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1.
Nat Rev Genet ; 21(6): 377-384, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251390

RESUMO

Addressing Indigenous rights and interests in genetic resources has become increasingly challenging in an open science environment that promotes unrestricted access to genomic data. Although Indigenous experiences with genetic research have been shaped by a series of negative interactions, there is increasing recognition that equitable benefits can only be realized through greater participation of Indigenous communities. Issues of trust, accountability and equity underpin Indigenous critiques of genetic research and the sharing of genomic data. This Perspectives article highlights identified issues for Indigenous communities around the sharing of genomic data and suggests principles and actions that genomic researchers can adopt to recognize community rights and interests in data.


Assuntos
Privacidade Genética/ética , Genômica/ética , Povos Indígenas/genética , Disseminação de Informação/ética , Acesso à Informação , Pesquisa em Genética/ética , Genoma Humano/genética , Direitos Humanos , Humanos
2.
BMC Med Ethics ; 25(1): 9, 2024 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-38238678

RESUMO

BACKGROUND: The conduct of research is critical to advancing human health. However, there are issues of ethical concern specific to the design and conduct of research in conflict settings. Conflict-affected countries often lack strong platform to support technical guidance and monitoring of research ethics, which may lead to the use of divergent ethical standards some of which are poorly elaborated and loosely enforced. Despite the growing concern about ethical issues in research, there is a dearth of information about ethical compliance in conflict areas. Valid and ethically informed decision-making is a premier pact with research participants in settling possible ethical issues before commencing the research, which is ensured by gaining informed consent from prospective participants of the research. AIMS: This research aimed to explore compliance with research ethics and consent validity in community-based epidemiological research conducted previously. METHODS: Research participants were recruited in the western part of Ethiopia in three districts subjected to conflicts. A community-based cross-sectional study design was utilized, and 338 residents were enrolled as study participants. All participants had previously been enrolled as research participants in epidemiological studies. Data was collected using a questionnaire that was pilot-tested before the commencement of the main data collection. The questionnaire focused on participants' experiences of the informed consent process followed when they were recruited for an epidemiological study and covered themes such as essential information provided, level of comprehension, and voluntarism of consent. RESULTS: Over half of the study participants, 176 (52%), were not provided with essential information before consenting. And 135 (40%) of them did not comprehend the information provided to them. One hundred and ninety (56%) participants freely and voluntarily agreed to partake in one of these epidemiological studies, with over a quarter (97; 28.7%) of them reporting they were subjected to undue influence. Written consent was obtained from only 32 (9.4%) of the participants.


Assuntos
Compreensão , Consentimento Livre e Esclarecido , Humanos , Estudos Transversais , Etiópia , Estudos Prospectivos , Ética em Pesquisa , Inquéritos e Questionários
3.
Genet Med ; 25(2): 100333, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36480001

RESUMO

PURPOSE: Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A presumed proportion is genetic, but this etiology is buried under the burden of infections and perinatal insults in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs) are most severely affected by this diagnostic gap in Africa, because the rate of actionable findings is highest in DEE-associated genes. METHODS: We tested 234 genetically naive South African children diagnosed with/possible DEE using gene panels, exome sequencing, and chromosomal microarray. Statistical comparison of electroclinical features in children with and children without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding. RESULTS: Of the 41 (of 234) children with likely/pathogenic variants, 26 had variants supporting precision therapy. Multivariate regression modeling highlighted neonatal or infantile-onset seizures and movement abnormalities as predictive of a positive genetic finding. We used this, coupled with an emphasis on precision medicine outcomes, to propose the pragmatic "Think-Genetics" strategy for early recognition of a possible genetic etiology. CONCLUSION: Our findings emphasize the importance of an early genetic diagnosis in DEE. We designed the Think-Genetics strategy for early recognition, appropriate interim management, and genetic testing for DEE in resource-constrained settings.


