The Khayelitsha Comorbidity Cohort: Establishing a multimorbidity cohort with integrated clinical, genomic and epidemiological data in South Africa.

In the Western Cape Province of South Africa, there is a large burden of diseases including infectious diseases HIV and TB as well as chronic diseases like hypertension, diabetes and kidney disease. Often patients have more than one condition at the same time. The Provincial Health Data Centre (PHDC) at the Department of Health collects ongoing patient information about their visits to health facilities, medicines received and laboratory tests done, in order to provide health care. Where patients consent, these health data can be used for research to better understand health conditions.

Genes and DNA are unique to each individual and can affect whether they will get some diseases, how ill they will get with those illnesses, and how they respond to treatment. By understanding this relationship between DNA and diseases, individual patients will be able to receive better health care tailored to their own DNA sequence. Most of the research done on DNA and diseases until now has been done on Caucasian populations, and African patients have been poorly represented in research. This means that most health care is not optimised for Africans, even though African populations have rich genetic diversity which can provide many insights into the mechanisms of disease through biomedical research. In addition, research about genetic effects on disease have generally been conducted from the perspective of looking at a single disease and doing the analysis on who has the disease or not without taking into consideration other health conditions that the participant might also be experiencing.

Recently, the H3Africa Bioinformatics Network (H3ABioNet) developed the H3Africa Illumina genotyping chip, a tool that is specifically optimised for measuring DNA variation in Africans, across the whole human genome. With the consent of research participants, health data from the PHDC can be combined with genetic data generated using the H3Africa genotyping chip, making it possible to research the relationship between DNA and different diseases in African individuals. In the first instance, this project aims to collect 700 DNA samples from consenting participants and link their DNA data to their health data from the PHDC. In this first stage it will be possible to research the more common diseases - hypertension, diabetes and kidney disease; but as the number of research participants increases in the future it will also become possible to research the less common illnesses. Updated health information will be received from the PHDC twice a year, to document all health outcomes as they occur in participants going forward. An additional benefit to this research is that it will use a participant-based approach rather than a disease-based view, researching the whole health profile of the participant instead of only looking at whether they have a single disease or not. By working in collaboration with the Department of Health, a system will be set up to return useful findings from the research so that they can be used to provide better tailored health care by the Department of Health for individuals as well as the whole population. The information will also help to inform health care in other African countries, and well as providing research insights that can help improve our understanding of disease processes across the world.

There is high multimorbidity in South Africa, consisting both infectious and non-communicable diseases. Elucidating diagnostic, therapeutic and prognostic genetic drivers of morbidities can help tailor preventative and therapeutic patient care at both population and individual levels, and requires research into associations between genetic factors, complex patient phenotypes, and how these factors work in concert to impact complex clinical phenotypes in African individuals. The Provincial Health Data Centre (PHDC) is a health information exchange collating routine health data on a daily basis from 6.6million health care clients in the Western Cape Province (South Africa), compiling a patient-centric longitudinal health profile for every individual, with daily updates available on an ongoing basis. This presents an opportunity to research complete, complex clinical phenotypes with prospective automated health data updates for consenting individuals. The H3Africa Bioinformatics Network has developed an African-specific 2.5million SNP genotyping chip including novel African variants, known disease markers and pharmacogenomic variants. With the appropriate informed consent from participants, individuals' genotypes generated with the H3Africa chip can be linked to complex, longitudinal clinical phenotypes from the PHDC to develop an infinitely-scalable comorbidity cohort. At the seed-stage of the project, nested case-control analyses and genetic epidemiology methods will be used to explore complex genotype-phenotype associations focusing on high prevalence morbidities - diabetes, hypertension and kidney disease - in conjunction with HIV and TB. As the cohort grows, going forward, other morbidities can be analysed. Clinical data will be updated from the PHDC biannually, growing the extent of the clinical profiles over time. Additionally, a framework will be developed for returning clinically actionable findings to the Western Cape government health service.

The pilot project proposed here aims to establish a framework, with established sample and data workflows and analysis methodologies, for the collection and linkage of complex clinical longitudinal data from routine health records collated at the Provincial Health Data Centre to genotype data generated using the H3Africa Illumina genotyping chip. The pilot project will generate a seed-stage cohort of 700 consenting participants, demonstrating that it is feasible and economical to establish and develop such a cohort for conducting health genomics research. A mechanism will be established for the return of actionable, validated research findings to the PHDC to inform health care by the Department of Health for individuals as well as at the population and health policy level. The pilot study will pave the way to grow this infinitely-scalable research cohort to a sufficient size to investigate the genetic drivers of multi-morbidities in an African population. During the project, additional outcomes will include the training and skills development of two early career African researchers, and a workshop with other comorbidities researchers in the region will enable sharing the new methodologies as well as inviting collaboration in growing the cohort further for future research into the multi-morbidities affecting patients in the Western Cape. The pilot project will thus impact African healthcare clients, through improving the effectiveness of the healthcare they receive, and will benefit the Department of Health by generating a knowledge-base that can be used to provide more effective health care. The project will also impact the research community by providing a framework for an economical and feasible growing research cohort that can be used for extensive health research into the future.