)	9(5.9)	1.87(0.85, 4.09)	0.69(0.23, 2.01)
Pain during sex	No	649(88.8)	56(7.7)	1	1	26(3.6)	1	1
Pelvic or back pain	Yes	213(79.8)	33(12.4)	1.87(1.16, 3.00)^*	1.60(0.90, 2.85)	21(7.9)	3.91(1.95, 7.84)^***	2.79(1.18, 6.58)^*
Pelvic or back pain	No	556(90.3)	46(7.5)	1	1	14(2.3)	1	1
Unusual vagina discharge	Yes	239(79.9)	37(12.4)	1.95(1.22, 3.11)^**	1.39(0.78, 2.49)	23(7.7)	4.26 (2.08, 8.68)^***	2.22(0.91, 5.38)
Unusual vagina discharge	No	530(90.8)	42(7.2)	1	1	12(2.1)	1	1

Open in a new tab

NB: P—value < 0.001 = ***,

0.001–0. 009 = ** and

0. 010–0. 05 = * and rrr = relative risk ratio, cRRR–crude relative risk ratio, aRRR—Adjusted relative risk ratio, C.I.—Confidence Interval

Discussion

Ethiopia’s Federal Ministry of Health has prioritized cervical cancer prevention and treatment [25]; however, there is a scarcity of data related to the prevalence of pre-cancerous cervical lesions. This study explored the prevalence of pre-cancerous cervical lesions in Tigray, Northern Ethiopia.

Our study showed that 79 (8.9%) respondents were VIA-positive and 35 (3.96%) were suspicious for cervical cancer. The overall prevalence of VIA-positive was higher in this study than a study at Alameda Textile Factory in Tigray, which showed a VIA-positive rate of 6.7% [20], which may be the fact that most the workers of the textile have similar lifestyle and are living in one town of Tigray. A study at a Family Guidance Association (FGA) Clinic in Jimma, southern Ethiopia, showed that 12.9% of women were VIA-positive and 1.2% of women were suspicious for cancer [19]. Those who attend the Family Guidance Association are those who feel that they need cervical screening which could have the probability of being VIA-positive. The long time service of cervical screening at family guidances prevents the pre-cancerous lesion from progression to suspicious for cancer. Studies in Swaziland, Cameroon, and Jakarta, Indonesia, showed VIA-positive rates of 15%, 3.33%, and 4.7%, respectively [10, 11, 12]. Though most are similar, the difference might be because of the skill difference of the care providers, and type of screening used.

After adjusting for other variables, marital and educational status, occupation, history of STIs, bleeding between period, and pelvic or back pain were statistically significant risk factors for VIA-positive or suspicious for cancer.

Divorced or widowed women had a risk of being VIA-positive (p = 0.023) and being suspicious (p = 0.049) for cervical cancer than single women. A study done in Dar Es Salaam, Tanzania, showed that divorced women were more likely to be VIA positive [13], which is similar to this study. A study in Jakarta, Indonesia, revealed that the overall VIA positive rate was 4.7%; of which, 8.3% were married more than one times in their life [12]. This implies that women who have started sexual practice and have divorced, widowed or separated and or without having a permanent husband are likely to be exposed to multiple sexual partner; which increases the risk of HPV infection. HPV infection increases the risk of cervical cancer development. Increasing outreach and screening intensity to divorced, separated, and widowed women could be a simple approach to streamlining the identification and treatment of women at risk for developing cervical cancer.

Women with primary education were approximately 70% less likely to be suspicious for cervical cancer (p = 0.034) than women with no education; and education was not significantly correlated with VIA positivity. What’s more, higher education levels, including secondary and tertiary, were not significantly associated with VIA-positive or suspicious. Similar to our study, a research findings from Dar Es Salaam, showed that women with low education had odds 4.3 higher of being VIA positive [13]. Studies in Gondar, Ethiopia, and India also showed that lack of awareness on cervical cancer was a risk factor for cervical cancer [7, 16]. This might be that increasing awareness including educational level could influence individuals to prevent themselves from any risk factors of cervical cancer. Having poor knowledge on cervical cancer attributes at least the delayance of screening for cervical cancer, which gives time for the advancement of the pre-cancerous lesion to cancer.

In this study, women who are farmers and merchants in occupation had odds of 4.8 times higher of being suspicious for cervical cancer. Farmers may have less awareness of cervical cancer and lack of ability to participate in the early screening of cervical cancer. Though merchants are believed to be rich individuals, and have capacity to make health, they could also have the opportunity to visit different areas and stay out of houses. This may expose them to heightened risk due to increased chance of sexual practices that expose them to HPV.

Respondents with a history of STI had 1.91 times the risk of being VIA-positive (p = 0.018), and history of STIs were not significantly associated with suspicious results. This was similar to studies done in Addis Ababa, Adama and Alameda Textile Factory, which revealed that the history of STI was a risk factor for pre-cancerous cervical lesion [17, 18, 20]. This could be that women with STIs are more prone to aquire HPV infection, which is by far the dominant pathway for cervical cancer to initiate.

Bleeding between period and pelvic or back pain were significantly associated with suspicious cancer, which were 3.26 (p = 0.010) and 2.79 (p = 0.019) times higher risk respectively than their counter parts. This finding was similar to a study done in Uganda revealed that the participants recognized inter-menstrual bleeding as a symptom of cervical cancer [9]. This might be mainly related to suspicious for cervical cancer; as the lesion advanced, the common sign and symptom are vaginal bleeding and pain.

In this study, 8.9% of 46 years or older women were found suspicious for cervical cancer compared to approximately 9.5% of women less than 46 years of age. Age was not statistically significant. Unlike this study, a study in India revealed that women 55 to 59 years of age had the highest risk of cervical cancer [8], this was also observed in one of the studies in Ethiopian [15]. This may implies that Ethiopian women may have earlier sexual initiation than Indian women that delaying introduction and progression of the disease to pre-cancerous cervical lesion. Indian is also more developed than Ethiopia, which could has advanced screening modality and helps them prevent the development of the lesion to suspicious for cancer.

In this study, the presence of pre-cancerous cervical lesion was not associated with current contraceptive use or age at first sexual contact. Unlike to this study, the age at first sexual contact was significant risk factor for pre-cancerous cervical lesion’in a study done in Jimma [19]. Unlike to this study, a research findings done in Jakarta, Addis Ababa and Adama, Uganda, and India showed that contraceptive use was a risk factor for pre-cancerous cervical lesions [9, 8, 12, 17, 18]. Logically, long term contraceptive uses might be the risk factor for cervical cance. This could be because of the long time sexual exposure without mechanical prevention could increase the chance of HPV acquiring, which is a risk factor for cancer. Hence, it might be because of that there are no more long time contraceptive users in the study area, which is evidenced by having high fertility rate. This might be preventive to pre-cancerous cervical lesion.

Strength and limitation of the study

The primary data of pre-cancerous cervical lesion was ascertained using active VIA screening, which minimizes recall bias. Other pre-cancerous cervical lesion screening are better identify the lesion than VIA, though the methods are not available in the study sites and are expensive than VIA.

This study used cross-sectional design for ease of screening implementation, though a case control study design could better estimate the association of independent variables with the outcome variable.

This study did not include variables that have probability of being risk factors like HIV status and history of cervical cancer screening because of the absence of the services in some sites. Though the variable HIV status is common risk factor for cervical cancer in other studies, it had been removed from analysis because of some sites have no HIV testing clinics and questionnaire form those areas were filled as unknown.

Conclusion

In this study, 8.9% and 3.96% of the women were positive and suspicious for pre-cancerous cervical lesion respectively. The prevalence of pre-cancerous cervical lesion is high as compared to other regional prevalence in the country. Marital status, educational status, occupation, history of an STI, bleeding between period, and pelvic or back pain were risk factors for pre-cancerous cervical lesion. This finding implies that the sexual exposure, having no permanent husband and being not educated attributes to the high prevalence of pre-cancerous cervical lesion and may aggravate the transmission of HPV.

Recommendation

We recommend that cervical cancer prevention is better to be strengthened focusing on preventable risk factors, including exposure to sexually transmitted infections and specific vulnerable groups like divorced and widowed women. Further study of the age distribution of pre-cancerous cervical lesions is merited.

Supporting information

S1 Dataset

(XLSX)

Click here for additional data file.^{(86KB, xlsx)}

Acknowledgments

Our great appreciation goes to healthcare workers of the health facilities involved in the data collection and all study participants of the study. Moreover we would like to extend our acknowledgment for administrative and community health care workers for their support during data collection and facilitation of the project.

List of abbreviations

aRRR: Adjusted Relative Risk Ratio
cRRR: Crude Relative Risk Ratio
FMoH: Ethiopia’s federal ministry of health
HEWs: Health Extension Workers
HIC: High Income Countries
HIV: Human Immunodeficiency Virus
HPV: Human Papilloma Virus
LMICs: low-and-middle income countries
RRR: Relative Risk Ration
SCJ: Squamous-Columnar Junction
SD: Standard Deviation
STATA: STATistical Analysis
STI: Sexually Transmitted Infection
TRHB: Tigray Regional Health Bureau
VIA: Visual Inspection With Acetic acid
WDA: Women Development Army

Data Availability

All data that are used to analyze this paper are within the paper and its Supporting Information files.

Funding Statement

This project is funded by Mekelle University, Mekelle, Ethiopia and Tiray Regiona Health Bureau with the registration number of CRPO/CHS/Ext001/08/2015. “The author(s) received no any funding for this paperwork or manuscript publication from any source." “The Mekelle University and Regional Health Bureau had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

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PLoS One. doi: 10.1371/journal.pone.0280191.r001

Decision Letter 0

Joseph KB Matovu

4 Dec 2020

PONE-D-20-24267

Epidemiology of precancerous cervical lesion and risk factors among adult women in Tigray, Ethiopia

PLOS ONE

Dear Dr. Gerezgiher Buruh Abera:

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.

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Additional Editor Comments (if provided):

Editor's comments to the authors

Title: Epidemiology of precancerous cervical lesion and risk factors among adult women in Tigray, Ethiopia

1. In general, I agree that there are grammatical errors throughout the paper. I think the authors may find it helpful to consult an English Language Specialist or a native English Language speaker to edit the entire paper.

