9 research outputs found
Designing Data-Driven Learning Algorithms: A Necessity to Ensure Effective Post-Genomic Medicine and Biomedical Research
Advances in sequencing technology have significantly contributed to shaping the area of genetics and enabled the identification of genetic variants associated with complex traits through genome-wide association studies. This has provided insights into genetic medicine, in which case, genetic factors influence variability in disease and treatment outcomes. On the other side, the missing or hidden heritability has suggested that the host quality of life and other environmental factors may also influence differences in disease risk and drug/treatment responses in genomic medicine, and orient biomedical research, even though this may be highly constrained by genetic capabilities. It is expected that combining these different factors can yield a paradigm-shift of personalized medicine and lead to a more effective medical treatment. With existing “big data” initiatives and high-performance computing infrastructures, there is a need for data-driven learning algorithms and models that enable the selection and prioritization of relevant genetic variants (post-genomic medicine) and trigger effective translation into clinical practice. In this chapter, we survey and discuss existing machine learning algorithms and post-genomic analysis models supporting the process of identifying valuable markers
Modelling early iInitiation of HAART to forestall AIDS-related lymphoma in South Africa: a cost-effectiveness analysis.
Thesis (MSc)--Stellenbosch University, 2017.ENGLISH SUMMARY: The burden of cancer in low and middle income countries has been projected to shift
from 59% (in 2012) to 65% (by 2030) of all cancer cases globally. Since the introduction
of highly active antiretroviral therapy (HAART) in South Africa, there has
been a marked decline in AIDS-related illnesses and premature death. However, this
has not been the case with AIDS-related lymphoma which was observed to be on the
rise despite the large HAART roll-out programme. It was discovered that 37% of all
lymphoma cases diagnosed in 2009 in the Western Cape province, were HIV-related,
indicating a remarkable increase from 5% in 2002. The ineffectiveness of HAART in
reducing the incidence of lymphoma is largely attributed to late commencement of
treatment. However, increasing HAART coverage is still a major challenge to many
developing countries in Africa as well as South Africa due to limited resources.
Therefore, increasing early HAART initiation has a cost implication that needs to
be investigated in resource limited settings. In this study we used a deterministic
compartmental model to investigate the potential impact of initiating HAART at different CD4 cell count levels on the incidence of lymphoma in HIV-infected individuals.
We also developed a linked transmission and health state transition (Markov)
model in TreeAge Pro to determine the cost-effectiveness of early HAART initiation
from the public healthcare payer perspective. The CD4 count driven transmission
model predicted lymphoma incidence in HIV-infected adults (aged 15 to 80 years)
over a period of ten years. The Markov model predicted the health outcomes and
costs. Data on transmission, transition probabilities, CD4 count thresholds, life expectancy,
effectiveness and costs were obtained from literature. We compared early
initiation of HAART at a CD4 cell count of greater than 500 cells= L to initiation
at less than 500 cells= L, the current standard of care. Our primary outcomes were
Quality-adjusted life years (QALYs), expected costs, net monetary benefit and the
incremental cost-effectiveness ratio (ICER). Health outcomes and costs were discounted
at a rate of 5% per annum as recommended in Southern Africa. We also
performed deterministic sensitivity analyses to assess parameter uncertainty.
Results indicated that early HAART initiation prevents lymphoma cases and related
deaths, translating to 3.76 QALYs gained over the 10-year time horizon (6.47
vs. 2.71 expected QALYs with HAART initiation at greater than 500 cells= L and
less than 500 cells= L, respectively). The incremental cost of early initiation was
90,581 and 3,890/QALY gained.
Sensitivity analysis showed outcomes were sensitive to the effectiveness of HAART
in preventing lymphoma, with early initiation being more sensitive than the base
case. Therefore, early HAART initiation at CD4 greater than 500 cells= L would
not only be effective in forestalling AIDS-related lymphoma but also cost-effective
in resource limited settings.AFRIKAANSE OPSOMMING: Die las van kanker in ’n lae en middel-inkomste lande is geprojekteer vanaf 59%
(in 2012) te skuif na 65% (in 2030) van alle kankergevalle wêreldwyd. Sedert die
bekendstelling van hoogs aktiewe antiretrovirale terapie in Suid-Afrika, daar was ’n
merkbare afname in vigs - verwante siektes en voortydige dood. Maar dit is nog nie
die geval met vigsverwante limfoom wat waargeneem om op te gewees die opkoms
ten spyte van die groot HAART uitrol program. Daar is vasgestel dat 37% van al
limfoom gevalle gediagnoseer in 2009 in Wes-Kaap was MIV-verwante wat dui op
’n merkwaardige toename van 5% in 2002. Die ondoeltreffendheid van HAART in
die vermindering van die voorkoms van limfoom is grootliks toegeskryf word aan die
laat aanvang behandeling. Maar, die verhoging van HAART dekking is nog steeds
’n groot uitdaging om baie ontwikkelende lande in Afrika, insluitend Suid-Afrika
as gevolg van beperkte hulpbronne. Daarom, die verhoging van die vroeë HAART
inisiasie het ’n koste-implikasie wat gevolg moet word ondersoek in hulpbron beperk
instellings. Ons gebruik ’n deterministiese kompartementele model om die potensiële impak van die inisiëring HAART op verskillende CD4-seltelling vlakke op
die voorkoms van limfoom in MIV-geïnfekteerde individue te ondersoek. Ons het
ook ’n gekoppelde transmissie en gesondheid toestand oorgang (Verborge) model in
TreeAge Pro om die koste-effektiwiteit van die vroeë HAART inleiding bepaal uit
die openbare gesondheidsorg betaler perspektief. Die CD4-telling gedryf transmissie
model voorspel limfoom voorkoms van MIV-geïnfekteerde volwassenes (15-80 jaar
oud) oor ’n tydperk van tien jaar. Die Markov model voorspel dat die gesondheid
uitkomste en koste. Data oor die oordrag , oorgang waarskynlikhede, tel CD4 drempels,
lewensverwagting, doeltreffendheid en koste is verkry uit die literatuur. Ons
vergelyk vroeë aanvang van HAART op ’n CD4-seltelling van meer as 500 selle= L
na inisiasie teen minder as 500 selle= L, die huidige standaard van sorg. Ons primêre
uitkomste was lewe jaar Kwaliteit-aangepaste (QALYs), verwagte koste, netto
monetêre voordeel en die inkrementele koste-effektiwiteit verhouding (ICER). Gesondheid
uitkomste en koste word verdiskonteer teen ’n koers van 5% per jaar soos
aanbeveel in Suider-Afrika. Ons het ook uitgevoer deterministiese sensitiwiteitsanalises
om parameter onsekerheid te evalueer. Resultate het aangedui dat vroeë
HAART inisiasie verhoed limfoom gevalle en verwante sterftes, vertaal na 3.76 QALYs
wat oor die 10-jarige tydhorison (6,47 teen 2,71 verwag QALYs met HAART
inleiding op groter as 500 selle= L en teen minder as 500 selle= L , onderskeidelik).