Assuntos
Epilepsia , Medicina de Precisão , Criança , Recém-Nascido , Humanos , Região de Recursos Limitados , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Epilepsia/genética , Testes Genéticos , África
4.
BMC Med Ethics ; 23(1): 119, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36434585

RESUMO

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.


Assuntos
Termos de Consentimento , Consentimento Livre e Esclarecido , Humanos , Pesquisadores , Idioma , Genômica
5.
J Clin Psychopharmacol ; 41(3): 250-254, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33843819

RESUMO

BACKGROUND: Clozapine may cause life-threatening hematological side effects (HSEs). Hematological side effect incidence data from Sub-Saharan Africa are lacking. Furthermore, clozapine reduces cellular immunity, and it is unknown whether clozapine is a risk factor for tuberculosis or whether HIV is a risk factor for developing HSEs. We assessed the incidence of HSEs in South Africans from the Western Cape Province on clozapine, and the secondary objective was to determine the association of HIV and tuberculosis with clozapine exposure. METHODS: We conducted a 24-week retrospective descriptive study of patients initiated on clozapine between January 2015 and December 2017 using anonymized data from the Provincial Health Data Centre. A control group of patients initiated on risperidone was selected. RESULTS: We identified 23,328 patients and included 5213 who had white blood cell monitoring (n = 1047 clozapine, n = 4166 risperidone). The incidence of leukopenia in patients on clozapine was 0.38% (95% confidence interval [CI], 0.01%-0.76%) measured over a 24-week period and was 0.41% in patients on risperidone (95% CI, 0.21%-0.6%) (P = 0.91). The incidence of agranulocytosis in patients on clozapine was 0.19% (95% CI, 0.00%-0.46%) measured over a 24-week period and was 0.24% in patients on risperidone (95% CI, 0.09%-0.39%) (P = 0.266). HIV-infected patients had a 7.46 times increased risk of developing leukopenia (95% CI, 3.37-16.48; P < 0.01). Patients who developed leukopenia had a 6.24 times increased risk of contracting tuberculosis (95% CI, 1.84-21.11; P < 0.01). CONCLUSIONS: Our incidence of clozapine-induced HSEs was lower than previously reported and not significantly different compared with risperidone. HIV infection was associated with HSEs. Patients with HSEs had an increased risk of developing tuberculosis.


Assuntos
Agranulocitose/induzido quimicamente , Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Leucopenia/induzido quimicamente , Adulto , Agranulocitose/epidemiologia , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Estudos de Coortes , Feminino , Infecções por HIV/epidemiologia , Humanos , Incidência , Leucopenia/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Risperidona/administração & dosagem , Risperidona/efeitos adversos , África do Sul , Tuberculose/epidemiologia
6.
BMC Infect Dis ; 20(1): 900, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33256634

RESUMO

BACKGROUND: South Africa has one of the highest tuberculosis incidence rates. Biologic disease-modifying anti-rheumatic drugs are associated with an increased risk of tuberculosis. The objective of this study was to describe the tuberculosis disease incidence rate among public sector patients receiving biologic therapies in the Western Cape Province. METHODS: A retrospective, descriptive analysis was undertaken using routine health data collated by the Provincial Health Data Centre from January 2007 (first use of biologic therapy in the Western Cape) to September 2018. RESULTS: We identified 609 patients treated with tumour necrosis factor-alpha (TNF-α) or non-TNF-α biologic therapies. Thirty-seven (37) patients developed tuberculosis after biologic therapy exposure, of whom the majority (78%) had an immune mediated inflammatory disease and the remainder (22%) a haematologic malignancy. The incidence rate of tuberculosis per 100,000 person-years was 2227 overall [95% confidence interval (CI): 1591, 3037]. Patients treated with TNF-α inhibitors and non-TNF-α inhibitors had estimated incidence rates of 2819 [95% CI: 1669, 4480] and 1825 [95% CI: 1131, 2797], respectively (p = 0.10). CONCLUSION: Patients exposed to both TNF-α and non-TNF-α biologic therapies may have a higher incidence of tuberculosis disease compared to the background risk of 681 cases per 100,000 per year in the Western Cape.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Produtos Biológicos/efeitos adversos , Terapia Biológica/efeitos adversos , Mycobacterium tuberculosis , Tuberculose/epidemiologia , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Antirreumáticos/farmacologia , Produtos Biológicos/farmacologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , África do Sul/epidemiologia , Tuberculose/microbiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto Jovem
7.
Clin Infect Dis ; 68(9): 1522-1529, 2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-30165431