2. The covering letter is not well structured. The authors should note that this is a ‘letter’ to the Editor; as such, it should be structured as a letter, addressed to the Editor, PLoS ONE, and signed off by the corresponding author. It should be clearly dated and state why the paper should be considered by the journal.

3. The authors should write in the language of research.

* “pre-cancer lesion” – should be written as ‘precancerous lesion’

* “Divorced or widowed women had risked 2.5 and 4.7 times more likely to be positive and suspicious” – the language used: ‘…women had risked 2.5 and 4.7 times…’ is not proper research language.

* “… were associated with suspicious for cancer” – associated with suspicious for cancer is not proper English

* “Data was 95 collected from March 2016 to June 2017”. The word ‘data’ is plural; the authors should use ‘were’ after the word ‘data’

4. The authors write: ‘Data were collected using an interviewer administered questionnaire…’ What data were actually collected? This is neither provided in the abstract nor in the main text of the paper.

5. The authors write, ‘We added 10% to the calculated sample size to account for non-responses’. I don’t think it is just ‘adding’ for the sake of adding. Can the authors explain why they adjusted the sample size by 10% and not any other percentage? Can they include a citation to back this up? How was the decision to adjust the sample size by 10% reached?

6. The authors should provide a little more detail on how the multistage sampling procedures were conducted. The information provided is not sufficient to explain what exactly happened at each stage.

7. In Table 4, the authors should include n/N to guide interpretation of the findings from the bivariate and multivariable models. Besides, in principle, the primary outcome is not included in the table. So, I am surprised that Table 4 includes a column for ‘VIA result’. In my view, this inclusion points to a serious error in the way the regression models were constructed.

8. The ARRR (95%CI) column within Table 4 is not well structured. The authors should ensure that all results are visible to the reader to aid interpretation.

9. The authors should ensure that all references are written in line with the journal’s referencing style and there should be consistency in the way all the references are presented.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

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Comments to the Author

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Reviewer #1: No

Reviewer #2: Partly

**********

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

Reviewer #1: No

Reviewer #2: I Don't Know

**********

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Reviewer #1: No

Reviewer #2: No

**********

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

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Reviewer #1: No

Reviewer #2: No

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5. Review Comments to the Author

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Reviewer #1: Abstract

1. Rewrite this sentence -Divorced or widowed women had risked 2.5 and 4.7 times more 35 likely to be positive for pre-cancer lesion and suspicious, respectively, compared to single women (rrr=2.5, 95% CI [1.13, 5.52]); (rrr=4.69, 95% CI [1.00, 21.84]).

2. How is the formal education suspicious result is (rrr=0.32 below zero , and 95% CI [1.00, 21.84]) is above one? Please justify it?

3. The associated risk factor is pre-cancer lesion or/and suspicious, please clear it.

generally -the sentence is incomplete and incorrect and grammatically wrong

the analysis is wrong .

Reviewer #2: Summary: In their manuscript, Abera and colleagues present the findings of a study assessing the prevalence of precancerous cervical lesions and associated risk factors in Tigray, Ethiopia. Based on multistage sampling they recruited 900 women from the Tigray region, who then underwent visual inspection with acetic acid (VIA) and completed a questionnaire. The study question is interesting, as limited data on prevalence on cervical pre-cancer in Ethiopia are available. However, some aspects of the methodology and the results need to be clarified. Furthermore, the article would benefit from some language editing to improve comprehensibility.

Please find below specific comments for each section.

Data availability:

1. The authors state that the data are fully available and included in the manuscript. Is there an appendix with the individual patient data, or where can they be found?

Abstract:

1. In the background section the authors state that cervical cancer is the leading cause of mortality in women in LMIC. Are they referring to cancer-related mortality, or overall mortality?

2. The study aim was to assess the magnitude of precancerous lesions. May be better to use the term “prevalence” instead of “magnitude”, as magnitude could also refer to the size of the lesions.

3. In the methods part the authors state that they estimated predictors. Predictors for what?

4. The abbreviation rrr should be introduced.

5. In the conclusion, please state the implications of your findings.

Introduction:

1. Page 3, line 49: It’s important to highlight that CC is preventable only if treated early (not only detected early).

2. Page 3, line 52: Reference 5 does not fit that statement well. Rather cite Globocan?

3. Page 3, line 54: Which host factors are the authors referring to?

4. Reference 14 seems incomplete. Can this report be found online?

Methods:

1. Page 5, line 102: Why did the authors assume a cervical precancer prevalence of 50% for the sample size calculation when a previous institution-based study had found a prevalence of 6.7% in the Tigray region?

2. What were the eligibility criteria for women to participate?

3. How did the systematic random sampling work? The process should be described in more detail. Under “data collection procedure” it sounds like a convenience sample from the selected sub-districts was used.

4. Please state which variables were included in the multivariable model finally.

Results:

1. How did the authors determine the categorization of the variables, e.g. of parity (0-4. 5-12 children) and monthly income? Some of the categories contain few participants.

2. How was history of STI determined? Symptoms? Treated STI?

3. Why was history of cervical cancer screening not included as a potential predictor? It would have been interesting to see how many women had been screened previously, and whether that was associated with having cervical precancer.

4. Table 4: Please report p-values for whole variables not individual categories of variables.

Discussion:

1. Page 12, line 232: HIV status mentioned here, but not in the results section?

2. The authors should discuss the limitations of their study.

3. The discussion is mainly a comparison with results from other studies. It would be helpful if the authors could also expand on hypotheses and explanations of why certain factors may predict cervical precancer. For example, why would divorced and widowed women be at increased risk of precancer after adjustment for age? Any hypotheses?

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2023 Jan 6;18(1):e0280191. doi: 10.1371/journal.pone.0280191.r002

Author response to Decision Letter 0

1 Jun 2021

To: PLOSOne Editor-in-Chief

Subject: -Point by point response for the comments and recommendations of our reviewers

Title: “Epidemiology of precancerous cervical lesion and risk factors among adult women in Tigray, Ethiopia."

Reference: PONE-D-20-24267

Dear Editor-in-Chief

We are very grateful for the consideration of the manuscript. In accordance with the reviewers’ valuable comments and recommendations, we have revised the manuscript and we hereby submit the revised work for your consideration.

Comments from the Editor:

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

• Response: This manuscript is prepared based on the information for author format from website of PLOSOne as much as possible

• Response: based on your valuable comment, we made clarification about the recruitment procedure, mentioned under the method section of the main document.

• The eligibility criteria specify who to include in the study. As mentioned under the multistage sampling technique, areas and participants were allocated proportionally and were selected using probability sampling method. We assume that this selection approach suffice the representativeness of the study participants.

• Response: We accept the comment and written informed consent was obtained as mentioned under ethical consideration subsection of the method section.

• Responses: Since most participants were village dwellers, married and live independently, those above 15 years married and live independently were considered to sign the consent by their selves. This was mentioned in the protocol before obtaining the ethical clearance.

• Response: We agree with your concern and we can assure that we prepared the questionnaire from different literatures. We can submit our questionnaire up on request.

6. Please include a discussion of the limitations of your study in the Discussion section of your manuscript.

• Response: We accept the comment and correction was made in the main text of the discussion section.

Additional Editor Comments (if provided):

Editor's comments to the authors

Title: Epidemiology of precancerous cervical lesion and risk factors among adult women in Tigray, Ethiopia

• Response: We accept the comment and we have received a copy edit of English language from English language professional.

• Response: We accept the comment and we have made revision of the cover.

3. The authors should write in the language of research.

* “pre-cancer lesion” – should be written as ‘precancerous lesion’

* “… were associated with suspicious for cancer” – associated with suspicious for cancer is not proper English

* “Data was 95 collected from March 2016 to June 2017”. The word ‘data’ is plural; the authors should use ‘were’ after the word ‘data’

• Response: We accept the comments above and we have made corrections in the abstract and pages 5 and 12 in the main txt.

• Response: The content of the questionnaire comprises information on socio-demographic and risk-factors, including health related behaviors, lifestyle, knowledge, attitude, and clinical attributes With due resection, we can assure that it has been mentioned under data collection section, in the previous version

• Response: We accept that it needs justification. Sample size determination gives a minimum possible sample and maximizing sample size provides good representativeness, while more cot. After we determine the sample size, we assume that there will be non-respondents because of the cervical screening procedure using VIA. But we did not know how many of the recruited participants may refuse the procedure. Therefore 10% as compared to 5% would better compensate the number of non-respondents.

6. The authors should provide a little more detail on how the multistage sampling procedures were conducted. The information provided is not sufficient to explain what exactly happened at each stage.

• Response: We accept the comments and we have made corrections under the sampling technique section of the main text.

• Response: The analysis model used is multinomial logistic regression with “Negative” result as base reference. Based on your valuable recommendation, we have made correction in the format of table 4.

8. The ARRR (95%CI) column within Table 4 is not well structured. The authors should ensure that all results are visible to the reader to aid interpretation.

• Response: Based on your valuable recommendation, we have made correction in the format of table 4.

9. The authors should ensure that all references are written in line with the journal’s referencing style and there should be consistency in the way all the references are presented.

• Response: We accept the comment and all published journals are written in Vancouver style as per the PLOSOne information for authors. Reference number 23 is used in the method section page 8.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: No

Reviewer #2: Partly

________________________________________

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

Reviewer #1: No

Reviewer #2: I Don't Know

________________________________________

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

Reviewer #1: No

Reviewer #2: No

________________________________________

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

Reviewer #1: No

Reviewer #2: No

________________________________________

5. Review Comments to the Author

Reviewer #1: Abstract

• Response: We accept the comment and correction has been made under abstract and result sections.

2. How is the formal education suspicious result is (rrr=0.32 below zero , and 95% CI [1.00, 21.84]) is above one? Please justify it?

• Response: Dear/Sir/Madam, if we did not mistaken, rrr = 0.32 is for the Primary Education, while and 95% CI [1.00, 21.84] is for divorced or widowed variable. The C.I. for primary education variable with rrr = 0.32 is 0.32(0.11, 0.91), which does not include 1.

