Search

Purpose: Little is known regarding differences in childhood growth between somatic and heritable retinoblastoma (Rb) populations. We aimed to compare childhood growth parameters between somatic and heritable Rb cohorts at birth and at time of diagnosis with Rb., Methods: A multinational, longitudinal cohort study was conducted with patients from 11 centers in 10 countries who presented with treatment naïve Rb from January to December 2019. Variables of interest included age, sex, and size characteristics at birth and at time of presentation, as well as germline mutation status. After Bonferroni correction, results were statistically significant if the P value was less than 0.005., Results: We enrolled 696 patients, with 253 analyzed after exclusion criteria applied. Between somatic (n = 39) and heritable (n = 214) Rb cohorts, with males and females analyzed separately, there was no significant difference in birth weight percentile, weight percentile at time of diagnosis, length percentile at time of diagnosis, weight-for-length percentile at time of diagnosis, or change of weight percentile from birth to time of diagnosis. Patients with heritable Rb had a smaller mean weight percentile at birth and smaller mean weight and length percentiles at time of diagnosis with Rb, although this difference was not statistically significant. All cohorts experienced a slight negative change of weight percentile from birth to time of diagnosis. No cohort mean percentiles met criteria for failure to thrive, defined as less than the 5th percentile., Conclusions: Children with Rb seem to have normal birth and childhood growth patterns. There is no definitive evidence that somatic or heritable Rb has a biological or environmental impact on childhood growth parameters.

Objective: Several artificial intelligence (AI) systems for diabetic retinopathy screening have been validated but there is limited evidence on their performance in real-world settings. This study aimed to assess the performance of an AI software deployed within the diabetic retinopathy screening programme in Dominica., Methods and Analysis: We conducted a prospective, cross-sectional clinical validation study. Patients with diabetes aged 18 years and above attending the diabetic retinopathy screening in primary care facilities in Dominica from 5 June to 3 July 2021 were enrolled.Grading was done at the point of care by the field grader, followed by counselling and referral to the eye clinic. Images were then graded by an AI system. Sensitivity, specificity with 95% CIs and area under the curve (AUC) were calculated for comparing the AI to field grader as gold standard., Results: A total of 587 participants were screened. The AI had a sensitivity and specificity for detecting referable diabetic retinopathy of 77.5% and 91.5% compared with the grader, for all participants, including ungradable images. The AUC was 0.8455. Excluding 52 participants deemed ungradable by the grader, the AI had a sensitivity and specificity of 81.4% and 91.5%, with an AUC of 0.9648., Conclusion: This study provides evidence that AI has the potential to be deployed to assist a diabetic screening programme in a middle-income real-world setting and perform with reasonable accuracy compared with a specialist grader., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Rates of care abandonment for retinoblastoma (RB) demonstrate significant geographical variation; however, other variables that place a patient at risk of abandoning care remain unclear. This study aims to identify the risk factors for care abandonment across a multinational set of patients., Methods: A prospective, observational study of 692 patients from 11 RB centres in 10 countries was conducted from 1 January 2019 to 31 December 2019. Multivariate logistic regression was used to identify risk factors associated with higher rates of care abandonment., Results: Logistic regression showed a higher risk of abandoning care based on country (high-risk countries include Bangladesh (OR=18.1), Pakistan (OR=45.5) and Peru (OR=9.23), p<0.001), female sex (OR=2.39, p=0.013) and advanced clinical stage (OR=4.22, p<0.001). Enucleation as primary treatment was not associated with a higher risk of care abandonment (OR=0.59, p=0.206)., Conclusion: Country, advanced disease and female sex were all associated with higher rates of abandonment. In this analysis, enucleation as the primary treatment was not associated with abandonment. Further research investigating cultural barriers can enable the building of targeted retention strategies unique to each country., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/objectives: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1., Subjects/methods: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods., Results: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant., Conclusions: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma., (© 2022. The Author(s).)

Objective: To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer., Methods: A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries., Results: For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p < 0.001). Analysis at economic grouping, continent, and country-level demonstrated differences in the sex ratio in the sample compared to the ratio at birth in lower-middle-income countries (n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p < 0.001); and India (n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ 2  = 6.925, corrected p = 0.025) and for Asia (χ 2  = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ 2  = 2.205, p = 0.14)., Conclusions: No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes., (© 2021. The Author(s).)

