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Machine Learning versus Cox Models for Predicting Overall Survival in Patients with Osteosarcoma: A Retrospective Analysis of the EURAMOS-1 Clinical Trial Data.
Get PDFSince the mid-1980s, there has been little progress in improving survival of patients diagnosed with osteosarcoma. Survival prediction models play a key role in clinical decision-making, guiding healthcare professionals in tailoring treatment strategies based on individual patient risks. The increasing interest of the medical community in using machine learning (ML) for predicting survival has sparked an ongoing debate on the value of ML techniques versus more traditional statistical modelling (SM) approaches. This study investigates the use of SM versus ML methods in predicting overall survival (OS) using osteosarcoma data from the EURAMOS-1 clinical trial (NCT00134030). The well-established Cox proportional hazard model is compared to the extended Cox model that includes time-varying effects, and to the ML methods random survival forests and survival neural networks. The impact of eight variables on OS predictions is explored. Results are compared on different model performance metrics, variable importance, and patient-specific predictions. The article provides comprehensive insights to aid healthcare researchers in evaluating diverse survival prediction models for low-dimensional clinical data
Evaluation of the potential impact and cost-effectiveness of respiratory syncytial virus (RSV) prevention strategies for infants in Argentina.
Get PDFBACKGROUND: New interventions are available for the prevention of respiratory syncytial virus (RSV) disease in young infants. We aimed to assess the potential impact and cost-effectiveness of using a long-acting monoclonal antibody (RSV mAb) or maternal RSV vaccine in the Argentine context.
METHODS: We used a static proportionate outcomes model to calculate the costs and consequences of using RSV mAb or maternal RSV vaccine over a ten-year period (2025-2034) in Argentina, assuming both year-round and seasonal administration. We compared each intervention to no pharmaceutical RSV intervention. The primary outcome was the discounted cost per disability-adjusted life year (DALY) averted from a societal perspective. We assumed willingness-to-pay of USUS 50, both products have a 100% probability of being cost-effective compared to no intervention (US5203- 5522 [95%CI 5617] per DALY averted for year-round use of RSV mAb and maternal RSV vaccine, respectively). Similar health impact could be achieved by a six-month seasonal strategy, which could improve cost-effectiveness by around 45% (assuming the dose price is unchanged).
INTERPRETATION: Either RSV mAb or maternal RSV vaccine are worth consideration in Argentina when priced at ≤US$ 50 per dose. A seasonal strategy could improve cost-effectiveness.
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Expanding the roles of malaria post workers in Thailand: A qualitative study of stakeholder perspectives.
Get PDFIn Thailand, since the 2000s, malaria post (MP) workers have been tasked with promptly detecting and treating all malaria cases to prevent onward transmission in the communities. Expanding their roles to provide health services beyond malaria has been proposed as a strategy to sustain their activities until elimination is reached. This article examines the perspectives of stakeholders on community-based malaria care to assess prospects for expanding the role of MPs. The study incorporated in-depth interviews (IDIs) and focus group discussions (FGDs). In forested communities and local health facilities in northeast Thailand bordering Lao PDR and Cambodia, where malaria transmission is low, IDIs were conducted with 13 MPs and 23 community members. An additional 14 policymakers and implementers across the health sector in Thailand were interviewed. The respondents highlighted how in these border areas population groups most at risk of malaria, namely forest goers and migrants, are reluctant to visit public health facilities. In these areas, MP workers are well integrated in their communities and remain relevant although the communities no longer see malaria as spriority. Common conditions such as dengue, diabetes, insect bites, diarrhea, mental illness and substance abuse, were identified as local health concerns needing potential add-on services from MP workers. Although challenges in terms of training, supervision, and financing were raised, opportunities included additional funds from local administrative offices to maintain and integrate malaria activities with other health programmes. Changes to the roles of MPs should be adapted to changing local needs, some of which were identified in this study, should avoid duplication and potential tensions with other local health programmes, and need to build on the capacity of the community and primary care system. These enabling factors are worthy of consideration by any malaria programmes looking into maintaining their village malaria workers in the Greater Mekong Subregion
Ethnic differences in the manifestation of early-onset type 2 diabetes.