RESUMO

BACKGROUND: Bedaquiline is used as a substitute for second-line injectable (SLI) intolerance in the treatment of multidrug-resistant (MDR) tuberculosis, but the efficacy and safety of this strategy is unknown. METHODS: In this retrospective cohort study adults receiving bedaquiline substitution for MDR tuberculosis therapy, plus a matched control group who did not receive bedaquiline, were identified from the electronic tuberculosis register in the Western Cape Province, South Africa. The primary outcome measure was the proportion of patients with death, loss to follow-up, or failure to achieve sustained culture conversion at 12 months of treatment. RESULTS: Data from 162 patients who received bedaquiline substitution and 168 controls were analyzed; 70.6% were infected with human immunodeficiency virus. Unfavorable outcomes occurred in 35 of 146 (23.9%) patients in the bedaquiline group versus 51 of 141 (36.2%) in the control group (relative risk, 0.66; 95% confidence interval, .46 -.95). The number of patients with culture reversion was lower in those receiving bedaquiline (1 patient; 0.8%) than in controls (12 patients; 10.3%; P = .001). Delayed initiation of bedaquiline was independently associated with failure to achieve sustained culture conversion (adjusted odds ratio for every 30-day delay, 1.5; 95% confidence interval, 1.1-1.9). Mortality rates were similar at 12 months (11 deaths in each group; P = .97). CONCLUSIONS: Substituting bedaquiline for SLIs in MDR tuberculosis treatment resulted in improved outcomes at 12 months compared with patients who continued taking SLIs, supporting the use of bedaquiline for MDR tuberculosis treatment in programmatic settings.


Assuntos
Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Coinfecção , Etambutol/uso terapêutico , Etionamida/uso terapêutico , Feminino , HIV/efeitos dos fármacos , HIV/patogenicidade , Infecções por HIV/mortalidade , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Isoniazida/uso terapêutico , Isoxazóis/uso terapêutico , Levofloxacino/uso terapêutico , Masculino , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Oxazolidinonas/uso terapêutico , Pirazinamida/uso terapêutico , Estudos Retrospectivos , África do Sul , Análise de Sobrevida , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/mortalidade , Tuberculose Resistente a Múltiplos Medicamentos/patologia
8.
Genome Res ; 26(2): 271-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26627985

RESUMO

The application of genomics technologies to medicine and biomedical research is increasing in popularity, made possible by new high-throughput genotyping and sequencing technologies and improved data analysis capabilities. Some of the greatest genetic diversity among humans, animals, plants, and microbiota occurs in Africa, yet genomic research outputs from the continent are limited. The Human Heredity and Health in Africa (H3Africa) initiative was established to drive the development of genomic research for human health in Africa, and through recognition of the critical role of bioinformatics in this process, spurred the establishment of H3ABioNet, a pan-African bioinformatics network for H3Africa. The limitations in bioinformatics capacity on the continent have been a major contributory factor to the lack of notable outputs in high-throughput biology research. Although pockets of high-quality bioinformatics teams have existed previously, the majority of research institutions lack experienced faculty who can train and supervise bioinformatics students. H3ABioNet aims to address this dire need, specifically in the area of human genetics and genomics, but knock-on effects are ensuring this extends to other areas of bioinformatics. Here, we describe the emergence of genomics research and the development of bioinformatics in Africa through H3ABioNet.