Purpose: To examine the current provision and practice patterns of diabetic retinopathy screening (DRS) in Haryana., Methods: This was a descriptive cross-sectional survey in Haryana. All ophthalmologists registered with Haryana Ophthalmological Society in Haryana state were invited to participate on an online survey comprised of twenty questions exploring diabetic retinopathy screening provision, and barriers to screening services in Haryana., Results: The response rate was 82% (153/186). The majority (84%) of the eye care providers practiced in urban areas. Most ophthalmologists (89%, 136/153), considered diabetic retinopathy screening by non-ophthalmic human resource inappropriate because of technical feasibility issues (62%) followed by non-availability of trained staff (33%). Only half (54%) of the respondents had access to written protocols for the diagnosis and management of diabetic retinopathy in their practice. Barriers to optimize diabetic retinopathy screening were lack of knowledge or awareness among patients (95.5%), perception that eye complications were unlikely (76%) and cost of care (30%)., Conclusion: Diabetic retinopathy screening practices are mainly opportunistic and urban-centric, likely delivering inequitable services for the rural populations in the state. The inclusion of other personnel in screening will require stakeholder engagement from all health professions and changing the perceptions of ophthalmologists about task shifting., Competing Interests: None

Background: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe., Methods: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries., Results: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease., Conclusions: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis ( p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group ( p = 0.62) and success of eye salvage ( p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation ( p = 0.74), lymph node involvement ( p = 0.20), and distant metastases ( p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes., Methods: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019., Results: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB ( p = 0.001), distance from home to nearest primary healthcare centre ( p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre ( p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation ( p < 0.001), higher chances of high-risk histopathology features ( p = 0.003), regional lymph node metastasis ( p < 0.001), systemic metastasis ( p < 0.001) and death ( p < 0.001)., Conclusions: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale., Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis., Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017., Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis., Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68])., Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Background: The Royal College of Ophthalmologists (RCOphth) and the College of Ophthalmology of Eastern Central and Southern Africa (COECSA) are collaborating to cascade a Training the Trainers (TTT) Programme across the COECSA Region. Within the VISION 2020 Links Programme, it aims to develop a skilled motivated workforce who can deliver high quality eye care. It will train a lead, faculty member and facilitator in 8 countries, who can cascade the programme to local trainers., Methods: In phase 1 (2013/14) two 3-day courses were run for 16/17 selected delegates, by 3 UK Faculty. In phase 2 (2015/16) 1 UK Faculty Member ran 3 shorter courses, associated with COECSA events (Congress and Examination). A COECSA Lead was appointed after the first course, and selected delegates were promoted as Facilitators then Faculty Members on successive courses. They were given appropriate materials, preparation, training and mentoring., Results: In 4 years the programme has trained 87 delegates, including 1 COECSA Lead, 4 Faculty Members and 7 Facilitators. Delegate feedback on the course was very good and Faculty were impressed with the progress made by delegates. A questionnaire completed by delegates after 6-42 months demonstrated how successfully they were implementing new skills in teaching and supervision. The impact was assessed using the number of eye-care workers that delegates had trained, and the number of patients seen by those workers each year. The figures suggested that approaching 1 million patients per year were treated by eye-care workers who had benefited from training delivered by those who had been on the courses. Development of the Programme in Africa initially followed the UK model, but the need to address more extensive challenges overseas, stimulated new ideas for the UK courses., Conclusions: The Programme has developed a pyramid of trainers capable of cascading knowledge, skills and teaching in training with RCOphth support. The third phase will extend the number of facilitators and faculty, develop on-line preparatory and teaching materials, and design training processes and tools for its assessment. The final phase will see local cascade of the TTT Programme in all 8 countries, and sustainability as UK support is withdrawn.