Get PDFINTRODUCTION: We undertook phenotypic characterization of early-onset and late-onset type 2 diabetes (T2D) in adult black African and white European populations with recently diagnosed T2D to explore ethnic differences in the manifestation of early-onset T2D.
RESEARCH DESIGN AND METHODS: Using the Uganda Diabetes Phenotype study cohort of 500 adult Ugandans and the UK StartRight study cohort of 714 white Europeans with recently diagnosed islet autoantibody-negative T2D, we compared the phenotypic characteristics of participants with early-onset T2D (diagnosed at <40 years) and late-onset T2D (diagnosed at ≥40 years).
RESULTS: One hundred and thirty-four adult Ugandans and 113 white Europeans had early-onset T2D. Compared with late-onset T2D, early-onset T2D in white Europeans was significantly associated with a female predominance (52.2% vs 39.1%, p=0.01), increased body mass index (mean (95% CI) 36.7 (35.2-38.1) kg/m2 vs 33.0 (32.4-33.6) kg/m2, p<0.001), waist circumference (112.4 (109.1-115.6) cm vs 108.8 (107.6-110.1) cm, p=0.06), and a higher frequency of obesity (82.3% vs 63.4%, p<0.001). No difference was seen with the post-meal C-peptide levels as a marker of beta-cell function (mean (95% CI) 2130.94 (1905.12-2356.76) pmol/L vs 2039.72 (1956.52-2122.92), p=0.62).In contrast, early-onset T2D in Ugandans was associated with less adiposity (mean (95% CI) waist circumference 93.1 (89.9-96.3) cm vs 97.4 (95.9-98.8) cm, p=0.006) and a greater degree of beta-cell dysfunction (120 min post-glucose load C-peptide mean (95% CI) level 896.08 (780.91-1011.24) pmol/L vs 1310.10 (1179.24-1440.95) pmol/L, p<0.001), without female predominance (53.0% vs 57.9%, p=0.32) and differences in the body mass index (mean (95% CI) 27.3 (26.2-28.4) kg/m2 vs 27.9 (27.3-28.5) kg/m2, p=0.29).
CONCLUSIONS: These differences in the manifestation of early-onset T2D underscore the need for ethnic-specific and population-specific therapeutic and preventive approaches for the condition
Silence is golden, but my measures still see-why cheaper-but-noisier outcome measures in large simple trials can be more cost-effective than gold standards.
Get PDFOBJECTIVE: To assess the cost-effectiveness of using cheaper-but-noisier outcome measures, such as a short questionnaire, for large simple clinical trials.
BACKGROUND: To detect associations reliably, trials must avoid bias and random error. To reduce random error, we can increase the size of the trial and increase the accuracy of the outcome measurement process. However, with fixed resources, there is a trade-off between the number of participants a trial can enrol and the amount of information that can be collected on each participant during data collection.
METHODS: To consider the effect on measurement error of using outcome scales with varying numbers of categories, we define and calculate the variance from categorisation that would be expected from using a category midpoint; define the analytic conditions under which such a measure is cost-effective; use meta-regression to estimate the impact of participant burden, defined as questionnaire length, on response rates; and develop an interactive web-app to allow researchers to explore the cost-effectiveness of using such a measure under plausible assumptions.
RESULTS: An outcome scale with only a few categories greatly reduced the variance of non-measurement. For example, a scale with five categories reduced the variance of non-measurement by 96% for a uniform distribution. We show that a simple measure will be more cost-effective than a gold-standard measure if the relative increase in variance due to using it is less than the relative increase in cost from the gold standard, assuming it does not introduce bias in the measurement. We found an inverse power law relationship between participant burden and response rates such that a doubling the burden on participants reduces the response rate by around one third. Finally, we created an interactive web-app ( https://benjiwoolf.shinyapps.io/cheapbutnoisymeasures/ ) to allow exploration of when using a cheap-but-noisy measure will be more cost-effective using realistic parameters.
CONCLUSION: Cheaper-but-noisier questionnaires containing just a few questions can be a cost-effective way of maximising power. However, their use requires a judgement on the trade-off between the potential increase in risk of information bias and the reduction in the potential of selection bias due to the expected higher response rates
HBHA induces IL-10 from CD4+ T cells in patients with active tuberculosis but IFN-γ and IL-17 from individuals with Mycobacterium tuberculosis infection.