3. The associated risk factor is pre-cancer lesion or/and suspicious, please clear it.

generally -the sentence is incomplete and incorrect and grammatically wrong

the analysis is wrong .

• Response: We accept the comment and we have a concern on that VIA could not diagnose a cancer but it is good to understand that precancerous cervical lesion screening will come up with the results of negative, positive, and suspicious for cancer. In this sense, auspicious means not a cancer but pre-cancer till confirmed with diagnosis.

Please find below specific comments for each section.

Data availability:

1. The authors state that the data are fully available and included in the manuscript. Is there an appendix with the individual patient data, or where can they be found?

• Response: only data in table 1, 2, and 3 were collected in this paper. Except the identifiers (like ID), there is no additional information collected than tables 1, 2, and 3. If the format of the empty questionnaire is needed, we can upload when requested.

1. In the background section the authors state that cervical cancer is the leading cause of mortality in women in LMIC. Are they referring to cancer-related mortality, or overall mortality?

• Response: We accept the comment and correction is made in the main text

3. In the methods part the authors state that they estimated predictors. Predictors for what?

• Response: We accept the comment and it is to mention the predictors for cervical precancerous lesion.

4. The abbreviation rrr should be introduced.

• Response: The abbreviation rrr has been introduced in the “list of abbreviations” section.

5. In the conclusion, please state the implications of your findings.

• Response: We accept the comment and correction is made accordingly

Introduction:

1. Page 3, line 49: It’s important to highlight that CC is preventable only if treated early (not only detected early).

• Response: We accept the comment and correction is made under abstract and introduction sections

2. Page 3, line 52: Reference 5 does not fit that statement well. Rather cite Globocan?

• Response: We accept the comment and after checking the references, correction is made for the references

3. Page 3, line 54: Which host factors are the authors referring to?

• Response: We accept the comment and we refer the participants’ factor as the host factors.

4. Reference 14 seems incomplete. Can this report be found online?

• Response: We accept the comment and correction is made. It is an annual report filed as government document.

Methods:

• Response: In Ethiopia, VIA screening was not available for non HIV women until 2015. It was only three hospitals providing VIA screening for HIV patents in the stufdy area, Tigray. Therefore the above mentioned prevalence is for HIV patients. Moreover, the above prevalence would provide us less number of participants and it is advisable to increases sample size if affordable. Therefore, we assume increasing participants would improve the representativeness of the eligible participants

2. What were the eligibility criteria for women to participate?

• Response: It was not elaborated earlier, that all adult women, who were sexually active, voluntarily consented to participate, and those did not undergo hysterectomy were the inclusion criteria, as now mentioned in the main text.

• Response: Dear/Sir/Madam: about 3500 participants were estimated to attend the screening campaign (in fact 3866 were attending the screening campaign). Based on this source population, a key value of 4 was calculated (3500/900). Based on their arrival every forth was invited to participate in the study.

4. Please state which variables were included in the multivariable model finally.

• Response: Dear/Sir/Madam: the model variables are mentioned under the “factors associated---,” sub section, in paragraph two.

Results:

1. How did the authors determine the categorization of the variables, e.g. of parity (0-4. 5-12 children) and monthly income? Some of the categories contain few participants.

• Response: Related to the parity, in Ethiopia fertility rate is 4.4; hence we categorized those below fertility rate and above fertility rate. But for the income category, though we could merge it, in the suspicious category it is still below 5% because of the suspicious cases are few. Therefore, if it is advisable, we think it will be better to remove up on recommendation.

2. How was history of STI determined? Symptoms? Treated STI?

• Response: We determine the STI history based on items related to symptom of the infections taken from the national syndrome approach of the STI guideline.

3. Why was history of cervical cancer screening not included as a potential predictor? It would have been interesting to see how many women had been screened previously and whether that was associated with having cervical precancer.

• Response: we respect your valuable comment. First of all, there was no routine cervical screening mechanism in the country; except for HIV cases started 2011. In the absence of service, asking utilization is not logical.

4. Table 4: Please report p-values for whole variables not individual categories of variables.

• Response: We accept the concern, but this may not specify which category or level of a variable is associated with the outcome variable.

Discussion:

1. Page 12, line 232: HIV status mentioned here, but not in the results section?

• Response: We accept the comment and correction is made accordingly

2. The authors should discuss the limitations of their study.

• Response: We accept the comment and correction is made accordingly

________________________________________

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: No

Attachment

Submitted filename: Rebuttal letter - Response for the reviewers.docx

Click here for additional data file.^{(31.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0280191.r003

Decision Letter 1

Joseph KB Matovu

5 Jul 2021

PONE-D-20-24267R1

Epidemiology of Cervical Precancerous Lesion and Risk Factors Among Adult Women In Tigray, Ethiopia

PLOS ONE

Dear Dr. Abera,

Please submit your revised manuscript by August 2, 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 applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Joseph K.B. Matovu, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The authors have tried to address some of my comments but the paper still requires a lot of work before a decision can be made. I would like to request the authors to take time to think about the comments raised and try to offer appropriate responses to ALL the comments raised. We can't continue to return the same comments forever. So, the authors should look at the comments returned by reviewer No. 2 as well as myself and endeavor to fully address all the areas that were inadequately addressed. For instance, I raised issues on the grammatical errors which the authors indicated were addressed but to the contrary, the same errors as before still exist in the paper. I had a comment on the formatting of the references and requested the authors to revise them according to the journal's formatting requirements. However, the references were returned with the same errors as before. Besides, the explanation provided for adjusting the sample size by 10% is not sufficient. What is needed is to include a citation that backs up the use of this percentage. This was not done. Here are other additional comments for the authors to consider.

1. The paper STILL has many grammatical errors that would benefit from being reviewed by an English Specialist. I raised similar comments earlier but these aspects are not yet fully addressed. For instance, within the abstract, instead of writing, ‘Divorced or widowed women had risked 2.5 and 4.7 times more likely to be positive and suspicious, respectively, compared to single women…’, the authors should write: ‘Divorced or widowed women were 2.5 and 4.7 times more likely to be positive and suspicious… than single women’ The expressed: “had risked” is wrongly used. In addition, the use of ‘more likely’ begs the use of ‘than’ rather than ‘compared to’. Similar statements exist in the abstract and in the main manuscript that should be addressed.

Please also fix the following errors/issues in the abstract:

*Expand ‘rrr’ at first mention, and then abbreviate thereafter

*The word ‘In’ in the title should be changed to ‘in’, while ‘Among’ should be written as ‘among’.

*95%CI should be written in expanded form at first mention, and then abbreviate thereafter

*’…68% lower for women with primary education compared to those with no formal education’ – use ‘than’ instead of ‘compared to’.

*’…History of sexually transmitted infection was associated with positive pre-cancer lesion’ – change ‘pre-cancer lesion’ to ‘pre-cancerous cervical lesion’.

*’Seventy-nine (8.95%) women were positive for pre-cancer lesion’ – “pre-cancer lesion” should be written as ‘pre-cancerous cervical lesions’

*’…were associated with suspicious for cancer’ – rewrite as: ‘… were associated with having a suspicious cervical cancer result’

*In the title, the authors refer to ‘risk factors’ but in the conclusion, they refer to ‘predictors’. Do these two terms mean the same?

2. In the abstract, the expression: ‘A community-based cross sectional study was used…’ should be written as: ‘This was a community-based, cross-sectional study conducted among 900 women in Tigray region, Ethiopia, from --- to ----‘. In other words, the opening statement on the ‘Methods’ sub-section should tell the reader what the study design was, where the study was conducted, and when the study was done. Please note the use of the ‘comma’ after the word ‘community-based’ and the ‘hyphen’ inserted in the words ‘cross sectional’ to turn them into one word.

3. General formatting requirements. The authors should ensure that they follow the general formatting requirements of the journal. For instance, the formatting for the sections indicates how the headings and sub-headings should be formatted, etc. For instance, under the ‘Methods’ section (the authors write it as ‘Method’), this should be formatted as:

Materials and Methods (Level 1: bold type; 18pt font)

xxx

Study setting and design (Level 2: for sub-sections of major sections; Bold type, 16pt font)

4. Other corrections

*Use of abbreviations: Please ensure that ALL abbreviations are presented in expanded form at first mention in the abstract or body of the manuscript. Even if these abbreviations have been listed in the list of abbreviations at the end of the paper, this does not take away the need to expand all abbreviations at first mention.

*Line 153, page 7: ‘Data was analysed…’ Data is a plural word; so, revise as: ‘Data were analysed…’

*Lines 163-164, page 8: the authors write: ‘…ethicalclearance was obtained from mekelle university, collage of health sience research and community service commiyyee’. The word ‘ethicalclearance’ should be written as two words (ethical clearance). Names of places should always begin with a capital letter, e.g. Mekelle University… The word ‘sience’ should be edited to ‘Sciences’. This also applies to ‘collage’ which should be written as ‘College’. The word ‘commiyyee’ does not exist in English. I think the authors meant to write: ‘committee’. In general, the entire paper should be edited to address any other areas that are not included in this report. The entire sentence should be revised as follows:

‘… ethical clearance was obtained from Mekelle University College of Health Sciences Research and Community Service Committee …’

*Please note that should include the study protocol clearance numbers (e.g. Protocol#: 001/2019’) as per your country’s national research management guidelines.

*Ensure consistency in writing the word ‘pre-cancerous’. In some sections of the paper, the word is written as ‘precancerous’ while in others, it is written as ‘pre-cancerous’. Please choose one form and maintain it throughout the paper.

*Check ALL the references used against the journal’s referencing guidelines. I can see that some journal names are italicized while others are not; I can also see that the referenced paper’s title ends with a comma instead of a full stop. Other references have the journal name written in full. Please check the journal’s referencing style (https://journals.plos.org/plosone/s/submission-guidelines) and fix all the errors in the reference section. When you click on the link, scroll down and look for ‘references’. There is a table that shows you how different references should be written.