Die inkrementele koste van vroeë aanvang was 90,581 en
3,890/QALY opgedoen. Sensitiwiteitsanalise
het uitkomste was sensitief vir die doeltreffendheid van HAART in die voorkoming
van limfoom, met vroeë aanvang om meer sensitief as die basis geval. Daroom, vroeë
HAART inleiding op CD4 groter as 500 selle= L sou nie net effektief in forestalling
vigsverwante limfoom, maar ook koste-effektief in beperkte hulpbronne instellings
wees
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Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV.
BackgroundApproaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy.MethodsConsecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough ≥ 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificity of the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to ≥ 90% as recommended for TB screening.ResultsThe median plasma level of 5 biomarkers (IL-6, INF-γ, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90%, all had low specificity with IL-6 showing the highest specificity (44%; 95% CI 37.4-49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-γ and IL-6 had the highest specificity (50%; 95% CI 46.7-53.3). Sensitivity remained high (>85%) for all panels among sputum smear-negative TB patients.ConclusionsDirect measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common
Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV.
BACKGROUND:Approaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy. METHODS:Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough ≥ 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificity of the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to ≥ 90% as recommended for TB screening. RESULTS:The median plasma level of 5 biomarkers (IL-6, INF-γ, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90%, all had low specificity with IL-6 showing the highest specificity (44%; 95% CI 37.4-49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-γ and IL-6 had the highest specificity (50%; 95% CI 46.7-53.3). Sensitivity remained high (>85%) for all panels among sputum smear-negative TB patients. CONCLUSIONS:Direct measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common
The data use ontology to streamline responsible access to human biomedical datasets
Human biomedical datasets that are critical for research and clinical studies to benefit human health also often contain sensitive or potentially identifying information of individual participants. Thus, care must be taken when they are processed and made available to comply with ethical and regulatory frameworks and informed consent data conditions. To enable and streamline data access for these biomedical datasets, the Global Alliance for Genomics and Health (GA4GH) Data Use and Researcher Identities (DURI) work stream developed and approved the Data Use Ontology (DUO) standard. DUO is a hierarchical vocabulary of human and machine-readable data use terms that consistently and unambiguously represents a dataset's allowable data uses. DUO has been implemented by major international stakeholders such as the Broad and Sanger Institutes and is currently used in annotation of over 200,000 datasets worldwide. Using DUO in data management and access facilitates researchers' discovery and access of relevant datasets. DUO annotations increase the FAIRness of datasets and support data linkages using common data use profiles when integrating the data for secondary analyses. DUO is implemented in the Web Ontology Language (OWL) and, to increase community awareness and engagement, hosted in an open, centralized GitHub repository. DUO, together with the GA4GH Passport standard, offers a new, efficient, and streamlined data authorization and access framework that has enabled increased sharing of biomedical datasets worldwide.G.K., M.A.F., H.P., J.D.S., and M.C. were funded by EMBL-EBI Core Funds and Wellcome Trust GA4GH award number 201535/Z/16/Z. T. T. Boughtwood was funded by NHMRC GNT111353, GNT200001, and the Australian MRFF. P.A. was funded by ELIXIR Luxembourg. S.D. and K.R. were funded by the Broad Institute. M.A.H. and M.B. received funding from NIH #5R24OD011883. M.L. and M.C. were funded by the CINECA project (H2020 No 825775). N.M. and L.Z. were funded by H3ABioNet, NIH grant number U24HG006941. S.O. and C.Y. received funding from the Japan Agency for Medical Research and Development (AMED) under grant numbers JP19kk020501 and JP18kk0205012. A.A.P. was funded by NHGRI AnVIL, award number U24HG010262. F.P. was supported, in part, by the European Union’s Horizon 2020 research and innovation program under the EJP RD COFUND-EJP #825575. M.A.S. and E.J.v.E. were funded by FAIR genomes (ZonMW #846003201) and EOSC-Life (H2020 #824087
Prospective observational cohort study on grading the severity of postoperative complications in global surgery research
Background
The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs).
Methods
This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs.
Results
A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59).
Conclusion
Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally
Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries
This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London
The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis
© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine