UWCScholar :: Browsing by Author "Tiffin, Nicki"

Browsing by Author "Tiffin, Nicki"

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Blood pressure gradients and cardiovascular risk factors in urban and rural populations in Abia State South Eastern Nigeria using the WHO STEPwise approach
(Public Library of Science, 2013) Okpechi, Ikechi Gareth; Chukwuonye, Innocent Ijezie; Tiffin, Nicki; Madukwe, Okechukwu Ojoemelam; Onyeonoro, Ugochukwu Uchenna; Umeizudike, Theophilus Ifeanyichukwu; Ogah, Okechukwu Samuel; Onyeonoro, Ugochukwu Uchenna
Background: Developing countries of sub-Saharan Africa (SSA) face a double burden of non-communicable diseases (NCDs) and communicable diseases. As high blood pressure (BP) is a common global cardiovascular (CV) disorder associated with high morbidity and mortality, the relationship between gradients of BP and other CV risk factors was assessed in Abia State, Nigeria. Methods: Using the WHO STEPwise approach to surveillance of chronic disease risk factors, we conducted a populationbased cross-sectional survey in Abia state, Nigeria from August 2011 to March 2012. Data collected at various steps included: demographic and behavioral risk factors (Step 1); BP and anthropometric measurements (Step 2), and fasting blood cholesterol and glucose (Step 3). Results: Of the 2983 subjects with complete data for analysis, 52.1% were females and 53.2% were rural dwellers. Overall, the distribution of selected CV disease risk factors was diabetes (3.6%), hypertension (31.4%), cigarette smoking (13.3%), use of smokeless tobacco (4.8%), physical inactivity (64.2%) and being overweight or obese (33.7%). Presence of hypertension, excessive intake of alcohol, smoking (cigarette and smokeless tobacco) and physical inactivity occurred more frequently in males than in females (p,0.05); while low income, lack of any formal education and use of smokeless tobacco were seen more frequently in rural dwellers than in those living in urban areas (p,0.05). The frequency of selected CV risk factors increased as BP was graded from optimal, normal to hypertension; and high BP correlated with age, gender, smokeless tobacco, overweight or obesity, annual income and level of education. Conclusion: Given the high prevalence of hypertension in this part of Nigeria, there is an urgent need to focus on the reduction of preventable CV risk factors we have observed to be associated with hypertension, in order to effectively reduce the burden of NCDs in Africa.
A computational characterisation of the relationship between genome structure and disease genes
(University of the Western Cape, 2012) Kibler, Tracey Deborah; Tiffin, Nicki; Christoffels, Alan
This is a pilot study to investigate the relationship between disease gene status and the structure of the human genome with specific reference to regions of recombination. It compares certain characteristics of a control set of genes, with no reported association or function in any known disease, with a second set of well-curated genes with a known association to a disease. One of the benefits of recombination is the introduction of new combinations of genetic variation in the genome. Recombination hotspots are regions on the chromosome where higher than normal frequencies of breaking and rejoining between homologous chromosomes occur during meiosis. The hotspot regions exhibit both a non-random distribution across the human genome and varying frequencies of breaking and rejoining. The study analyzed a set of features that represent general properties of human genes; namely base composition (percentage GC content), genetic variation (single nucleotide polymorphisms - SNPs), gene length, and positional effect (distance from chromosome end), in both the disease-associated gene set and the control set. These features were linked to recombination hotspots in the human genome and the frequency of recombination at these hotspots. Descriptive statistics was used to determine differences between the occurrences of these features in disease-associated genes compared to the control set, as well as differences in the occurrence of these same features in subset of genes containing an internal recombination hotspot compared to the genes with no internal recombination hotspot. The study found that disease-associated genes are generally longer than those in the control set, which is consistent with previous studies. It also found that disease-associated genes are much more likely to contain a recombination hotspot than those genes with no disease association. The study did not, however, find any association between disease gene status and the other set of features; namely GC content, SNP numbers or the position of a gene on the chromosome. Further analysis of the data suggested that the increased probability of disease-associated genes containing a recombination hotspot is most likely an effect of longer gene length and that the presence of a recombination hotspot is not sufficient in its own right to cause disease gene status.