*Reference 15 reads: ‘Dye D et al., 2009) Dye D., Solomon B., Claire H., Yared T., Vanessa H., Teshome D., 384 Marion B., Anne R., (2009) Complex care systems in developing countries. Breast 385 Cancer Patient Navigation in Ethiopia 116:577–85.)’ This is an example of bad referencing style. In general, please ensure that the references are well formatted based on the journal style. Please note that:

- Where there are more than six authors, please cite three of them followed by the word ‘et al.’

- Where there are six authors or less, list all the authors.

- A reference cannot have two years of publication in the same reference, as shown in the example above

- The year of publication should come at the end, after the journal’s name

- PLoS ONE does not use the author version (Anne R., or Marion B., ...). Click on the link above for guidance on how to write authors' names in the references section.

- PLoS ONE uses abbreviated journal names. Please ensure that the journal names are abbreviated but not italicized.

5. Supplementary information. The journal requires that: “Authors can submit essential supporting files and multimedia files along with their manuscripts. All supporting information will be subject to peer review. All file types can be submitted, but files must be smaller than 20 MB in size.” I did not see any supplementary information provided. Please click on the link above and check for ‘supplementary information’. Here are examples of supplementary information that should be included:

*Data collection tools

*Dataset used during the analysis

* Please check the journal’s guidelines on how supplementary information should be formatted.

6. Additional information requested at submission: All manuscripts should carry the following sub-section (please click on the link above for guidance on how to include this sub-section):

- Authors’ contributions

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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: (No Response)

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: Summary: The comments have been incompletely addressed, and there are still numerous spelling/grammatical errors.

Please find below specific comments for each section.

Data availability:

1. Previous comment: The authors state that the data are fully available and included in the manuscript. Is there an appendix with the individual patient data, or where can they be found?

Author reply: only data in table 1, 2, and 3 were collected in this paper. Except the

identifiers (like ID), there is no additional information collected than tables 1, 2, and 3.

If the format of the empty questionnaire is needed, we can upload when requested.

Comment: Data in table 1,2, and 3 are aggregate data, not individual patient data. It is not possible to replicate the analyses with these data. Can the dataset with the individual patient data be accessed somewhere? If not, the data availability statement needs to be addressed accordingly.

Abstract:

1. Previous comment: The abbreviation rrr should be introduced.

Author reply: The abbreviation rrr has been introduced in the “list of abbreviations”

section.

Comment: All abbreviations should be introduced in the manuscript text, not only in the list of abbreviations.

2. Previous comment: In the conclusion, please state the implications of your findings.

Author reply: We accept the comment and correction is made accordingly.

Comment: What changes were made? I don’t see any in the conclusion.

Introduction:

1. Previous comment: Page 3, line 54: Which host factors are the authors referring to?

Author reply: We accept the comment and we refer the participants’ factor as the host

factors.

Comment: It is not enough to refer to participants’ factors instead of host factors. Which participant factors may be relevant?

Methods:

1. Previous comment: Page 5, line 102: Why did the authors assume a cervical precancer prevalence of 50% for the sample size calculation when a previous institution-based study had found a prevalence of 6.7% in the Tigray region?

Author reply: In Ethiopia, VIA screening was not available for non HIV women until

2015. It was only three hospitals providing VIA screening for HIV patents in the stufdy

area, Tigray. Therefore the above mentioned prevalence is for HIV patients. Moreover,

the above prevalence would provide us less number of participants and it is advisable

to increases sample size if affordable. Therefore, we assume increasing participants

would improve the representativeness of the eligible participants.

Comment: I do not understand this reply. Women living with HIV are at higher risk of developing precancerous cervical lesions. If the estimate of 6.7% stems from a study among women living with HIV, then a lower prevalence should be assumed for the reported study including HIV-negative women.

2. Previous comment: Please state which variables were included in the multivariable model finally.

Author reply: Dear/Sir/Madam: the model variables are mentioned under the “factors

associated---,” sub section, in paragraph two.

Response: From that paragraph it is not clear which variables were included in the final multivariable model. Furthermore, the authors should explain how they chose variables for inclusion in the multivariable model. This information should be given in the methods section.

3. Eligibility criteria: “all adult women” – please state an age range. Were women eligible for screening from the age of 15 already? What do the national cervical cancer screening guidelines recommend?

Results:

1. Previous comment: How was history of STI determined? Symptoms? Treated STI?

Author response: We determine the STI history based on items related to symptom of the

infections taken from the national syndrome approach of the STI guideline.

Comment: This information should be added to the manuscript.

2. Previous comment: Why was history of cervical cancer screening not included as a potential predictor? It would have been interesting to see how many women had been screened previously, and whether that was associated with having cervical precancer.

Author response: we respect your valuable comment. First of all, there was no routine

cervical screening mechanism in the country; except for HIV cases started 2011. In

the absence of service, asking utilization is not logical.

Comment: This background information should be added to the manuscript as readers may not be aware of this.

3. Table 4: For some of the variables (e.g., age) there is no reference category for aRRR. The analysis looks wrong.

4. Table 4: explanations for *, **, and *** are missing.

Discussion:

1. Previous comment: Page 12, line 232: HIV status mentioned here, but not in the results section?

Author response: We accept the comment and correction is made accordingly.

Comment: What is the correction? That HIV status is removed entirely? Does that mean that no information was available on HIV status?

2. Previous comment: The authors should discuss the limitations of their study.

Author response: We accept the comment and correction is made accordingly.

Comment: Discussion of study limitations is insufficient.

3. Previous comment: The discussion is mainly a comparison with results from other studies. It would be helpful if the authors could also expand on hypotheses and explanations of why certain factors may predict cervical precancer. For example, why would divorced and widowed women be at increased risk of precancer after adjustment for age? Any hypotheses?

Author response: We accept the comment and correction is made accordingly.

Comment: This comment has been inadequately addressed, and the discussion section is difficult to understand sometimes. E.g., “In Ethiopia, long time contraceptive users are few, which is evidenced by having high fertility rate. This may not predispose to cervical precancerious lesion.” – what does that mean? What does not predispose to precancerous cervical lesions? The discussion section needs to be restructured and improved.

**********

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: No

PLoS One. 2023 Jan 6;18(1):e0280191. doi: 10.1371/journal.pone.0280191.r004

Author response to Decision Letter 1

1 Jul 2022

Date: February 12 2022

To: PLOS ONE" plosone@plos.org

From: Gerezgiher Buruh Abera" gbamsc2002@gmail.com (PI)

Subject: Point by Point response to editor and reviewer(s).

Title Epidemiology of Pre-cancerous Cervical Lesion and Risk Factors among Adult Women in Tigray, Ethiopia

Reference PONE-D-20-24267R1

Dear/Sir/ professors: editor and reviewer:

We apologize for the late response! It is because of the internet lockdown in Tigray, North Ethiopia, due to crises. We are responding through the internet from NGOs that allow to use for publications, international projects and PhD students only. We are very grateful for the consideration of the manuscript. In accordance with the editors and reviewers’ valuable comments and recommendations, we have revised the manuscript and we are hereby submitting the revised work for your consideration. Pages referred in this letter are based on the manuscript with track change.

Additional Editor Comments (if provided):

• Response: Sorry for the inconvenience! We were not to refuse comments. To be genuine, I am not competent in English, since it is my second language. In the previous time, we provide it to colleagues in Illinois University, a native English speaker (through the last listed co-author in this manuscript, She is from Chicago), and at that time we received the copy of the language edited version. Now we tried to go through the manuscript to correct grammatical errors as much as possible based on the direction given.

• We accept the comment on the format of the reference and we tried to correct especially reference 15 based on the old version of the paper, but we could not able to Google to recheck the citation style.

• A different contingency are commonly used from 5% to up to 30% (as in trials), based on the study design. In our cross sectional study, VIA screening was used, which is among the factors that could increase nonresponse rate. Now, we had added sample references to our manuscript. Based on previous studies, response rates ranges from 77.1% (24) to 98.2%, (25). This implies a non-response rate of 1.8% to 29.9% Therefore, based on the average of the references; we assume that 10% would enough to maximize the sample size to compensate the non-response rate expected.

1. The paper STILL has many grammatical errors that would benefit from being reviewed by an English Specialist. I raised similar comments earlier but these aspects are not yet fully addressed. For instance, within the abstract, instead of writing, ‘Divorced or widowed women had risked 2.5 and 4.7 times more likely to be positive and suspicious, respectively, compared to single women…’, the authors should write: ‘Divorced or widowed women were 2.5 and 4.7 times more likely to be positive and suspicious… than single women’ The expressed: “had risked” is wrongly used. In addition, the use of ‘more likely’ begs the use of ‘than’ rather than ‘compared to’. Similar statements exist in the abstract and in the main manuscript that should be addressed.

• Response - We accept the comments and it is corrected accordingly, as it can be seen in abstract, page 2 and result sections.

Please also fix the following errors/issues in the abstract:

*Expand ‘rrr’ at first mention, and then abbreviate thereafter

*The word ‘In’ in the title should be changed to ‘in’, while ‘Among’ should be written as ‘among’.

*95%CI should be written in expanded form at first mention, and then abbreviate thereafter

*’…68% lower for women with primary education compared to those with no formal education’ – use ‘than’ instead of ‘compared to’.

*’…History of sexually transmitted infection was associated with positive pre-cancer lesion’ – change ‘pre-cancer lesion’ to ‘pre-cancerous cervical lesion’.

*’Seventy-nine (8.95%) women were positive for pre-cancer lesion’ – “pre-cancer lesion” should be written as ‘pre-cancerous cervical lesions’

*’…were associated with suspicious for cancer’ – rewrite as: ‘… were associated with having a suspicious cervical cancer result’

*In the title, the authors refer to ‘risk factors’ but in the conclusion, they refer to ‘predictors’. Do these two terms mean the same?

• Response: We accept the comment and rrr is written in expanded form (relative risk ratio) under the title of “data analysis” at last paragraph. In abstract, we prefer modification, to delete the values of regression including the rrr and represents using summarized statements. This minimizes the presentation of abstract and did not compromise the meaning, since it is already described under the result in detail.

• We accept the comment and the initial letter of ‘In’ ‘and ‘Among’ in the title has been changed to small letters.

• We accept the comment and CI is written in expanded form (confidence interval) under the title of “Factors associated with cervical screening VIA result” at first paragraph of page 12.