Background: Cancer care remains inadequate in low-middle income countries (LMICs). Children with cancer have 80% chance of surviving in high-income countries compared to 20% in LMICs. Retinoblastoma (RB), an aggressive eye cancer of childhood and top childhood cancer in sub-Saharan Africa (SSA), has a low survival rate, due to a delay in diagnosis and abandonment of treatment. The purpose of this study is to provide a tool for planning human resources required to manage RB in SSA., Procedure: Online tool was developed with 19 modifiable fields and 23 estimates. Routine data were used to populate modifiable fields: population, birthrate, infant mortality rate, and total fertility rate. Values were held constant: frequency, 1:17,000; familial cases, 8%; unilateral RB, 74%; extraocular disease, 70%; and survival postextraocular treatment, 10%., Results: One thousand twenty-three RB incident and familial cases are estimated each year across Ethiopia, Ghana, Malawi, Nigeria, Tanzania, Uganda, Zambia, and Zimbabwe: 75 familial, 700 unilateral, 717 extraocular disease, and 645 palliative. Nigeria represents 431 cases and Zimbabwe 33 cases. Over the eight countries, a total of 41,558 patient visits are estimated each year consisting of unilateral enucleation, follow-up visits, intensive treatment, and familial screening, with a total of 2,802 prosthetic eyes being required each year., Conclusions: In the absence of data, estimates are essential for planning countrywide medical services. More attention is needed around planning for services from the Ministry level including emphasis on building multidisciplinary teams for diseases such as RB, including countrywide database and integrated clinical practice guidelines among all levels of care., (© 2016 Wiley Periodicals, Inc.)

Background: There is an extreme health workforce shortage in Eastern, Central, and Southern Africa. Shortage of eye care workers impedes effective implementation of prevention of blindness programs. The World Health Organization has identified education, partnership, leadership, financing, and policy as intertwined interventions that are critical to resolving this crisis on the long term., Case Presentation: The VISION 2020 LINK between the College of Ophthalmology of Eastern, Central, and Southern Africa and the Royal College of Ophthalmologists in the United Kingdom aims to increase the quantity and quality of eye care training in East, Central, and Southern Africa through a focus on five strategic areas: fellowship examination for ophthalmologists, training the trainers, curriculum development for residents in ophthalmology and ophthalmic clinical officers, continuous professional development (CPD), and mentoring program for young ophthalmologists. This study examined how education and partnership can be linked to improve eye care, through an evaluation of this north-south link based on its own targets and established frameworks to guide north-south links., Methods: An exploratory qualitative case study design was used. Twenty-nine link representatives were recruited through purposive sampling and snowballing. Face-to-face interviews were conducted using a semi-structured interview schedule that incorporated the components of a successful link from an existing framework. Documents pertaining to the link were also examined. Thematic analysis was used for data analysis., Results: The findings revealed that the perception to the contribution of the link to eye care in the region is generally positive. Process indicators showed that the targets in three strategic objectives of the link have been achieved. Framework-based evaluation also showed that the link is successful. Mutual learning and development of friendships were the most commonly identified success factors. Inadequate awareness of the link by college members is a key challenge., Conclusion: The study concludes that the link is active and evolving and has achieved most of its targets. Further developments should be directed to influence health system strengthening in Eastern, Central, and Southern Africa more strategically. The study recommends expansion of the scope of collaboration to involve multiple health system building blocks.

Background: Over the past few decades diabetes has emerged as an important non-communicable disease in Sub-Saharan Africa (SSA). Sight loss from Diabetic Retinopathy (DR) can be prevented with screening and early treatment. The objective of this paper is to outline the required actions and considerations in the planning and development of DR screening services., Methods: A multiple-case study approach was used to analyse five DR screening services in Botswana, Ghana, Tanzania and Zambia. Cases included: two regional screening programmes, two hospital-based screening services and one nationwide screening service. Data was collected using qualitative methodologies including: document analysis, in-depth interviews and observation. The World Health Organization (WHO) Health Systems Framework was adopted as the conceptual framework for analysis., Results: Planning for a sustainable and integrated DR screening programme demanded a health systems approach. Collaboration with representatives from a variety of ministerial departments and professional bodies was required. Evolution of DR screening services may occur in a variety of ways including: increasing geographical coverage, integration into the general healthcare system, and stepwise progression from a passive, opportunistic service to one that systematically and proactively seeks to prevent DR. Lessons learned from the implementation of cervical cancer prevention programmes in resource-poor settings may assist the development of DR programmes in similar settings., Conclusion: To promote good planning of DR screening services and ensure limited resources are used effectively, there is a need to learn from screening programmes in other medical specialities and a need to share experiences between newly-developing DR programmes in resource-poor countries. The WHO Health Systems Framework presents an invaluable tool to ensure a systematic approach to planning DR screening services.