Assuntos
População Negra/genética , Promoção da Saúde , África , Biologia Computacional , Sistemas Computacionais , Variação Genética , Genética Médica , Genômica , Humanos
9.
BMC Nephrol ; 20(1): 44, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728003

RESUMO

BACKGROUND: The aim of this study was to assess, the efficacy and safety of add-on corticosteroids to antiretroviral therapy [ART] in patients with biopsy proven HIV associated nephropathy. METHODS: All included patients had histological evidence of either collapsing or non-collapsing focal segmental glomerulosclerosis (FSGS) or podocyte and/or parietal cell hypertrophy or hyperplasia. All patients had evidence of tubulointerstitial inflammation with microcysts. Patients were randomized to ART with the addition of 1 mg/kg of corticosteroids [ART+C] or remained in the group [ART Alone] and followed for 2 years. A repeat biopsy was performed at 6 months. RESULTS: Twenty-one patients were randomized to [ART+C] and 17 to [ART Alone]. The baseline estimated glomerular filtration rate (eGFR) was significantly lower in the [ART+C] vs. [ART Alone] group [35mls/min/1.73m2 vs. 47 mls/min/1.73m2, p = 0.015]. The [ART+C] cohort had a statistically significant improvement in median (eGFR) from baseline to last follow up compared with [ART Alone] i.e. [Δ = 25mls/min (IQR: 15;51) vs 9 mls/min (IQR: 0-24), p = 0.008]. There were no statistically significant differences between the groups when proteinuria and histology were analyzed. There were 8 deaths during the trial period, 7 from [ART+C] (Log rank p = 0.071). CONCLUSIONS: In the [ART+C] cohort there was a significant improvement in eGFR over 2-years with increased mortality. Routine corticosteroid use cannot currently be recommended. Further investigation to define which subgroup of this cohort would safely benefit from the positive effects is required. TRIAL REGISTRATION: ISRCTN study ID ( 56112439 ] was retrospectively registered on the 5 September 2018.


Assuntos
Nefropatia Associada a AIDS/tratamento farmacológico , Prednisona/uso terapêutico , Nefropatia Associada a AIDS/epidemiologia , Nefropatia Associada a AIDS/patologia , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Biópsia , Quimioterapia Combinada , Feminino , Seguimentos , Taxa de Filtração Glomerular , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/epidemiologia , Glomerulosclerose Segmentar e Focal/etiologia , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Estimativa de Kaplan-Meier , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Prospectivos , África do Sul/epidemiologia , Resultado do Tratamento , Tuberculose/complicações
10.
Stem Cells ; 35(10): 2184-2197, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28795454

RESUMO

Increasing evidence supports that modifications in the mitochondrial content, oxidative phosphorylation (OXPHOS) activity, and cell metabolism influence the fate of stem cells. However, the regulators involved in the crosstalk between mitochondria and stem cell fate remains poorly characterized. Here, we identified a transcriptional regulatory axis, composed of transcription factor 7-like 2 (TCF7L2) (a downstream effector of the Wnt/ß-catenin pathway, repressed during differentiation) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) (the master regulator of mitochondrial biogenesis, induced during differentiation), coupling the loss of pluripotency and early commitment to differentiation, to the initiation of mitochondrial biogenesis and metabolic shift toward OXPHOS. PGC-1α induction during differentiation is required for both mitochondrial biogenesis and commitment to the hepatocytic lineage, and TCF7L2 repression is sufficient to increase PGC-1α expression, mitochondrial biogenesis and OXPHOS activity. We further demonstrate that OXPHOS activity is required for the differentiation toward the hepatocytic lineage, thus providing evidence that bi-directional interactions control stem cell differentiation and mitochondrial abundance and activity. Stem Cells 2017;35:2184-2197.