• We accept the comment and the ‘compared to’ has been change to “than” as can be seen under the title of “Factors associated with cervical screening VIA result” at page 12, and under abstract.

• We accept the comment and the word “pre-cancerous cervical lesion’ is used in the whole manuscript to replace all miss spelled “cervical precancerous lesion.

• We accept the comment and the meaning of ‘risk factors’ (something that contributes or indicates to illness: a features or habits, or personal history that increases the probability of disease) and ‘predictors’ (something explains what is going to happen in the future, often on the basis of present). We corrected as ‘risk factors’ as it can be seen in the conclusion section of the abstract and result titles.

2. In the abstract, the expression: ‘A community-based cross sectional study was used…’ should be written as: ‘This was a community-based, cross-sectional study conducted among 900 women in Tigray region, Ethiopia, from --- to ----‘. In other words, the opening statement on the ‘Methods’ sub-section should tell the reader what the study design was, where the study was conducted, and when the study was done. Please note the use of the ‘comma’ after the word ‘community-based’ and the ‘hyphen’ inserted in the words ‘cross sectional’ to turn them into one word.

• Response: We accept the comment and corrected accordingly, as it can be seen in the abstract

Materials and Methods (Level 1: bold type; 18pt font)

xxx

Study setting and design (Level 2: for sub-sections of major sections; Bold type, 16pt font)

• Response: We accept the comment and the titles and subtitles has been formatted as level 1 and level 2 respectively and Method has been changed to Materials and Methods.

4. Other corrections

• Response: We accept the comments, and tried to correct accordingly through the whole manuscript.

*Line 153, page 7: ‘Data was analysed…’ Data is a plural word; so, revise as: ‘Data were analysed…’

*Lines 163-164, page 8: the authors write: ‘…ethicalclearance was obtained from mekelle university, collage of health sience research and community service commiyyee’. The word ‘ethicalclearance’ should be written as two words (ethical clearance). Names of places should always begin with a capital letter, e.g. Mekelle University… The word ‘sience’ should be edited to ‘Sciences’. This also applies to ‘collage’ which should be written as ‘College’. The word ‘commiyyee’ does not exist in English. I think the authors meant to write: ‘committee’. In general, the entire paper should be edited to address any other areas that are not included in this report. The entire sentence should be revised as follows:

‘… ethical clearance was obtained from Mekelle University College of Health Sciences Research and Community Service Committee …’

• Response: We accept the comments, and it is corrected accordingly under the ‘data analysis and ethical consideration sub sections.

*Please note that should include the study protocol clearance numbers (e.g. Protocol#: 001/2019’) as per your country’s national research management guidelines.

• Response: We accept the comments, and the registration number has been included in the manuscript, under “Ethical consideration sub section.

• Response: We accept the comments, and we tried to correct throughout the manuscript accordingly.

• Response: We accept the comments. As per our understanding, some journals specify citation preference with some abbreviations (example – BMC Res Notes is for BMC research Notes e.tc.), while others not, for those journals we took as it is. Because we may miss spell it when we abbreviate ourselves. The big challenge is that I am now in Tigray, North Ethiopia where the crisis found and all way of communication are locked. I am responding this Email through NGOs, which allow us to use internet for project and PhD publication only. I am sorry to say that I could not get internet access to either research the journals or to contact my most co-authors to recheck the reference (since they are living abroad). Anyway, I had tried to address some errors as I could.

• Response: We accept the comments, and we tried to correct reference 15 in the revised manuscript by referring the old version.

In general, please ensure that the references are well formatted based on the journal style.

Please note that:

- Where there are more than six authors, please cite three of them followed by the word ‘et al.’

- Where there are six authors or less, list all the authors.

- A reference cannot have two years of publication in the same reference, as shown in the example above

- The year of publication should come at the end, after the journal’s name

- PLoS ONE does not use the author version (Anne R., or Marion B., ...). Click on the link above for guidance on how to write authors' names in the references section.

- PLoS ONE uses abbreviated journal names. Please ensure that the journal names are abbreviated but not italicized.

• Response: We accept the comments. For the name of authors in the references, it is difficult to differentiate the surname to be abbreviated, example - Amos D. Mwaka. We understand D. could be the first name. Therefore, when we use initial letter of last name first, we could mistake the first name rather than last name; for that, we prefer to use as it has been published in the journals.

*Data collection tools

*Dataset used during the analysis

* Please check the journal’s guidelines on how supplementary information should be formatted.

• Response: We accept the comments, and we had uploaded the dataset in excel used during the analysis. There is no multimedia file which did not incorporated in the analysis and all of the relevant information is included in the manuscript. Data uploaded in the form of tables are used to analyze and develop the manuscript. For the confidentiality issue, we did not upload filled questionnaires.

6. Additional information requested at submission: All manuscripts should carry the following sub-section (please click on the link above for guidance on how to include this sub-section):

- Authors’ contributions

[Note: HTML markup is below. Please do not edit.]

• Response: We accept the comments. Since it is short time allowed to use internet, we could not check the link to recheck requirements, but we used the link when we were preparing the manuscript for PLoS ONE. We understand that declaration is important and we added the declaration section as additional information including Authors’ contributions and others at the end of this manuscript above acknowledgement sub section.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

________________________________________

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

Reviewer #1: Yes

Reviewer #2: No

________________________________________

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

Reviewer #1: Yes

Reviewer #2: No

________________________________________

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

Reviewer #1: Yes

Reviewer #2: No

________________________________________

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

Reviewer #1: Yes

Reviewer #2: No

________________________________________

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: Summary: The comments have been incompletely addressed, and there are still numerous spelling/grammatical errors.

Please find below specific comments for each section.

Data availability:

1. Previous comment: The authors state that the data are fully available and included in the manuscript. Is there an appendix with the individual patient data, or where can they be found?

Author reply: only data in table 1, 2, and 3 were collected in this paper. Except the

identifiers (like ID), there is no additional information collected than tables 1, 2, and 3.

If the format of the empty questionnaire is needed, we can upload when requested.

Comment: Data in table 1, 2, and 3 are aggregate data, not individual patient data. It is not possible to replicate the analyses with these data. Can the dataset with the individual patient data be access somewhere? If not, the data availability statement needs to be addressed accordingly.

• As per your good recommendation, the data availability sub section had been added in the manuscript under declaration section, describing all data are included in the manuscript.

Abstract:

1. Previous comment: The abbreviation rrr should be introduced.

Author reply: The abbreviation rrr has been introduced in the “list of abbreviations”

section.

Comment: All abbreviations should be introduced in the manuscript text, not only in the list of abbreviations.

• Response: We accept the comment and rrr is written in expanded form (relative risk ratio) under the title of “data analysis” at last paragraph in its first use. In abstract, since the result section is better to be summary of the findings, we prefer to summarize and to delete the values of regression including the rrr. This could not change the meaning of the results.

2. Previous comment: In the conclusion, please state the implications of your findings.

Author reply: We accept the comment and correction is made accordingly.

Comment: What changes were made? I don’t see any in the conclusion.

• Response: We accept the comment and implications for the prevalence and risk factors has been specified as seen under conclusion section.

Introduction:

1. Previous comment: Page 3, line 54: Which host factors are the authors referring to?

Author reply: We accept the comment and we refer the participants’ factor as the host

factors.

Comment: It is not enough to refer to participants’ factors instead of host factors. Which participant factors may be relevant?

• Response: We understand your concern and we are referring to the life style (habits) of participants like risk taking behavior, substance abuse, alcohol use e.tc.

Methods:

Author reply: In Ethiopia, VIA screening was not available for non HIV women until

2015. It was only three hospitals providing VIA screening for HIV patents in the study

area, Tigray. Therefore the above mentioned prevalence is for HIV patients. Moreover,

the above prevalence would provide us less number of participants and it is advisable

to increases sample size if affordable. Therefore, we assume increasing participants

would improve the representativeness of the eligible participants.

• Response: Yes, this is logically true. But to initiate our study, we base on a 4 years report from the regional health bureau and PATHFINDER, Ethiopia, Sep, 2014. In the report, 111 HIV unknown status were counseled and all were screened. Based on the result found, 29(26%) were VIA +ve for pre-cancerous cervical lesion with no specified reason. Therefore, we thought that it could be more and taking the 6.7% may provide less number of samples that could not represent the region and we decide to use if there is greater prevalence. We did not find any recent community based study in the region that could give us large sample size; for that reason we consider the prevalence that can provide us maximum sample size (50%). The drawback of this may be maximizing the cost of the study.

2. Previous comment: Please state which variables were included in the multivariable model finally.

Author reply: Dear/Sir/Madam: the model variables are mentioned under the “factors

associated---,” sub section, in paragraph two.

• Response: We apologize for our previous response. As now included under the analysis sub section, the variables with p-value < 0.05 in the unadjusted multinomial regression was considered as significant and used in the multivariable multinomial logistic regression.

• Response: We understand and accept the concern. When we depend on the national guideline, it recommends 30 – 49 years old female to be eligible for screening. This manual is developed based on different developing countries. Meaning, in our set up, there are 9 years old married (starting of sexual contact). The range of 30-49 ages implies that they started sex in the least 5 (immune-compromised) to 10 years (which is at 20 years to 44 years). In our set up, it is different, (which may be 14 - 19 years); for that we can find at least 15 to 19 years old married women stayed 5 to 10 yeast after sexual initiation on the ground. Moreover, this guideline is focusing on the HPV caused cervical cancer screening. But PHV is not the only factor that can cause cervical cancer. As part of our professional activities, we had faced with 16 years old women who had advanced cervical CA. This may be caused by other factors (not HPV) that are not related to early sexual initiation. Therefore, we consider 16 to 65 years old women who are with sexual experience (at least in the last 5 years) provided that they are living independent of their family or with husband for the justification of Ethical clearance. This provides a good coverage of eligible women in the community.

Results:

1. Previous comment: How was history of STI determined? Symptoms? Treated STI?

Author response: We determine the STI history based on items related to symptom of the

infections taken from the national syndrome approach of the STI guideline.

Comment: This information should be added to the manuscript.

