USE OF MOBILE TELEMEDICINE FOR CERVICAL USE OF MOBILE TELEMEDICINE FOR CERVICAL CANCER SCREENING CANCER SCREENING

Kelly E Quinley*, Rachel H Gormley†, Sarah J Ratcliffe‡, Ting Shih§, Zsofia Szep**, Ann Steiner††, Doreen Ramogola Masire‡‡ and Carrie L Kovarik†

*University of Pennsylvania School of Medicine, Philadelphia, USA; †Department of Dermatology, University of Pennsylvania Medical Center, Philadelphia, USA; ‡Department of Biostatistics and Epidemiology, CFAR Biostatistics Core, University of Pennsylvania School of Medicine, USA; §Click Diagnostics, Boston, Massachusetts, USA; **Department of Medicine, Division of

Infectious Diseases, University of Pennsylvania Medical Center, Philadelphia, USA; ††Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, USA; ‡‡Botswana-UPenn Partnership, Women’s Health Initiative, Gaborone, Botswana

Nurse PIA vs. Expert PIA for the 62 subjects whose PIA photographs were sufficient for interpretation by the expert gynecologist and who received readings by the nurse midwives

AbstractVisual inspection of the cervix with application of 4% acetic acid (VIA) is an inexpensive alternative to cytology-based screening in resource-limited areas, such as in many developing countries. We examined the diagnostic agreement between off-site (remote) expert diagnosis using photographs of the cervix (photographic inspection with acetic acid, PIA) and in-person VIA. The images for remote evaluation were taken with a mobile phone and transmitted to a database by MMS. The study population consisted of 95 HIV-positive women in Gaborone, Botswana. An expert gynecologist made a definitive positive or negative reading on the PIA results of 64 out of the 95 women whose PIA images were also read by the nurse midwives. For these images, positive nurse PIA readings were concordant with the positive expert PIA readings in 82% of cases, and the negative PIA readings between the two groups were fully concordant in 89% of cases. These results suggest that mobile telemedicine may be useful in improving access of women in remote areas to cervical cancer screening utilizing the VIA ‘see-and-treat’ method.

AbstractVisual inspection of the cervix with application of 4% acetic acid (VIA) is an inexpensive alternative to cytology-based screening in resource-limited areas, such as in many developing countries. We examined the diagnostic agreement between off-site (remote) expert diagnosis using photographs of the cervix (photographic inspection with acetic acid, PIA) and in-person VIA. The images for remote evaluation were taken with a mobile phone and transmitted to a database by MMS. The study population consisted of 95 HIV-positive women in Gaborone, Botswana. An expert gynecologist made a definitive positive or negative reading on the PIA results of 64 out of the 95 women whose PIA images were also read by the nurse midwives. For these images, positive nurse PIA readings were concordant with the positive expert PIA readings in 82% of cases, and the negative PIA readings between the two groups were fully concordant in 89% of cases. These results suggest that mobile telemedicine may be useful in improving access of women in remote areas to cervical cancer screening utilizing the VIA ‘see-and-treat’ method.

BackgroundCervical cancer is the leading cause of female cancer mortality in the developing world. Owing to lack of screening and appropriate referrals for women with cervical disease and HIV-HPV co-infection, women in resource-poor countries often present in advanced stages of cervical cancer despite the fact that precancerous lesions are detectable via cervical screening. Pap smear screening is frequently infeasible in low-resource settings due to high costs, prolonged time between testing and results availability, and a lack of both infrastructure and trained personnel. VIA is an inexpensive and simple alternative to cytology-based cervical cancer screening in resource-scarce settings, and can be performed by a wide range of health care workers.

Telemedicine utilizing mobile phones has the potential to assist non-physician health care workers in interpreting VIA results, thereby extending current resources to reach more women.

BackgroundCervical cancer is the leading cause of female cancer mortality in the developing world. Owing to lack of screening and appropriate referrals for women with cervical disease and HIV-HPV co-infection, women in resource-poor countries often present in advanced stages of cervical cancer despite the fact that precancerous lesions are detectable via cervical screening. Pap smear screening is frequently infeasible in low-resource settings due to high costs, prolonged time between testing and results availability, and a lack of both infrastructure and trained personnel. VIA is an inexpensive and simple alternative to cytology-based cervical cancer screening in resource-scarce settings, and can be performed by a wide range of health care workers.