Computational genomics approaches for kidney diseases in Africa
(University of the Western Cape, 2015) Mapiye, Darlington Shingirirai; Tiffin, Nicki; Gamieldien, Junaid
End stage renal disease (ESRD), a more severe form of kidney disease, is considered to be a complex trait that may involve multiple processes which work together on a background of a significant genetic susceptibility. Black Africans have been shown to bear an unequal burden of this disease compared to white Europeans, Americans and Caucasians. Despite this, most of the genetic and epidemiological advances made in understanding the aetiology of kidney diseases have been done in other populations outside of sub-Saharan Africa (SSA). Very little research has been undertaken to investigate key genetic factors that drive ESRD in Africans compared to patients from rest of world populations. Therefore, the primary aim of this Bioinformatics thesis was twofold: firstly, to develop and apply a whole exome sequencing (WES) analysis pipeline and use it to understand a genetic mechanism underlying ESRD in a South African population of mixed ancestry. As I hypothesized that the pipeline would enable the discovery of highly penetrate rare variants with large effect size, which are expected to explain an important fraction of the genetic aetiology and pathogenesis of ESRD in these African patients. Secondly, the aim was to develop and set up a multicenter clinical database that would capture a plethora of clinical data for patients with Lupus, one of the risk factors of ESRD. From WES of six family members (five cases and one control); a total of 23 196 SNVs, 1445 insertions and 1340 deletions, overlapped amongst all affected family members. The variants were consistent with an autosomal dominant inheritance pattern inferred in this family. Of these, only 1550 SNVs, 67 insertions and 112 deletions were present in all affected family members but absent in the unaffected family member. Following detailed evaluation of evidence for variant implication and pathogenicity, only 3 very rare heterozygous missense variants in 3 genes COL4A1 [p.R476W], ICAM1 [p.P352L], COL16A1 [p.T116M] were considered potentially disease causing. Computational relatedness analysis revealed approximate amount of DNA shared by family members and confirmed reported relatedness. Genotyping for the Y chromosome was additionally performed to assist in sample identity. The clinical database has been designed and is being piloted at Groote Schuur medical Hospital at the University of Cape Town. Currently, about 290 patients have already been entered in the registry. The resources and methodologies developed in this thesis have the potential to contribute not only to the understanding of ESRD and its risk factors, but to the successful application of WES in clinical practice. Importantly, it contributes significant information on the genetics of ESRD based on an African family and will also improve scientific infrastructure on the African continent. Clinical databasing will go a long way to enable clinicians to collect and store standardised clinical data for their patients.
Covid-19 among adults living with HIV: Correlates of mortality among public sector healthcare users in Western Cape, South Africa
(Wiley, 2023) Kassanjee, Reshma; Davies, Mary-Ann; Tiffin, Nicki
Introduction: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower-income settings. We studied the association of mortality with characteristics of HIV severity and management, and vaccination, among adult PWH. Methods: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with evidence of antiretroviral therapy (ART) collection, time since first HIV evidence, CD4 cell count, viral load (among those with evidence of ART collection) and COVID-19 vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. Results: Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17,831 first-diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis (especially more recent episodes of tuberculosis), chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults.
A diverse array of genetic factors contribute to the pathogenesis of Systemic Lupus Erythematosus
(Biomed Central, 2013) Tiffin, Nicki; Adeyemo, Adebowale A.; Okpechi, Ikechi
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with variable clinical presentation frequently affecting the skin, joints, haemopoietic system, kidneys, lungs and central nervous system. It can be life threatening when major organs are involved. The full pathological and genetic mechanisms of this complex disease are yet to be elucidated; although roles have been described for environmental triggers such as sunlight, drugs and chemicals, and infectious agents. Cellular processes such as inefficient clearing of apoptotic DNA fragments and generation of autoantibodies have been implicated in disease progression. A diverse array of disease-associated genes and microRNA regulatory molecules that are dysregulated through polymorphism and copy number variation have also been identified; and an effect of ethnicity on susceptibility has been described.
An e-consent framework for tiered informed consent for human genomic research in the global south, implemented as a REDCap template
(BMC Medics, 2022) Tamuhla, Tsaone; Tiffin, Nicki; Allie, Tarryn
Research involving human participants requires their consent, and it is common practice to capture consent information on paper and store those hard copies, presenting issues such as long-term storage requirements, inefficient retrieval of consent forms for reference or future use, and the potential for transcription errors when transcribing captured informed consent. There have been calls to move to electronic capture of the consent provided by research participants (e-consent) as a way of addressing these issues. A tiered framework for e-consent was designed using the freely available features in the inbuilt REDCap e-consent module. We implemented ‘branching logic’, ‘wet signature’ and ‘auto-archiver’ features to the main informed consent and withdrawal of consent documents. The branching logic feature streamlines the consent process by making follow-up information available depending on participant response, the ‘wet signature’ feature enables a timestamped electronic signature to be appended to the e-consent documents and the ‘auto-archiver’ allows for PDF copies of the e-consent documents to be stored in the database. When designing the content layout, we provided example participant information text which can be modified as required. Emphasis was placed on the flow of information to optimise participant understanding and this was achieved by merging the consent and participant information into one document where the consent questions were asked immediately after the corresponding participant information. In addition, we have provided example text for a generic human genomic research study, which can be easily edited and modified according to specific requirements. Building informed consent protocols and forms without prior experience can be daunting, so we have provided researchers with a REDCap template that can be directly incorporated into REDCap databases. It prompts researchers about the types of consent they can request for genomics studies and assists them with suggestions for the language they might use for participant information and consent questions. The use of this tiered e-consent module can ensure the accurate and efficient electronic capture and storage of the consents given by participants in a format that can be easily queried and can thus facilitate ethical and effective onward sharing of data and samples whilst upholding individual participant preferences.
Ethical and legal implications of whole genome and whole exome sequencing in African populations
(BioMed Central, 2013) Wright, Galen E.B.; Koornhof, Pieter G.J.; Adeyemo, Adebowale A.; Tiffin, Nicki
BACKGROUND: Rapid advances in high throughput genomic technologies and next generation sequencing are making medical genomic research more readily accessible and affordable, including the sequencing of patient and control whole genomes and exomes in order to elucidate genetic factors underlying disease. Over the next five years, the Human Heredity and Health in Africa (H3Africa) Initiative, funded by the Wellcome Trust (United Kingdom) and the National Institutes of Health (United States of America), will contribute greatly towards sequencing of numerous African samples for biomedical research. DISCUSSION: Funding agencies and journals often require submission of genomic data from research participants to databases that allow open or controlled data access for all investigators. Access to such genotype-phenotype and pedigree data, however, needs careful control in order to prevent identification of individuals or families. This is particularly the case in Africa, where many researchers and their patients are inexperienced in the ethical issues accompanying whole genome and exome research; and where an historical unidirectional flow of samples and data out of Africa has created a sense of exploitation and distrust. In the current study, we analysed the implications of the anticipated surge of next generation sequencing data in Africa and the subsequent data sharing concepts on the protection of privacy of research subjects. We performed a retrospective analysis of the informed consent process for the continent and the rest-of-the-world and examined relevant legislation, both current and proposed. We investigated the following issues: (i) informed consent, including guidelines for performing culturally-sensitive next generation sequencing research in Africa and availability of suitable informed consent documents; (ii) data security and subject privacy whilst practicing data sharing; (iii) conveying the implications of such concepts to research participants in resource limited settings. SUMMARY: We conclude that, in order to meet the unique requirements of performing next generation sequencing-related research in African populations, novel approaches to the informed consent process are required. This will help to avoid infringement of privacy of individual subjects as well as to ensure that informed consent adheres to acceptable data protection levels with regard to use and transfer of such information.
How to use relevant data for maximal benefit with minimal risk: Digital health data governance to protect vulnerable populations in low-income and middle- income countries
(BMJ Global Health, 2019) Tiffin, Nicki; George, Asha; LeFevre, Amnesty Elizabeth
Globally, the volume of private and personal digital data has massively increased, accompanied by rapid expansion in the generation and use of digital health data. These technological advances promise increased opportunity for data-driven and evidence-based health programme design, management and assessment; but also increased risk to individuals of data misuse or data breach of their sensitive personal data, especially given how easily digital data can be accessed, copied and transferred on electronic platforms if the appropriate controls are not implemented. This is particularly pertinent in low-income and middle-income countries (LMICs), where vulnerable populations are more likely to be at a disadvantage in negotiating digital privacy and confidentiality given the intersectional nature of the digital divide. The potential benefits of strengthening health systems and improving health outcomes through the digital health environment thus come with a concomitant need to implement strong data governance structures and ensure the ethical use and reuse of individuals’ data collected through digital health programmes. We present a framework for data governance to reduce the risks of health data breach or misuse in digital health programmes in LMICS. We define and describe four key domains for data governance and appropriate data stewardship, covering ethical oversight and informed consent processes, data protection through data access controls, sustainability of ethical data use and application of relevant legislation. We discuss key components of each domain with a focus on their relevance to vulnerable populations in LMICs and examples of data governance issues arising within the LMIC context.