To determine prevalence and risk factors of trachoma in communities receiving intervention with the SAFE strategy (surgery, antibiotic, face washing, environmental hygiene), a cross-sectional trachoma survey was undertaken in 2006 in the Enemor district of southern Ethiopia where the SAFE program has been implemented for over five years. A sample of 374 household heads and 2,080 individuals were interviewed and examined for trachoma using an established trachoma grading system of the World Health Organization. The most prominent risk factors were identified with logistic regression analysis. Among individuals >14 years of age, the prevalence of trichiasis was 9.04 % [confidence interval (CI) 7.4-10.6]. People >40 years of age [odds ratio (OR) 1.7; CI 1.2-2.7), women (OR 2.2; CI 1.1-4.3), and illiterates (OR 3; CI 1.4-6.8) had increased risk of trichiasis. Coverage of surgical and antibiotic services was 46 and 85.5 %, respectively. Prevalence of active follicular trachoma (TF) in children aged 1-9 years was 33.1 % (CI 29.4-37.1). Unclean faces (OR 5.9; CI 4.3-8.3) and not being in school (OR 2.1; CI 1.3-3.3) were significantly associated with TF. Clean faces were observed in 56.1 % of children and improved with age and schooling (P < 0.001, Chi-squared test). Household latrine use (74.4 %) was associated with knowledge about SAFE and economic level (P ≤ 0.004, Chi-squared tests). Elderly illiterate women remain at risk of becoming blind from trachoma even in intervention areas. Trachoma particularly affects children without clean faces or opportunity for schooling. Provision of SAFE services with high coverage should be sustained in trachoma-hyperendemic areas.

A cross-sectional survey of visual impairment (VI) was undertaken in the Enemor district in Southern Ethiopian where five years of trachoma control programme has been implemented using the SAFE (Surgery, Antibiotics, Face washing, Environmental hygiene) strategy. The prevalence of VI (presenting visual acuity in the better eye < 6/18) in 451 people above 40 years of age was 22% (CI: 17.6 to 27.6) and most of it was accounted for by cataract (67%) and trachoma (13%). Whereas cataract remains a prominent cause, contribution of trachoma among leading causes of VI is declining in communities where SAFE strategy has been implemented.

Objectives: Trachoma is a major cause of blindness. The objective of this initiative was to conduct participatory process evaluations of the trachoma control programmes receiving support from the International Trachoma Initiative in eight countries., Methods: During each 2- to 4-week evaluation we analysed information collected at the central, district and community level through interviews, focus groups, questionnaires, direct observation of trachoma control activities, and existing data., Results: Mapping and assessment of disease prevalence had been completed in four of eight countries. Integration of trachoma control activities into national planning and district-level service provision varied. Intersectoral partnerships to implement the SAFE strategy (i.e. surgery, antibiotics, facial cleanliness and environmental change) were well established in a few countries. In all eight countries, the number of surgeries performed annually was insufficient; and quality of surgery was rarely monitored. Mass distribution of antibiotics was carried out well in extremely resource-poor settings and good coverage was achieved, although the strategy for antibiotic distribution varied. Inadequate water and sanitation remained a major problem in all programme areas. Monitoring of programme activities was generally inadequate. The Morocco programme is an example from which lessons and processes can be learnt and adapted to other programme countries., Conclusions: Significant achievements have been made in implementing the SAFE strategy. Scaling up of activities to true national coverage should be planned and implemented provided the resources can be made available. Further standardization of how to assess, implement and monitor trachoma control activities will facilitate expansion of the programme.

Trachoma is an ocular disease caused by repeated infection with Chlamydia trachomatis. It is the leading cause of infectious blindness globally, responsible for 5.9 million cases of blindness. Although trachomatous blindness is untreatable, it is eminently possible to prevent and the World Health Organization promotes the use of the SAFE strategy (surgery to treat end-stage disease, antibiotics to reduce the reservoir of infection, facial cleanliness, and environmental improvement to reduce transmission of C trachomatis) for this purpose. In this review we have assessed the evidence base supporting the elements of the SAFE strategy. We find strong support for the efficacy of the surgery and antibiotics components, although the optimal antibiotic regimens have not yet been established. The evidence for an effect of health education and environmental improvement is weaker, and depends mostly on cross-sectional observational studies.