Assuntos
Fígado/citologia , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Fígado/crescimento & desenvolvimento , Biogênese de Organelas , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/biossíntese , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Transdução de Sinais , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Transfecção , beta Catenina/metabolismo
11.
BMC Infect Dis ; 18(1): 399, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30107791

RESUMO

BACKGROUND: Tuberculosis, bacterial community-acquired pneumonia (CAP), and Pneumocystis jirovecii pneumonia (PJP) are the three commonest causes of hospitalisation in HIV-infected adults. Prompt diagnosis and treatment initiation are important to reduce morbidity and mortality, but are hampered by limited diagnostic resources in resource poor settings. C-reactive protein (CRP) and procalcitonin have shown diagnostic utility for respiratory tract infections, however few studies have focussed on their ability to distinguish between tuberculosis, CAP, and PJP in HIV-infected inpatients. METHODS: We evaluated the diagnostic accuracy of CRP and procalcitonin, compared with composite reference standards, to discriminate between the three target infections in adult HIV-infected inpatients in two district level hospitals in Cape Town, South Africa. Participants were admitted with current cough and danger signs in accordance with the WHO algorithm for tuberculosis in seriously ill HIV-infected patients. Study clinicians were blinded to CRP and procalcitonin results. RESULTS: Two hundred forty-eight participants met study case definitions: 133 with tuberculosis, 61 with CAP, 16 with PJP, and 38 with mixed infection. In the 210 particpants with single infections the differences in median CRP and procalcitonin concentrations between the three infections were statistically significant, but distributions overlapped considerably. CRP and procalcitonin concentrations were highest in the CAP group and lowest in the PJP group. CRP and procalcitonin cut-offs with sensitivities of ≥90% were found for all three target infection pairs, but corresponding specificities were low. Highest receiver operating characteristic areas under the curve for CRP and procalcitonin were for PJP versus tuberculosis and PJP versus CAP (0.68 and 0.71, and 0.74 and 0.69 respectively). CONCLUSIONS: CRP and procalcitonin showed limited value in discriminating between the three target infections due to widely overlapping distributions, but diagnostic accuracy was higher for discriminating PJP from CAP or tuberculosis. Our findings show limitations for CRP and procalcitonin, particularly for discriminiation of tuberculosis form CAP, however they may have greater diagnostic utility as part of a panel of biomarkers or in clinical prediction rules.


Assuntos
Proteína C-Reativa/análise , Infecções por HIV/patologia , Pneumonia Bacteriana/diagnóstico , Pneumonia por Pneumocystis/diagnóstico , Pró-Calcitonina/análise , Tuberculose/diagnóstico , Adulto , Idoso , Antirretrovirais/uso terapêutico , Área Sob a Curva , Biomarcadores/análise , Análise Discriminante , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Bacteriana/complicações , Pneumonia Bacteriana/patologia , Pneumonia por Pneumocystis/complicações , Pneumonia por Pneumocystis/patologia , Estudos Prospectivos , Curva ROC , Índice de Gravidade de Doença , África do Sul , Tuberculose/complicações , Tuberculose/patologia
12.
PLoS Comput Biol ; 12(2): e1004395, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26845152

RESUMO

Bioinformatics is now a critical skill in many research and commercial environments as biological data are increasing in both size and complexity. South African researchers recognized this need in the mid-1990s and responded by working with the government as well as international bodies to develop initiatives to build bioinformatics capacity in the country. Significant injections of support from these bodies provided a springboard for the establishment of computational biology units at multiple universities throughout the country, which took on teaching, basic research and support roles. Several challenges were encountered, for example with unreliability of funding, lack of skills, and lack of infrastructure. However, the bioinformatics community worked together to overcome these, and South Africa is now arguably the leading country in bioinformatics on the African continent. Here we discuss how the discipline developed in the country, highlighting the challenges, successes, and lessons learnt.