Identification of coding variants associated with familial systemic lupus erythematosus through whole exome sequencing
(University of the Western Cape, 2016) van Vuuren, Larry Peter; Tiffin, Nicki
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by the production of a wide range of autoantibodies directed against selfantigens. SLE can influence almost any organ system and its appearance and course are highly varied, ranging from remission to disease flare. SLE demonstrates a variety of constitutional symptoms, such as the skin, musculoskeletal and mild hematologic involvement. On the other hand, some patients present with primarily hematologic, renal or neuropsychiatric manifestations.
Integrating regulatory and methylome data for the discovery of clear cell Renal Cell Carcinoma (ccRCC) variants
(University of the Western Cape, 2015) Calvert-Joshua, Tracey; Tiffin, Nicki; Gamieldien, Junaid
Kidney cancers, of which clear cell renal cell carcinoma comprises an estimated 70%, have been placed amongst the top ten most common cancers in both males and females. With a mortality rate that exceeds 40%, kidney cancer is considered the most lethal cancer of the genitourinary system. Despite advances in its treatment, the mortality- and incidence rates across all stages of the disease have continued to climb. Since the release of the Human Genome Project in the early 2000’s, most genetics studies have focused on the protein coding region of the human genome, which accounts for a mere 2% of the entire genome. It has been suggested that diverting our focus to the other 98% of the genome, which was previously dismissed as non-functional “junk DNA”, could possibly contribute significantly to our understanding of the underlying mechanisms of complex diseases.In this study a whole genome sequencing somatic mutation data set from the International Cancer Genome Consortium was used. The non-coding somatic mutations within the promoter, intronic, 5-prime untranslated and 3-prime untranslated regions of clear cell renal cell carcinoma-implicated genes were extracted and submitted to RegulomDB for their functional annotation.As expected, most of the variants were located within the intronic regions and only a small subset of identified variants was predicted to be deleterious. Although the variants all belonged to a selected subset of kidney cancer-associated genes, the genes frequently mutated in the non-coding regions were not the same genes that were frequently mutated in the whole exome studies (where the focus is on the coding sequences). This indicates that with whole genome sequencing studies a new set of genes/variants previously unassociated with the clear cell renal cell carcinoma could be identified. In addition, most of the non-coding somatic variants fell within multiple transcriptions factor binding sites. Since many of these variants were also deleterious (as predicted by RegulomDB), this suggests that mutations in the non-coding regions could contribute to disease due to their role in transcription factor binding site disruptions and their subsequent impact on transcriptional regulation. The substantial overlap between the genes with the most aberrantly methylated variants and the genes with the most transcription factor binding site disruptions signifies a potential link between differential methylation and transcription factor binding site affinities. In contrast to the upregulated DNA methylation generally seen in promoter methylation studies, all of the significant hits in this study were hypomethylated, with the subsequent up-regulation of the genes of interest, suggesting that in the clear cell renal cell carcinoma, aberrant methylation may play a role in activating proto-oncogenes, rather than the silencing of genes. When a cross-analysis was carried out between the gene expression patterns and the transcription factor binding site disruptions, the non-coding somatic variants and differential methylation profiles, the genes affected again showed a clear overlap. Interestingly, most of the variants were not present in the 1000genomes data and thus represent novel mutations, which possibly occurred as a result of genomic instability. However, identifying novel variants are always promising, since they epitomise the possibility of developing pioneering ways to target diseases. The numerous detrimental effects a single non-coding mutation can have on other genomic processes have been demonstrated in this study and therefore validate the inclusion of non-coding regions of the genome in genetic studies in order to study complex multifactorial diseases.
“An investigation into the MicroRNA-gene interactions involved in the pathogenesis of systemic lupus erythematosus”
(University of the Western Cape, 2015) Pitts, Stephanie Julia; Tiffin, Nicki; Gamieldien, Junaid
Systemic lupus erythematosus is a chronic, inflammatory disease characterised by the production of autoantibodies which target particularly the nuclear components of multiple cell types throughout the body. MicroRNA’s have been well-established to regulate gene function by partial-, or complete binding to the 3’-UTR of the target genes, causing repression or complete degradation of the target gene. As a result, proteins normally produced by the targeted mRNA would exhibit a decrease in production.The aim of this study was to investigate the interactions between genes and microRNAs implicated in the pathogenesis of SLE. Objectives included curating lists of miRNAs and genes associated with lupus pathogenesis, to identify regulatory targets of miRNAs and genes targeted by miRNAs, and to find the intersections of these outputs. By examining the intersections of the resultant targets, we aimed to identify novel interactions using Pathway Analysis, which have not been previously reported in scientific literature, to be associated with the pathogenesis of SLE. Understanding the miRNA-gene target interactions in the progression of SLE may provide us with essential biomarkers and targets for disease diagnosis and therapy.