Telemedicine utilizing mobile phones has the potential to assist non-physician health care workers in interpreting VIA results, thereby extending current resources to reach more women.

Specific Aims Primary Aim: To determine whether mobile telemedicine is safe and effective for cervical cancer screening when employed as an adjunct to VIA. Secondary Aim: To assess the prevalence of infection with various HPV high-risk and low-risk genotypic strains in our small cohort of HIV-positive women living in Gaborone, Botswana.

Specific Aims Primary Aim: To determine whether mobile telemedicine is safe and effective for cervical cancer screening when employed as an adjunct to VIA. Secondary Aim: To assess the prevalence of infection with various HPV high-risk and low-risk genotypic strains in our small cohort of HIV-positive women living in Gaborone, Botswana.

MethodsThe study was conducted in August 2009 in Gaborone, the capital city of Botswana. All enrolled subjects were women recruited as they presented to the Antiretroviral Therapy (ART)/HIV Bontleng Clinic, following counseling on increased risk for cervical cancer due to their HIV-positive status. All patient histories were self-reported. Subjects were deemed eligible for enrollment in the study if they were 18 years or older and able to provide informed consent. Since potential study candidates were drawn from women visiting HIV treatment clinics, all study subjects were HIV-positive. The exclusion criteria included previous treatment for cervical pre-cancer and cancer with surgical removal of part of the cervix. Pregnant women were also excluded.

MethodsThe study was conducted in August 2009 in Gaborone, the capital city of Botswana. All enrolled subjects were women recruited as they presented to the Antiretroviral Therapy (ART)/HIV Bontleng Clinic, following counseling on increased risk for cervical cancer due to their HIV-positive status. All patient histories were self-reported. Subjects were deemed eligible for enrollment in the study if they were 18 years or older and able to provide informed consent. Since potential study candidates were drawn from women visiting HIV treatment clinics, all study subjects were HIV-positive. The exclusion criteria included previous treatment for cervical pre-cancer and cancer with surgical removal of part of the cervix. Pregnant women were also excluded. ProcedureEach participant underwent a speculum exam with an endocervical swab to obtain cells for HPV testing, which were stored in ThinPrep medium. A nurse midwife used forceps to soak a cotton ball in 4% acetic acid and gently press it against the cervix and vaginal fornices for three minutes. The cervix was then examined for acetowhite lesions using standard VIA criteria.

Digital images of the cervix were obtained using a mobile phone (SGH-U900, Samsung, Seoul) equipped with a 5 megapixel camera and zoom function.

ProcedureEach participant underwent a speculum exam with an endocervical swab to obtain cells for HPV testing, which were stored in ThinPrep medium. A nurse midwife used forceps to soak a cotton ball in 4% acetic acid and gently press it against the cervix and vaginal fornices for three minutes. The cervix was then examined for acetowhite lesions using standard VIA criteria.

Digital images of the cervix were obtained using a mobile phone (SGH-U900, Samsung, Seoul) equipped with a 5 megapixel camera and zoom function.

Diagnostic ReliabilityFour nurse midwives trained in face-to-face VIA screening with the expert gynecologist for four months prior to the beginning of the study. These nurses made VIA diagnoses at the original patient speculum exam.  

Diagnostic ReliabilityFour nurse midwives trained in face-to-face VIA screening with the expert gynecologist for four months prior to the beginning of the study. These nurses made VIA diagnoses at the original patient speculum exam.  

Statistical AnalysisWe assessed the agreement between (1) diagnoses based on visualization of the cervix after VIA application of 4% acetic acid (control) during a live patient clinical encounter and (2) diagnoses for the same patient encounter based on PIA. Agreement between VIA and PIA results was defined as concordance in diagnosis as either positive, negative or insufficient. Kappa statistics were used to examine whether the concordance exceeded that expected by chance.

Statistical AnalysisWe assessed the agreement between (1) diagnoses based on visualization of the cervix after VIA application of 4% acetic acid (control) during a live patient clinical encounter and (2) diagnoses for the same patient encounter based on PIA. Agreement between VIA and PIA results was defined as concordance in diagnosis as either positive, negative or insufficient. Kappa statistics were used to examine whether the concordance exceeded that expected by chance.

Images were transmitted by MMS and stored in a database to be evaluated by the same nurse midwife who performed the face-to-face examination three months after the initial visit, and who was blinded to her original evaluation of the patient’s cervix.

HPV genotyping of ThinPrep endocervical samples was performed using Gold Taq with modified MY09/11 PCR to evaluate the presence of 32 different genotypic HPV strains: HPV 5, 8, 16, 18, 30, 31, 33, 34, 35, 39, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, 70, 71, 72, 73, 81, 82, 83, 84 and 85. PCR products from positive samples were typed by dot-blot hybridization.

Subjects deemed VIA-positive were treated at the same visit with cryotherapy in the ‘see-and-treat’ model of care. In cases where the lesions occupied over 75% of the cervix, could not be fully visualized, or were suggestive of invasive carcinoma, referral was made to a tertiary medical center for treatment by loop electrosurgical excision procedure (LEEP) or cervical cone biopsy.

Images were transmitted by MMS and stored in a database to be evaluated by the same nurse midwife who performed the face-to-face examination three months after the initial visit, and who was blinded to her original evaluation of the patient’s cervix.

HPV genotyping of ThinPrep endocervical samples was performed using Gold Taq with modified MY09/11 PCR to evaluate the presence of 32 different genotypic HPV strains: HPV 5, 8, 16, 18, 30, 31, 33, 34, 35, 39, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, 70, 71, 72, 73, 81, 82, 83, 84 and 85. PCR products from positive samples were typed by dot-blot hybridization.

Subjects deemed VIA-positive were treated at the same visit with cryotherapy in the ‘see-and-treat’ model of care. In cases where the lesions occupied over 75% of the cervix, could not be fully visualized, or were suggestive of invasive carcinoma, referral was made to a tertiary medical center for treatment by loop electrosurgical excision procedure (LEEP) or cervical cone biopsy.

After a three-month period, the nurses were blinded to the initial patient encounter, shown PIA images taken during the same patient speculum exam and asked to determine whether the subject was positive or negative for acetowhite cervical changes based on viewing the mobile phone photographs alone (PIA). Intra-rater VIA-PIA concordance was determined for the diagnoses made by the on-site nurse midwife using VIA and from PIA images.   The expert off-site gynecologist also labeled each nurse’s PIA images as positive, negative or insufficient for the presence of precancerous or cancerous-appearing acetowhite lesions. In order to evaluate the diagnostic reliability of PIA compared to conventional VIA, concordance was calculated between the diagnosis made by the on-site nurse midwife using VIA and the diagnosis made by the expert off-site gynecologist using PIA.

All digital PIA images were one megabyte in size when acquired and were not compressed when sent from the mobile phone to the web server and database, from which they were downloaded for nurse and expert review.

After a three-month period, the nurses were blinded to the initial patient encounter, shown PIA images taken during the same patient speculum exam and asked to determine whether the subject was positive or negative for acetowhite cervical changes based on viewing the mobile phone photographs alone (PIA). Intra-rater VIA-PIA concordance was determined for the diagnoses made by the on-site nurse midwife using VIA and from PIA images.   The expert off-site gynecologist also labeled each nurse’s PIA images as positive, negative or insufficient for the presence of precancerous or cancerous-appearing acetowhite lesions. In order to evaluate the diagnostic reliability of PIA compared to conventional VIA, concordance was calculated between the diagnosis made by the on-site nurse midwife using VIA and the diagnosis made by the expert off-site gynecologist using PIA.

All digital PIA images were one megabyte in size when acquired and were not compressed when sent from the mobile phone to the web server and database, from which they were downloaded for nurse and expert review.

ResultsVIA and detection of HPV: All 26 VIA-positive subjects were HPV-positive 92% of VIA-positive women were infected with at least one strain of high-risk HPV 47% of subjects infected with high-risk HPV subtypes tested positive with VIA The expert gynecologist deemed 31 PIA images insufficient in quality for a reading. Excluding these PIA cases: 89% of negative expert PIA readings were determined to be negative by nurse PIA 82% of positive expert PIA readings were determined to be positive by nurse PIA Nurses and experts agreed more often than expected by chance (P<0.001), kappa statistic (0.71) Nurse VIA and PIA showed overall 81% diagnostic concordance PIA results from all 93 study subjects who received VIA readings, including those deemed by the expert as insufficient: Individual nurse VIA and PIA diagnoses agreed in 70% of cases Nurse VIA and PIA agreed more than expected by chance (P<0.001), kappa statistic (0.38)