• Response: We accept the comment and we used - having history of STI, if any one of the S/S is present (discharge, offensive secretion, itching, dysuria, lower abdominal pain, and fever). We also added it to the manuscript at the last statement of the data collection procedure sub section.

Author response: we respect your valuable comment. First of all, there was no routine

cervical screening mechanism in the country; except for HIV cases started 2011. In

the absence of service, asking utilization is not logical.

Comment: This background information should be added to the manuscript as readers may not be aware of this.

• Response: We accept the concern, and we added it to the manuscript at the last statement of the data collection procedure sub section.

3. Table 4: For some of the variables (e.g., age) there is no reference category for aRRR. The analysis looks wrong.

• Response: We accept the concern, and 15-30 is the reference and we corrected it in the table (wrongly, last values of the category is pasted to first category in both positive and suspicious outcome variables).

4. Table 4: explanations for *, **, and *** are missing.

• Response: We accept your concern, it is included under the table as NB: P - value < 0.001 = ***, 0.001 - 0. 009 = ** and 0. 010 - 0. 05 = * and cRRR – crude relative risk ratio, aRRR - Adjusted relative risk ratio, C.I. - Confidence Interval

Discussion:

1. Previous comment: Page 12, line 232: HIV status mentioned here, but not in the results section?

Author response: We accept the comment and correction is made accordingly.

Comment: What is the correction? That HIV status is removed entirely? Does that mean that no information was available on HIV status?

• Response: At first, it was included as variable, and the statistician was used the raw data to analyze the draft result. But at that time when we evaluate the data collection process, we addressed that the collected data on the variable ‘HIV’ status was incomplete (some sites has no HIV testing clinic and filled as unknown, which could not be logically true to treat those sites with sites that have HIV clinic). Hence we agreed to discard this variable to prevent error. The problem that we included it at the first draft was because of all Co-authors did not meet in person, since they live at different countries (Addis Ababa, Mekelle - Tigray, German, and Chicago (USA).

2. Previous comment: The authors should discuss the limitations of their study.

Author response: We accept the comment and correction is made accordingly.

Comment: Discussion of study limitations is insufficient.

• Response: We accept the concern, and we have tried to incorporate more limitations as much as we can. We believe limitations beyond the study may not be explanatory for our findings.

3. Previous comment: The discussion is mainly a comparison with results from other studies. It would be helpful if the authors could also expand on hypotheses and explanations of why certain factors may predict cervical pre-cancer. For example, why would divorced and widowed women be at increased risk of precancer after adjustment for age? Any hypotheses?

Author response: We accept the comment and correction is made accordingly.

Comment: This comment has been inadequately addressed, and the discussion section is difficult to understand sometimes. E.g., “In Ethiopia, long time contraceptive users are few, which is evidenced by having high fertility rate. This may not predispose to cervical pre-cancerious lesion.” – what does that mean? What does not predispose to precancerous cervical lesions? The discussion section needs to be restructured and improved.

• Response: We accept the comment and tried to go through again to incorporate some hypothesis. It can be seen from track changes file.

________________________________________

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: No

________________________________________

In compliance with data protection regulations, you may request that we remove your personal registration details at any time. (Remove my information/details). Please contact the publication office if you have any questions.

Attachment

Submitted filename: Response to Reviewers_February - 12 - 2022.docx

Click here for additional data file.^{(43.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0280191.r005

Decision Letter 2

Sebsibe Tadesse

6 Sep 2022

PONE-D-20-24267R2Epidemiology of Pre-cancerous Cervical Lesion and Risk Factors among Adult Women n Tigray, EthiopiaPLOS ONE

Dear Dr. Gerezgiher Buruh Abera,

Please submit your revised manuscript by Oct 21 2022 11:59PM. 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 applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Sebsibe Tadesse, PhD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: (No Response)

Reviewer #4: (No Response)

**********

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

Reviewer #3: Yes

Reviewer #4: No

**********

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

Reviewer #3: Yes

Reviewer #4: I Don't Know

**********

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

Reviewer #3: No

Reviewer #4: No

**********

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

Reviewer #3: Yes

Reviewer #4: No

**********

6. Review Comments to the Author

Reviewer #3: The most recent version is much better but still needs some improvement. So I have 4 main comments:

1. Yu need to go through the attached document and see all my highlighted arts and suggestions for improvement etc. then do work on them

2. under the methods part what quality assurance measures were put in place apart from the training the nurses had? Did anyone else verify any screening findings?

3. I did not see any write up on what happened to screen positive women. You must always link screening to management so what happened?

4. the limitations part, the key issue is the limitation of VIA for finding lesions, that is important and must be stated. And should should then explain why that was used instead of more sensitive and specific screening modalities

Reviewer #4: 1. Previous comment: The abbreviation rrr should be introduced.

a. Author reply: The abbreviation rrr has been introduced in the “list of abbreviations” section.

b. Comment: All abbreviations should be introduced in the manuscript text, not only in the list of abbreviations.

c. •Response: We accept the comment and rrr is written in expanded form (relative risk ratio) under the title of “data analysis” at last paragraph in its first use. In abstract, since the result section is better to be summary of the findings, we prefer to summarize and to delete the values of regression including the rrr. This could not change the meaning of the results.

Comment on Revision 2: Results section in the abstracts do normally contain the relative risk or adjusted relative risk. I would recommend including the numerical estimates, with the appropriate introduction of the abbreviation in the abstract.

2. Previous comment: In the conclusion, please state the implications of your findings.

a. Author reply: We accept the comment and correction is made accordingly.

b. Comment: What changes were made? I don’t see any in the conclusion.

c. •Response: We accept the comment and implications for the prevalence and risk factors has been specified as seen under conclusion section.

Comment on Revision 2: I do not see any updates in the abstract’s conclusion section on implications of findings.

Introduction:

1. Previous comment: Page 3, line 54: Which host factors are the authors referring to?

a. Author reply: We accept the comment and we refer the participants’ factor as the host factors.

b. Comment: It is not enough to refer to participants’ factors instead of host factors. Which participant factors may be relevant?

c. Response: We understand your concern and we are referring to the life style (habits) of participants like risk taking behavior, substance abuse, alcohol use e.tc. Methods: 1.

Comment on Revision 2: Substance abuse, alcohol use, risk-taking behavior are not risk factors for CC, except as they would work through increase in risk for HPV or HIV. I believe an appropriate way to address this comment would include the specifically identified risk factors which include immune status and smoking.

2. Previous comment: Page 5, line 102: Why did the authors assume a cervical precancer prevalence of 50% for the sample size calculation when a previous institution-based study had found a prevalence of 6.7% in the Tigray region?

a. Author reply: In Ethiopia, VIA screening was not available for non HIV women until 2015. It was only three hospitals providing VIA screening for HIV patents in the study area, Tigray. Therefore the above mentioned prevalence is for HIV patients. Moreover, the above prevalence would provide us less number of participants and it is advisable to increases sample size if affordable. Therefore, we assume increasing participants would improve the representativeness of the eligible participants.

b. Comment: I do not understand this reply. Women living with HIV are at higher risk of developing precancerous cervical lesions. If the estimate of 6.7% stems from a study among women living with HIV, then a lower prevalence should be assumed for the reported study including HIV-negative women.

c. •Response: Yes, this is logically true. But to initiate our study, we base on a 4 years report from the regional health bureau and PATHFINDER, Ethiopia, Sep, 2014. In the report, 111 HIV unknown status were counseled and all were screened. Based on the result found, 29(26%) were VIA +ve for pre-cancerous cervical lesion with no specified reason. Therefore, we thought that it could be more and taking the 6.7% may provide less number of samples that could not represent the region and we decide to use if there is greater prevalence. We did not find any recent community based study in the region that could give us large sample size; for that reason we consider the prevalence that can provide us maximum sample size (50%). The drawback of this may be maximizing the cost of the study.

d. Comment on Revision 2: I am confused by the reply. Overestimating the prevalence of precancer would decrease the overall sample size estimate for the study, making it more feasible, but also more likely to be underpowered to show associations. There are multiple studies from East Africa which show prevalence of VIA positivity, and most are within the rates of 10-30%. As the prior reviewer suggested, using the actual estimate of 6.7% would have facilitated a more appropriate sample size calculation.

3. Previous comment: Please state which variables were included in the multivariable model finally.

a. Author reply: Dear/Sir/Madam: the model variables are mentioned under the “factors associated---,” sub section, in paragraph two.

b. Response: From that paragraph it is not clear which variables were included in the final multivariable model. Furthermore, the authors should explain how they chose variables for inclusion in the multivariable model. This information should be given in the methods section.

c. •Response: We apologize for our previous response. As now included under the analysis sub section, the variables with p-value < 0.05 in the unadjusted multinomial regression was considered as significant and used in the multivariable multinomial logistic regression.

d. Comment on Revision 2: This has been partially addressed. Did the authors use any additional assessments of fit for the final regression model?

4. 3. Eligibility criteria: “all adult women” – please state an age range. Were women eligible for screening from the age of 15 already? What do the national cervical cancer screening guidelines recommend?

a. •Response: We understand and accept the concern. When we depend on the national guideline, it recommends 30 – 49 years old female to be eligible for screening. This manual is developed based on different developing countries. Meaning, in our set up, there are 9 years old married (starting of sexual contact). The range of 30-49 ages that they started sex in the least 5 (immune-compromised) to 10 years (which is at 20 years to 44 years). In our set up, it is different, (which may be 14 - 19 years); for that we can find at least 15 to 19 years old married women stayed 5 to 10 yeast after sexual initiation on the ground. Moreover, this guideline is focusing on the HPV caused cervical cancer screening. But PHV is not the only factor that can cause cervical cancer. As part of our professional activities, we had faced with 16 years old women who had advanced cervical CA. This may be caused by other factors (not HPV) that are not related to early sexual initiation. Therefore, we consider 16 to 65 years old women who are with sexual experience (at least in the last 5 years) provided that they are living independent of their family or with husband for the justification of Ethical clearance. This provides a good coverage of eligible women in the community.

b. Comment on Revision 2: I am concerned that the authors’ state screening women 15-19 or even younger would help identify non-HPV related cervical cancer. These numbers are vanishingly low (<0.01%), and multiple studies across many settings have shown that early screening, even in the setting of early sexual debut will have more harms, and costs, than benefits.

Results:

1. Previous comment: How was history of STI determined? Symptoms? Treated STI?

a. Author response: We determine the STI history based on items related to symptom of the infections taken from the national syndrome approach of the STI guideline. Comment: This information should be added to the manuscript.

b. Response: We accept the comment and we used - having history of STI, if any one of the S/S is present (discharge, offensive secretion, itching, dysuria, lower abdominal pain, and fever). We also added it to the manuscript at the last statement of the data collection procedure sub section.

c. Comment on Revision 2: These was previously resolved

a. Author response: we respect your valuable comment. First of all, there was no routine cervical screening mechanism in the country; except for HIV cases started 2011. In the absence of service, asking utilization is not logical.

b. Comment: This background information should be added to the manuscript as readers may not be aware of this.

c. •Response: We accept the concern, and we added it to the manuscript at the last statement of the data collection procedure sub section.

d. Comment on Revision 2: This has been addressed, but I also wonder why HIV status was not included as a risk factor?

3. Table 4: For some of the variables (e.g., age) there is no reference category for aRRR. The analysis looks wrong.

a. •Response: We accept the concern, and 15-30 is the reference and we corrected it in the table (wrongly, last values of the category is pasted to first category in both positive and suspicious outcome variables).

b. This was addressed. Table 4 needs additional formatting to ensure visibility of complete variable names.

4. Table 4: explanations for *, **, and *** are missing. •Response: We accept your concern, it is included under the table as NB: P - value < 0.001 = ***, 0.001 - 0. 009 = ** and 0. 010 - 0. 05 = * and cRRR – crude relative risk ratio, aRRR - Adjusted relative risk ratio, C.I. - Confidence Interval

a. Comment on Revision 2: This has been addressed.

Discussion:

1. Previous comment: Page 12, line 232: HIV status mentioned here, but not in the results section?

a. Author response: We accept the comment and correction is made accordingly.

b. Comment: What is the correction? That HIV status is removed entirely? Does that mean that no information was available on HIV status?

c. •Response: At first, it was included as variable, and the statistician was used the raw data to analyze the draft result. But at that time when we evaluate the data collection process, we addressed that the collected data on the variable ‘HIV’ status was incomplete (some sites has no HIV testing clinic and filled as unknown, which could not be logically true to treat those sites with sites that have HIV clinic). Hence we agreed to discard this variable to prevent error. The problem that we included it at the first draft was because of all Co-authors did not meet in person, since they live at different countries (Addis Ababa, Mekelle - Tigray, German, and Chicago (USA).

d. Comment on Revision 2: This absence and reason for the absence of this important variable needs to be addressed,

2. Previous comment: The authors should discuss the limitations of their study.

a. Author response: We accept the comment and correction is made accordingly.

b. Comment: Discussion of study limitations is insufficient.

c. •Response: We accept the concern, and we have tried to incorporate more limitations as much as we can. We believe limitations beyond the study may not be explanatory for our findings.

d. Comment on Revision 2: This is still underdeveloped. This would be a place to include limitations on data for follow-up (VIA is a proxy for precancer and cancer), and lack of data on HIV status.

3. Previous comment: The discussion is mainly a comparison with results from other studies. It would be helpful if the authors could also expand on hypotheses and explanations of why certain factors may predict cervical pre-cancer. For example, why would divorced and widowed women be at increased risk of precancer after adjustment for age? Any hypotheses?

a. Author response: We accept the comment and correction is made accordingly. Comment: This comment has been inadequately addressed, and the discussion section is difficult to understand sometimes. E.g., “In Ethiopia, long time contraceptive users are few, which is evidenced by having high fertility rate. This may not predispose to cervical pre-cancerious lesion.” – what does that mean? What does not predispose to precancerous cervical lesions? The discussion section needs to be restructured and improved.

b. •Response: We accept the comment and tried to go through again to incorporate some hypothesis. It can be seen from track changes file.

c. Comment on Revision 2: I feel like this comment has still not been appropriately addressed. The discussion still reads as a list of comparisons, rather than an exploration of the reasons for these differences. Major restructuring would improve this section. The conclusions sections does not make sense either—cervical cancer prevention through “preventable risk factors” is not as effective as through HPV testing and vaccination. I don’t think study of the age distribution of pre-cancerous lesions makes as much sense as study of the relationship between VIA and diagnosis of pre-cancer or cancer.

**********

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 #3: No

Reviewer #4: No

**********

Attachment

Submitted filename: PONE-D-20-24267_R2_reviewer comments 08-22.pdf

Click here for additional data file.^{(3.1MB, pdf)}

PLoS One. 2023 Jan 6;18(1):e0280191. doi: 10.1371/journal.pone.0280191.r006

Author response to Decision Letter 2

7 Dec 2022

Date: September 14_2022

To: PLOS ONE" plosone@plos.org

From: Gerezgiher Buruh Abera" gbamsc2002@gmail.com (PI)

Subject: Point by Point response to editor and reviewer(s).

Title Epidemiology of Cervical Precancerous Lesion and Risk Factors Among Adult Women In Tigray, Ethiopia

Reference PONE-D-20-24267R2

Dear/Sir/ professors: editor and reviewers:

Thank you for your constructive and supportive comments. We are very grateful for the consideration of the manuscript. In accordance with the editors and reviewers’ valuable comments and recommendations, we have revised the manuscript and we are hereby submitting the revised work for your consideration.

Reviewers' comments:

Reviewer's Responses to Questions

Reviewer #3: (No Response)

Reviewer #4: (No Response)

________________________________________

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

Reviewer #3: Yes

Reviewer #4: No

________________________________________

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

Reviewer #3: Yes

Reviewer #4: I Don't Know

________________________________________

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

Reviewer #3: No

Reviewer #4: No

________________________________________

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

Reviewer #3: Yes

Reviewer #4: No

________________________________________

6. Review Comments to the Author

Reviewer #3:

The most recent version is much better but still needs some improvement. So I have 4 main comments:

1. Yu need to go through the attached document and see all my highlighted arts and suggestions for improvement etc. then do work on them.

• Response: Thank you for detail comments on the attachment. We went through the attached pdf and tried to address comments highlighted. We accept all comments and that help us to made more correction in the manuscript.

2. Under the methods part what quality assurance measures were put in place apart from the training the nurses had? Did anyone else verify any screening findings?

• Response: We accept the comment and the provider was supported by the guideline protocol of VIA screening and supervised by gynecologists and assigned supervisors available in the institutions as appropriate to assure the quality of data collection. We include the quality steps in the main text as well.

3. I did not see any write up on what happened to screen positive women. You must always link screening to management so what happened?

• Response: We accept your comment and each client with positive or suspicious result was liked to related medical centers for further investigation and/or management. Most data collection sites have at least Cryotherapy for management and Gynecologic algorithm was used to follow clients with certain sign of pre-cancerous lesion. This is also added in the main text under the “Risk factors of cervical cancer:” subsection at page 11.

4. The limitations part, the key issue is the limitation of VIA for finding lesions, that is important and must be stated. And should then explain why that was used instead of more sensitive and specific screening modalities

• Response: We accept your comment and we added that other cervical screening are better identify pre-cancerous lesion, though the methods are not available in the study sites and are expensive than VIA.

Reviewer #4:

1. Previous comment: The abbreviation rrr should be introduced.

a. Author reply: The abbreviation rrr has been introduced in the “list of abbreviations” section.

b. Comment: All abbreviations should be introduced in the manuscript text, not only in the list of abbreviations.

Comment on Revision 2: Results sections in the abstracts do normally contain the relative risk or adjusted relative risk. I would recommend including the numerical estimates, with the appropriate introduction of the abbreviation in the abstract.

• Response: We accept the comment and effects size estimations are included in the abstract with introduction of the rrr. We introduced the rrr in the abstract, under subsection “Factors associated with pre-cancerous Cervical Lesion) of page 12 and as footnote of table 4.

2. Previous comment: In the conclusion, please state the implications of your findings.

a. Author reply: We accept the comment and correction is made accordingly.

b. Comment: What changes were made? I don’t see any in the conclusion.

c. •Response: We accept the comment and implications for the prevalence and risk factors have been specified as seen under conclusion section.

Comment on Revision 2: I do not see any updates in the abstract’s conclusion section on implications of findings.

• Response: We accept the comment and sorry for that we missed correcting in the abstract, now we added the statement as “The prevalence of pre-cancerous cervical lesion is high as compared to other regional prevalence in the country. This finding implies that the sexual exposure, having no permanent husband and being not educated attributes to the high prevalence of pre-cancerous cervical lesion and may aggravate the transmission of HPV.”

Introduction:

1. Previous comment: Page 3, line 54: Which host factors are the authors referring to?

a. Author reply: We accept the comment and we refer the participants’ factor as the host factors.

b. Comment: It is not enough to refer to participants’ factors instead of host factors. Which participant factors may be relevant?

c. Response: We understand your concern and we are referring to the life style (habits) of participants like risk taking behavior, substance abuse, alcohol use e.tc. Methods: 1.

• Response: Dear/Sir, sorry for confusing you about our response statements, as per the Ethiopian cervical cancer prevention and control guideline, we tried to see if similar risk factors found in different researches. The ‘host factor” is mentioned in other studies as reference 5 and 6, but it is not ass variable of our study. There are many associated factors in different studies, example: risk taking behavior like sex without condom use, substance use including alcohol use or smoking and exposing to STI as risk factors for cervical cancer. Therefore we are referring to those factors as participant’s risk factors to unsafe sex and exposing to HPV, as HPV is prevalent STI. HPV is most common cause of cervical cancer. Hence those participants’ factors could have association with cervical cancer.