Lenses and levels: the why, what and how of measuring health system drivers of women’s, children’s and adolescents’ health with a governance focus
(BMJ, 2019) George, Asha; LeFevre, Amnesty Elizabeth; Jacobs, Tanya; Kinney, Mary; Buse, Kent; Chopra, Mickey; Daelmans, Bernadette; Haakenstad, Annie; Huicho, Luis; Khosla, Rajat; Rasanathan, Kumanan; Sanders, David; Singh, Neha S; Tiffin, Nicki; Ved, Rajani; Zaidi, Shehla Abbas; Schneider, Helen
Health systems are critical for health outcomes as they underpin intervention coverage and quality, promote users’ rights and intervene on the social determinants of health. Governance is essential for health system endeavours as it mobilises and coordinates a multiplicity of actors and interests to realise common goals. The inherently social, political and contextualised nature of governance, and health systems more broadly, has implications for measurement, including how the health of women, children and adolescents health is viewed and assessed, and for whom. Three common lenses, each with their own views of power dynamics in policy and programme implementation, include a service delivery lens aimed at scaling effective interventions, a societal lens oriented to empowering people with rights to effect change and a systems lens concerned with creating enabling environments for adaptive learning. We illustrate the implications of each lens for the why, what and how of measuring health system drivers across micro, meso and macro health systems levels, through three examples (digital health, maternal and perinatal death surveillance and review, and multisectoral action for adolescent health). Appreciating these underpinnings of measuring health systems and governance drivers of the health of women, children and adolescents is essential for a holistic learning and action agenda that engages a wider range of stakeholders, which includes, but also goes beyond, indicator-based measurement. Without a broadening of approaches to measurement and the types of research partnerships involved, continued investments in the health of women, children and adolescents will fall short.
A meta-analysis of public microarray data identifies gene regulatory pathways deregulated in peripheral blood mononuclear cells from individuals with Systemic Lupus Erythematosus compared to those without
(BioMed Central, 2017) Kroger, Wendy; Mapiye, Darlington; Entfellner, Jean-Baka Domelevo; Tiffin, Nicki
BACKGROUND: Systemic Lupus Erythematosus (SLE) is a complex, multi-systemic, autoimmune disease for which the underlying aetiological mechanisms are poorly understood. The genetic and molecular processes underlying lupus have been extensively investigated using a variety of -omics approaches, including genome-wide association studies, candidate gene studies and microarray experiments of differential gene expression in lupus samples compared to controls. METHODS: This study analyses a combination of existing microarray data sets to identify differentially regulated genetic pathways that are dysregulated in human peripheral blood mononuclear cells from SLE patients compared to unaffected controls. Two statistical approaches, quantile discretisation and scaling, are used to combine publicly available expression microarray datasets and perform a meta-analysis of differentially expressed genes. RESULTS: Differentially expressed genes implicated in interferon signaling were identified by the meta-analysis, in agreement with the findings of the individual studies that generated the datasets used. In contrast to the individual studies, however, the meta-analysis and subsequent pathway analysis additionally highlighted TLR signaling, oxidative phosphorylation and diapedesis and adhesion regulatory networks as being differentially regulated in peripheral blood mononuclear cells (PBMCs) from SLE patients compared to controls. CONCLUSION: Our analysis demonstrates that it is possible to derive additional information from publicly available expression data using meta-analysis techniques, which is particularly relevant to research into rare diseases where sample numbers can be limiting.
Record linkage for routinely collected health data in an African health information exchange
(Swansea University, 2023) Mutemaringa, Themba; Heekes, Alexa; Tiffin, Nicki
The Patient Master Index (PMI) plays an important role in management of patient information and epidemiological research, and the availability of unique patient identifiers improves the accuracy when linking patient records across disparate datasets. In our environment, however, a unique identifier is seldom present in all datasets containing patient information. Quasi identifiers are used to attempt to link patient records but sometimes present higher risk of over-linking. Data quality and completeness thus affect the ability to make correct linkages. This paper describes the record linkage system that is currently implemented at the Provincial Health Data Centre (PHDC) in the Western Cape, South Africa, and assesses its output to date.

Browsing by Author "Tiffin, Nicki"

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