Get PDFBACKGROUND: To effectively control tuberculosis (TB), it is crucial to distinguish between active TB disease and latent TB infection (LTBI) to provide appropriate treatment. However, no such tests are currently available. Immune responses associated with active TB and LTBI are dynamic and exhibit distinct patterns. Comparing these differences is crucial for developing new diagnostic methods and understanding the etiology of TB. This study aimed to investigate the relationship between pro- and anti-inflammatory CD4+ cytokine production following stimulation with two types of latency-associated Mycobacterium tuberculosis (M.tb) antigens to allow differentiation between active TB and LTBI.
METHODS: Cryopreserved PBMCs from patients with active TB disease or LTBI were stimulated overnight with replication-related antigen [ESAT-6/CFP-10 (E/C)] or two latency-associated antigens [heparin-binding hemagglutinin (HBHA) and alpha-crystallin-like protein (Acr)]. Responses were analyzed using multiparameter flow cytometry: active TB disease (n=15), LTBI (n=15) and ELISA: active TB disease (n=26) or LTBI (n=27).
RESULTS: CD4+ central memory T cells (Tcm) specific to E/C and CD4+ effector memory T cells specific to Acr and HBHA were higher in LTBI than in TB patients. IFN-γ+Tcm and IL-17+ Tem cells was higher in the LTBI group (p= 0.012 and p=0.029 respectively), but IL-10+ Tcm was higher in the active TB group (p= 0.029) following HBHA stimulation. Additionally, following stimulation with HBHA, IL-10 production from CD4+ T cells was significantly elevated in patients with active TB compared to those with LTBI (p= 0.0038), while CD4+ T cell production of IL-17 and IFN-γ was significantly elevated in LTBI compared to active TB (p= 0.0076, p< 0.0001, respectively). HBHA also induced more CCR6+IL-17+CD4Tcells and IL-17+FoxP3+CD25+CD4Tcells in LTBI than in TB patients (P=0.026 and P=0.04, respectively). HBHA also induced higher levels of IFN-γ+IL-10+CD4+ T cells in patients with active TB (Pp=0.03) and higher levels of IFN-γ+IL-17+ CD4+ T cells in those with LTBI (p=0.04). HBHA-specific cytokine production measured using ELISA showed higher levels of IFN-γ in participants with LTBI (P=0.004) and higher levels of IL-10 in those with active TB (P=0.04).
CONCLUSION: Stimulation with HBHA and measurement of CD4+ T cell production of IFN-γ, IL-10, and IL-17 could potentially differentiate active TB from LTBI. The characteristics of cytokine-expressing cells induced by HBHA also differed between participants with active TB and LTBI
Spatial distribution and characteristics of women reporting cervical cancer screening in Malawi: An analysis of the 2020 to 2021 Malawi Population-based HIV Impact Assessment survey data.
Get PDFBACKGROUND: Malawi has one of the highest incidence and mortality rates of cervical cancer in the world. Despite a national strategic plan and the roll-out of VIA and screen-and-treat services, cervical cancer screening coverage in Malawi remains far below the national target.Using a nationally representative sample of women enumerated in the Malawi Population-based Impact Assessment (MPHIA) survey we estimated the prevalence and spatial distribution of self-reported cervical cancer screening as a proxy for uptake in Malawi.
METHODS: MPHIA was a nationally representative household survey in Malawi, targeting adults aged 15 and above, that employed a cross-sectional, two-stage, cluster design. The primary aim of MPHIA was to assess the regional prevalence of viral load suppression and the progress towards achieving the UNAIDS 95-95-95 goals among adults aged 15 and above. The survey was carried out between January 2020 and April 2021. Prevalence of self-reported cervical cancer screening by different characteristics was estimated accounting for the survey design using the Taylor series approach. We used univariable and multivariable logistic regression approaches to examine associations between the prevalence of cervical cancer screening and demographic characteristics.