2. Previous comment: Page 5, line 102: Why did the authors assume a cervical pre-cancer prevalence of 50% for the sample size calculation when a previous institution-based study had found a prevalence of 6.7% in the Tigray region?

a. Author reply: In Ethiopia, VIA screening was not available for non HIV women until 2015. It was only three hospitals providing VIA screening for HIV patents in the study area previously, Tigray. Therefore the above mentioned prevalence is for HIV patients. Moreover, the above prevalence would provide us less number of participants and it is advisable to increases sample size if affordable. Therefore, we assume increasing participants would improve the representativeness of the eligible participants.

c. •Response: Yes, this is logically true. But to initiate our study, we base on a 4 years report from the regional health bureau and PATHFINDER Ethiopia, Sep, 2014. In the report, 111 HIV unknown status were counseled and all were screened. Based on the result found, 29(26%) were VIA +ve for pre-cancerous cervical lesion with no specified reason. Therefore, we thought that it could be more and taking the 6.7% may provide less number of samples that could not represent the region and we decide to use if there is greater prevalence. We did not find any recent community based study in the region that could give us large sample size; for that reason we consider the prevalence that can provide us maximum sample size (50%). The drawback of this may be maximizing the cost of the study.

• Response: We accept that it was good if the prevalence of cervical cancer among the HIV cases based screening to be used to calculate the sample size. The contextual differences between countries make us not to use other countries prevalence. We were standing on the fact that it could be good if all the communities included in the study, hence increasing participants would increase the power of the study. Because a prevalence cold give us minimum possible sample size, provided that maximizing is promoted. Besides, in the absence of prevalence among HIV unknown stats, in the study area, 50% is an alternative.

Three options are commonly used to determine sample size; the survey based, pre-existing study, and 50%. Therefore, at the conception of this project, we agreed to use 50%, as other alternative was not convenient. Being at this stage of the manuscript, we are happy if we get recommendation on the sample determination modification, but we believe it is difficult to modify the proportion size at this stage.

3. Previous comment: Please state which variables were included in the multivariable model finally.

a. Author reply: Dear/Sir/Madam: the model variables are mentioned under the “factors associated,” sub section, in paragraph two.

d. Comment on Revision 2: This has been partially addressed. Did the authors use any additional assessments of fit for the final regression model?

• Response: Variables like age, marital and education status, occupation, symptoms of cervical cancer, parity, STI history of partner, and lower abdominal pain were included in the multivariate analysis. Those variables were selected based on the p-value < 0.05 in the unadjusted multinomial regression. No other tests were used to select the model variables.

a. • Response: We understand and accept the concern. When we depend on the national guideline, it recommends 30 – 49 years old female to be eligible for screening. This manual is developed based on different developing countries. Meaning, in our set up, there are 9 years old married (starting of sexual contact). The range of 30-49 ages that they started sex in the least 5 (immune-compromised) to 10 years (which is at 20 years to 44 years). In our set up, it is different, (which may be 14 - 19 years); for that we can find at least 15 to 19 years old married women stayed 5 to 10 yeast after sexual initiation on the ground. Moreover, this guideline is focusing on the HPV caused cervical cancer screening. But PHV is not the only factor that can cause cervical cancer. As part of our professional activities, we had faced with 16 years old women who had advanced cervical CA. This may be caused by other factors (not HPV) that are not related to early sexual initiation. Therefore, we consider 16 to 65 years old women who are with sexual experience (at least in the last 5 years) provided that they are living independent of their family or with husband for the justification of Ethical clearance. This provides a good coverage of eligible women in the community.

• Response: We accept your concern, but as per our senior gynecologists (member of the research) recommendation, we based on the community marital status and accepted as participants if they are married and had at least child, being in the age of 16 and above.

Results:

1. Previous comment: How was history of STI determined? Symptoms? Treated STI?

a. Author response: We determine the STI history based on items related to symptom of the infections taken from the national syndrome approach of the STI guideline.

Comment: This information should be added to the manuscript.

c. Comment on Revision 2: These was previously resolved

• Response: Thank you for helping us to address the above mentioned statement in the manuscript.

b. Comment: This background information should be added to the manuscript as readers may not be aware of this.

c. •Response: We accept the concern, and we added it to the manuscript at the last statement of the data collection procedure sub section.

d. Comment on Revision 2: This has been addressed, but I also wonder why HIV status was not included as a risk factor?

• We accept the comment and the variable HIV status was included in our questionnaire, but excluded from analysis, because it was filled incomplete, since some sites has no HIV testing clinic and filled as unknown, which could not be logically true to treat those sites with sites that have HIV clinic. This has been added in the text at page 11 above table 2.

3. Table 4: For some of the variables (e.g., age) there is no reference category for aRRR. The analysis looks wrong.

b. This was addressed. Table 4 needs additional formatting to ensure visibility of complete variable names.

• Thank you for making us to see the table again, we tried to make the values visible by stretching the table space especially in the clean manuscript.

4. Table 4: explanations for *, **, and *** are missing.

•Response: We accept your concern, it is included under the table as NB: P - value < 0.001 = ***, 0.001 - 0. 009 = ** and 0. 010 - 0. 05 = * and cRRR – crude relative risk ratio, aRRR - Adjusted relative risk ratio, C.I. - Confidence Interval

a. Comment on Revision 2: This has been addressed.

• Thank you for confirmation of the response, your comment makes us to see our manuscript in different view.

Discussion:

1. Previous comment: Page 12, line 232: HIV status mentioned here, but not in the results section?

a. Author response: We accept the comment and correction is made accordingly.

b. Comment: What is the correction? That HIV status is removed entirely? Does that mean that no information was available on HIV status?

d. Comment on Revision 2: This absence and reason for the absence of this important variable needs to be addressed,

• Response: We accept the comment and we added the reason of removal of the “HIV status” variable under “risk factors of cervical cancer” subsection at last paragraph of page 11 above table 2, as follows “the variable HIV status was excluded from analysis, since it was filled incomplete, because some sites has no HIV testing clinic”, which is illogical to treat sites that has no HIV testing with those that has testing centers.

2. Previous comment: The authors should discuss the limitations of their study.

a. Author response: We accept the comment and correction is made accordingly.

b. Comment: Discussion of study limitations is insufficient.

c. •Response: We accept the concern, and we have tried to incorporate more limitations as much as we can. We believe limitations beyond the study may not be explanatory for our findings.

d. Comment on Revision 2: This is still underdeveloped. This would be a place to include limitations on data for follow-up (VIA is a proxy for pre-cancer and cancer), and lack of data on HIV status.

• Response: Thank you for helping us to see the limitation again. We tried to add the missed variables, used design and screening method other than VIA as limitation in the main text.

3. Previous comment: The discussion is mainly a comparison with results from other studies. It would be helpful if the authors could also expand on hypotheses and explanations of why certain factors may predict cervical pre-cancer. For example, why would divorced and widowed women be at increased risk of precancer after adjustment for age? Any hypotheses?

a. Author response: We accept the comment and correction is made accordingly.

Comment: This comment has been inadequately addressed, and the discussion section is difficult to understand sometimes. E.g., “In Ethiopia, long time contraceptive users are few, which is evidenced by having high fertility rate. This may not predispose to cervical pre-cancerious lesion.” – What does that mean? What does not predispose to precancerous cervical lesions? The discussion section needs to be restructured and improved.

b. •Response: We accept the comment and tried to go through again to incorporate some hypothesis. It can be seen from track changes file.

• We accept and agreed with your comments. We tried still to synthesis and justify the findings in the discussion part as can be seen from the track change of the manuscript. Or limitation is that we have no internet right now to find backgrounds of cited countries for justification and comparison of the other studies. It is a fact that HPV testing and vaccination is effective to prevent cervical cancer than doing on risk factors, but, it is not available in our setup and dealing with the absence of the service may not give meaning. The preventable risk factors could be in the capacity of poor countries like our country Ethiopia. In research findings, contraceptive use is mentioned as associated factors for cervical cancer. This could be because of the long term use of contraceptive example pills, expose them to STI, including HPV. This has been added to the main text

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PLoS One. doi: 10.1371/journal.pone.0280191.r007

Decision Letter 3

Sebsibe Tadesse

22 Dec 2022

Epidemiology of Pre-cancerous Cervical Lesion and Risk Factors among Adult Women in Tigray, Ethiopia

PONE-D-20-24267R3

Dear Dr. Gerezgiher Buruh Abera,

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.

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Academic Editor

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PLoS One. doi: 10.1371/journal.pone.0280191.r008

Acceptance letter

Sebsibe Tadesse

29 Dec 2022

PONE-D-20-24267R3

Epidemiology of Pre-cancerous Cervical Lesion and Risk Factors among Adult Women n Tigray, Ethiopia

Dear Dr. Abera:

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.

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Data Availability Statement

All data that are used to analyze this paper are within the paper and its Supporting Information files.

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PERMALINK

Epidemiology of pre-cancerous cervical lesion and risk factors among adult women in Tigray, Ethiopia

Gerezgiher B Abera

Henock G Yebyo

Haftamu Hailekiros

Selam Niguse

Yibrah Berhe

Goitom Gigar

Tsehaye Asmelash

Gelila Goba

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Materials and methods

Ethical consideration

Study setting and design

Study population

Study participants

Eligibility criteria

Sample size and sampling technique

Recruitment process

Data collection procedure

Data analysis

Results

Socio-demographic characteristics of the study participants

Table 1. Distribution of socio-demographic characteristics by pre-cancerous cervical lesion status among women of reproductive age in Tigray, (n = 883).

Risk factors of cervical cancer

Table 2. Distribution of risk factors by pre-cancerous cervical lesion status among women of reproductive age in Tigray, (n = 883).

Signs and symptoms of cervical cancer

Table 3. Distribution of signs and symptoms by pre-cancerous cervical lesion status among women of reproductive age in Tigray, (n = 883).

Factors associated with pre-cancerous cervical lesion

Table 4. Bivariate and multivariable analysis of independent variables with pre-cancerous cervical lesion status among reproductive age women in Tigray, (n = 883).

Discussion

Strength and limitation of the study

Conclusion

Recommendation

Supporting information

Acknowledgments

List of abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Joseph KB Matovu

Roles

Author response to Decision Letter 0

Decision Letter 1

Joseph KB Matovu

Roles

Author response to Decision Letter 1

Decision Letter 2

Sebsibe Tadesse

Roles

Author response to Decision Letter 2

Decision Letter 3

Sebsibe Tadesse

Roles

Acceptance letter

Sebsibe Tadesse

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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