Assuntos
Biologia Computacional , Biotecnologia , Biologia Computacional/educação , Biologia Computacional/história , Biologia Computacional/organização & administração , História do Século XX , História do Século XXI , Humanos , África do Sul
13.
Crit Rev Clin Lab Sci ; 52(3): 120-37, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25597499

RESUMO

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic non-communicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighted between the application of PSGT and exome or WGS, as the next logical step in genetically uncharacterized patients for whom a particular disease pattern and/or therapeutic failure are not adequately accounted for during the PSGT pre-screen. Discrepancies between different next generation sequencing platforms and low concordance among variant-calling pipelines caution against offering exome or WGS as a stand-alone diagnostic approach. The public reference human genome sequence (hg19) contains minor alleles at more than 1 million loci and variant calling using an advanced major allele reference genome sequence is crucial to ensure data integrity. Understanding that genomic risk prediction is not deterministic but rather probabilistic provides the opportunity for disease prevention and targeted treatment in a way that is unique to each individual patient.


Assuntos
Medicina Baseada em Evidências , Predisposição Genética para Doença , Genômica/métodos , Medicina de Precisão/métodos , Bases de Dados Genéticas , Saúde da Família , Testes Genéticos , Humanos , Medicina de Precisão/ética
14.
Hum Genomics ; 8: 18, 2014 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-25339190

RESUMO

Rapid advances in human genomic research are increasing the availability of genomic data for secondary analysis. Particularly in the case of vulnerable African populations, ethics and informed consent processes need to be transparent--both to ensure participant protection, as well as to share skills and to evolve best practice for informed consent from a shared knowledge base. An open dialogue between all stakeholders can facilitate this.


Assuntos
População Negra/genética , Bases de Dados Genéticas/ética , Genômica/ética , Consentimento Livre e Esclarecido/ética , Estudos de Associação Genética/ética , Estudos de Associação Genética/métodos , Genoma Humano , Genômica/métodos , Humanos , Populações Vulneráveis
15.
BMC Genomics ; 15: 437, 2014 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-24906912

RESUMO

BACKGROUND: Population differentiation is the result of demographic and evolutionary forces. Whole genome datasets from the 1000 Genomes Project (October 2012) provide an unbiased view of genetic variation across populations from Europe, Asia, Africa and the Americas. Common population-specific SNPs (MAF > 0.05) reflect a deep history and may have important consequences for health and wellbeing. Their interpretation is contextualised by currently available genome data. RESULTS: The identification of common population-specific (CPS) variants (SNPs and SSV) is influenced by admixture and the sample size under investigation. Nine of the populations in the 1000 Genomes Project (2 African, 2 Asian (including a merged Chinese group) and 5 European) revealed that the African populations (LWK and YRI), followed by the Japanese (JPT) have the highest number of CPS SNPs, in concordance with their histories and given the populations studied. Using two methods, sliding 50-SNP and 5-kb windows, the CPS SNPs showed distinct clustering across large genome segments and little overlap of clusters between populations. iHS enrichment score and the population branch statistic (PBS) analyses suggest that selective sweeps are unlikely to account for the clustering and population specificity. Of interest is the association of clusters close to recombination hotspots. Functional analysis of genes associated with the CPS SNPs revealed over-representation of genes in pathways associated with neuronal development, including axonal guidance signalling and CREB signalling in neurones. CONCLUSIONS: Common population-specific SNPs are non-randomly distributed throughout the genome and are significantly associated with recombination hotspots. Since the variant alleles of most CPS SNPs are the derived allele, they likely arose in the specific population after a split from a common ancestor. Their proximity to genes involved in specific pathways, including neuronal development, suggests evolutionary plasticity of selected genomic regions. Contrary to expectation, selective sweeps did not play a large role in the persistence of population-specific variation. This suggests a stochastic process towards population-specific variation which reflects demographic histories and may have some interesting implications for health and susceptibility to disease.