ResultsVIA and detection of HPV: All 26 VIA-positive subjects were HPV-positive 92% of VIA-positive women were infected with at least one strain of high-risk HPV 47% of subjects infected with high-risk HPV subtypes tested positive with VIA The expert gynecologist deemed 31 PIA images insufficient in quality for a reading. Excluding these PIA cases: 89% of negative expert PIA readings were determined to be negative by nurse PIA 82% of positive expert PIA readings were determined to be positive by nurse PIA Nurses and experts agreed more often than expected by chance (P<0.001), kappa statistic (0.71) Nurse VIA and PIA showed overall 81% diagnostic concordance PIA results from all 93 study subjects who received VIA readings, including those deemed by the expert as insufficient: Individual nurse VIA and PIA diagnoses agreed in 70% of cases Nurse VIA and PIA agreed more than expected by chance (P<0.001), kappa statistic (0.38)

Conclusions

Mobile telemedicine technology allows for safe and efficacious remote diagnosis by expert gynecologists. When photographs are taken with sufficient quality, mobile phone technology can be an effective method of transmitting high-quality images, allowing clinicians to make a diagnosis from a PIA photo remotely that is similar to the diagnosis they would make with VIA in person.

One inherent limitation of mobile cervical cancer screening is that VIA relies on acetowhitening of the cervix, and while the sensitivity for detecting precancerous lesions is significant, the specificity remains low.

To improve PIA picture quality and concordance between VIA and PIA, training of health providers should focus on ensuring sufficient photograph quality for making a PIA diagnosis. Considerations in taking adequate photographs of the cervix with the Samsung Soul U900 mobile phone include using adequate and appropriate lighting, minimizing glare from the metal speculum, and correctly placing the speculum for full visualization of the cervix.

Telemedicine performed with an appropriate mobile camera phone has the advantages of not requiring Internet connections or an electrical supply, low cost and ease of use, and allows for immediate image transmission. This could provide an opportunity for evaluation by a remote expert while the patient is still in the clinic. Increasing cervical cancer screening services by using mobile telemedicine PIA could reduce the prevalence of cervical cancer, especially in areas where a high HIV infection rate and limited access to gynecological services and cervical cancer screening increase the burden of cervical cancer morbidity and mortality.

ConclusionsMobile telemedicine technology allows for safe and efficacious remote diagnosis by expert gynecologists. When photographs are taken with sufficient quality, mobile phone technology can be an effective method of transmitting high-quality images, allowing clinicians to make a diagnosis from a PIA photo remotely that is similar to the diagnosis they would make with VIA in person.

One inherent limitation of mobile cervical cancer screening is that VIA relies on acetowhitening of the cervix, and while the sensitivity for detecting precancerous lesions is significant, the specificity remains low.

To improve PIA picture quality and concordance between VIA and PIA, training of health providers should focus on ensuring sufficient photograph quality for making a PIA diagnosis. Considerations in taking adequate photographs of the cervix with the Samsung Soul U900 mobile phone include using adequate and appropriate lighting, minimizing glare from the metal speculum, and correctly placing the speculum for full visualization of the cervix.

Telemedicine performed with an appropriate mobile camera phone has the advantages of not requiring Internet connections or an electrical supply, low cost and ease of use, and allows for immediate image transmission. This could provide an opportunity for evaluation by a remote expert while the patient is still in the clinic. Increasing cervical cancer screening services by using mobile telemedicine PIA could reduce the prevalence of cervical cancer, especially in areas where a high HIV infection rate and limited access to gynecological services and cervical cancer screening increase the burden of cervical cancer morbidity and mortality.

Medical provider applies 4% acetic acid to cervix,

precancerous lesions appear white

Medical provider performs cryotherapy per

expert advice or refers patient for further

treatment

Cervical image and patient information

captured with mobile phone, sent to

gynecological expert

Diagnosis and treatment advice transmitted from expert reviewer back to

on-site provider

Ideal cervical cancer screening and treatment process using VIA and mobile telemedicine

Expert PIA

Nurse PIA Negative Positive

Negative 40 1

Positive 4 14

Insufficient 1 2

Nurse PIA versus Expert PIA n %

Complete concordance of positive diagnoses

40 88.9

Complete concordance of negative diagnoses

14 82.4

Cervical photographs taken with the Samsung SGH-900 mobile phone with zoom function and hand-held LED flashlight light source. A: Healthy cervix B: Cervix with acetowhite lesion at 7 o’clock

A B