Assuntos
Genética Populacional , Genoma Humano , Polimorfismo de Nucleotídeo Único , Grupos Raciais/genética , Alelos , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Evolução Molecular , Humanos , Recombinação Genética , Seleção Genética
16.
PLOS Glob Public Health ; 4(5): e0002526, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38753721

RESUMO

In South Africa, PLHIV are eligible for free ART and kidney function screening. Serum creatinine (SCr) laboratory test data from the National Health Laboratory Service are collated at the Provincial Health Data Centre and linked with other routine health data. We analysed SCr and estimated glomerular filtration rate (eGFR) results for PLHIV and HIV-negative healthcare clients aged 18-80 years accessing healthcare in Khayelitsha, South Africa and comorbidity profiles at SCr and eGFR testing. 45 640 individuals aged 18-80 years with at least one renal test accessed Khayelitsha public health facilities in 2016/2017. 22 961 (50.3%) were PLHIV. Median age at first SCr and eGFR test for PLHIV was 33yrs (IQR: 27,41) to 36yrs (IQR: 30,43) compared to 49yrs (IQR: 37,57) and 52yrs (IQR: 44,59) for those without HIV. PLHIV first median SCr results were 66 (IQR: 55,78) µmol/l compared to 69 (IQR: 58,82) µmol/l for HIV-negative individuals. Hypertension, diabetes, and CKD at testing were more common in HIV-negative people than PLHIV. HIV, diabetes and tuberculosis (TB) are associated with higher eGFR results; whilst hypertension, being male and older are associated with lower eGFR results. These data reflect testing practices in the Western Cape: younger people without HIV have generally worse kidney function test results; younger PLHIV have generally good test results, and older people with/without HIV have generally similar test results, reflecting regular screening for kidney function in asymptomatic PLHIV whereas young HIV-negative people are tested only when presenting with renal symptoms. Our analysis suggests we cannot infer the future healthcare requirements of younger PLHIV based on the current ageing population, due to changing ART availability for different generations of PLHIV. Instead, routine health data may be used in an agile way to assess ongoing healthcare requirements of ageing PLHIV, and to reflect implementation of treatment guidelines.

17.
BMC Med Ethics ; 14: 21, 2013 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-23714101

RESUMO

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.


Assuntos
População Negra/genética , Exoma , Privacidade Genética/ética , Privacidade Genética/legislação & jurisprudência , Pesquisa em Genética/ética , Pesquisa em Genética/legislação & jurisprudência , Genoma Humano/genética , Genômica , Consentimento Livre e Esclarecido/ética , Consentimento Livre e Esclarecido/legislação & jurisprudência , Sujeitos da Pesquisa/legislação & jurisprudência , Análise de Sequência de DNA/ética , África , Pesquisa Participativa Baseada na Comunidade/ética , Pesquisa Participativa Baseada na Comunidade/legislação & jurisprudência , Segurança Computacional/ética , Segurança Computacional/legislação & jurisprudência , Confidencialidade/ética , Confidencialidade/legislação & jurisprudência , Escolaridade , Exoma/genética , Genômica/ética , Genômica/legislação & jurisprudência , Humanos , Achados Incidentais , Disseminação de Informação/ética , Disseminação de Informação/legislação & jurisprudência , National Institutes of Health (U.S.) , Pesquisadores/ética , Apoio à Pesquisa como Assunto , Estudos Retrospectivos , Reino Unido , Estados Unidos , Populações Vulneráveis
18.
BMJ Glob Health ; 8(10)2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37802544

RESUMO

Evidence-based healthcare relies on health data from diverse sources to inform decision-making across different domains, including disease prevention, aetiology, diagnostics, therapeutics and prognosis. Increasing volumes of highly granular data provide opportunities to leverage the evidence base, with growing recognition that health data are highly sensitive and onward research use may create privacy issues for individuals providing data. Concerns are heightened for data without explicit informed consent for secondary research use. Additionally, researchers-especially from under-resourced environments and the global South-may wish to participate in onward analysis of resources they collected or retain oversight of onward use to ensure ethical constraints are respected. Different data-sharing approaches may be adopted according to data sensitivity and secondary use restrictions, moving beyond the traditional Open Access model of unidirectional data transfer from generator to secondary user. We describe collaborative data sharing, facilitating research by combining datasets and undertaking meta-analysis involving collaborating partners; federated data analysis, where partners undertake synchronous, harmonised analyses on their independent datasets and then combine their results in a coauthored report, and trusted research environments where data are analysed in a controlled environment and only aggregate results are exported. We review how deidentification and anonymisation methods, including data perturbation, can reduce risks specifically associated with health data secondary use. In addition, we present an innovative modularised approach for building data sharing agreements incorporating a more nuanced approach to data sharing to protect privacy, and provide a framework for building the agreements for each of these data-sharing scenarios.


Assuntos
Consentimento Livre e Esclarecido , Privacidade , Humanos , Atenção à Saúde , Disseminação de Informação , Projetos de Pesquisa
19.
PLOS Glob Public Health ; 3(12): e0002730, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38127875

RESUMO

Type 2 diabetes mellitus (T2DM) is managed with combined lifestyle modifications and antidiabetic drugs, but people on treatment often fail to reach glycaemic control. Adherence is important for achieving optimal glycaemic control, and management of diabetes with drugs is a lifelong process, so understanding adherence through analysis of longitudinal medications data is important. Using retrospective routine health data and metformin dispensing records as a proxy for medication use, we describe longitudinal persistence and adherence to oral diabetes medication in a virtual cohort of 10541 people with diabetes (PLWD) in Khayelitsha subdistrict, Cape Town. Adherence was measured in 120-day sliding windows over two years and used to estimate metformin adherence trajectories. Multinomial logistic regression identified factors influencing these trajectories. Analysis of pharmacy dispensing records showed varying medication refill patterns: while some PLWD refilled prescriptions consistently, others had treatment gaps with periods of non-persistence and multiple treatment episodes-from one to five per individual across two years. There was a general trend of decreasing adherence over time across all sliding windows in the two-year period, with only 25% of the study population achieved medication adherence (> = 80% adherence) after two years. Four adherence trajectories; 'low adherence gradual decline (A), 'high adherence rapid decline' (B), 'low adherence gradual increase (C) and 'adherent' (D) were identified. Only trajectory D represented participants who were adherent at treatment start and remained adherent after two years. Taking HIV antiretroviral treatment before or concurrently with diabetes treatment and taking metformin in combination with sulphonylurea and/or insulin were associated with the long-term adherence (trajectory D). Routine data shows real life medication implementation patterns which might not be seen under controlled study conditions. This study illustrates the utility of these data in describing longitudinal adherence patterns at both an individual and population level.

20.
Int J Popul Data Sci ; 8(1): 1771, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37636832

RESUMO

Introduction: 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. Aim: 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. Methods: We apply a stepwise deterministic record linkage approach to link patient data that are routinely collected from health information systems in the Western Cape province of South Africa. Variables used in the linkage process include South African National Identity number (RSA ID), date of birth, year of birth, month of birth, day of birth, residential address and contact information. Descriptive analyses are used to estimate the level and extent of duplication in the provincial PMI. Results: The percentage of duplicates in the provincial PMI lies between 10% and 20%. Duplicates mainly arise from spelling errors, and surname and first names carry most of the errors, with the first names and surname being different for the same individual in approximately 22% of duplicates. The RSA ID is the variable mostly affected by poor completeness with less than 30% of the records having an RSA ID.The current linkage algorithm requires refinement as it makes use of algorithms that have been developed and validated on anglicised names which might not work well for local names. Linkage is also affected by data quality-related issues that are associated with the routine nature of the data which often make it difficult to validate and enforce integrity at the point of data capture.


Assuntos
Troca de Informação em Saúde , Dados de Saúde Coletados Rotineiramente , Humanos , Algoritmos , População Negra/estatística & dados numéricos , Confiabilidade dos Dados , Troca de Informação em Saúde/estatística & dados numéricos , África do Sul/epidemiologia
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