FINDINGS: A total of 13,067 adult (15 years and older) female individuals were surveyed during the MPHIA 2020 to 2021 survey, corresponding to a weighted total of 5,604,578. The prevalence of self-reported cervical cancer screening was 16.5% (95% CI 15.5-18.0%), with women living with HIV having a higher prevalence of 37.8% (95% CI 34.8-40.9) compared to 14.0% (95% CI 13.0-15.0) in HIV negative women. The highest prevalence of screening was reported in the Southwest zone (SWZ) (24.1%, 95% CI 21.3-26.9) and in major cities of Blantyre (25.9%, 95% CI 22.9-29.0), and Lilongwe (19.6%, 95% CI 18.0-21.3). Higher self-reported screening was observed in women who resided in urban regions ((22.7%; 95% CI 21.4-24.0) versus women who resided in rural areas (15.2%; 95% CI 14.0-16.8). Cervical cancer screening was strongly associated with being HIV positive (aOR 2.83; 95% CI 2.29-3.50), ever having been pregnant (aOR 1.93; 95% CI 1.19-3.14), attaining higher education level than secondary education (aOR 2.74; 95% CI 1.67-4.52) and being in the highest wealth quintile (aOR 2.86; 95% CI 2.01-4.08).
INTERPRETATION: The coverage of cervical cancer screening in Malawi remains low and unequal by region and wealth/education class. Current screening efforts are largely being focussed on women accessing HIV services. There is need for deliberate interventions to upscale cervical cancer screening in both HIV negative women and women living with HIV
Exploring the association between multidimensional poverty and antenatal care utilization in two provinces of Papua New Guinea: a cross-sectional study.
Get PDFBACKGROUND: Although global poverty rates have declined in the last decade, the fall in the Asia-Pacific region has been slow relative to the rest of the world. Poverty continues to be a major cause of poor maternal and newborn health, and a barrier to accessing timely antenatal care. Papua New Guinea has one of the highest poverty rates and some of the worst maternal and neonatal outcomes in the Asia-Pacific region. Few studies have investigated equity in antenatal care utilization in this setting. We explored equity in antenatal care utilization and the determinants of service utilization, which include a measure of multidimensional poverty in Papua New Guinea.
METHODS: To explore the association between poverty and antenatal care utilization this study uses data from a ten-cluster randomized controlled trial. The poverty headcount, average poverty gap, adjusted poverty headcount, and multidimensional poverty index of antenatal clinic attendees are derived using the Alkire-Foster method. The distribution of service utilization is explored using the multidimensional poverty index, followed by multivariate regression analyses to evaluate the determinants of service utilization.
RESULTS: The poverty headcount was 61.06%, the average poverty gap 47.71%, the adjusted poverty headcount 29.13% and the average multidimensional poverty index was 0.363. Further, antenatal care utilization was regressive with respect to poverty. The regression analyses indicated that older women; being a widow (small number of widows (n = 3) asserts interpreting result with caution); or formally employed increase the likelihood of accessing antenatal care more often in pregnancy. Travelling for over an hour to receive care was negatively associated with utilization.
CONCLUSION: This study indicated high levels of multidimensional poverty in PNG and that ANC utilization was regressive; highlighting the need to encourage pregnant women, especially those who are economically more vulnerable to visit clinics regularly throughout pregnancy
Is heat wave a predictor of diarrhoea in Dhaka, Bangladesh? A time-series analysis in a South Asian tropical monsoon climate.
Get PDFWhile numerous studies have assessed the association between temperature and diarrhoea in various locations, evidence of relationship between heat wave and diarrhoea is scarce. We defined elevated daily mean and maximum temperature over the 95th and 99th percentiles lasting for at least one day between March to October 1981-2010 as TAV95 and TAV99 and D95 and D99 heat wave, respectively. We investigated the association between heat wave and daily counts of hospitalisations for all-cause diarrhoea in Dhaka, Bangladesh using time series regression analysis employing constrained distributed lag-linear models. Effects were assessed for all ages and children aged under 5 years of age. Diarrhoea hospitalisation increased by 6.7% (95% CI: 4.6%- 8.9%), 8.3% (3.7-13.1), 7.0 (4.8-9.3) and 7.4 (3.1-11.9) in all ages on a TAV95, TAV99, D95 and D99 heat wave day, respectively. These effects were more pronounced for under-5 children with an increase of 13.9% (95% CI: 8.3-19.9), 24.2% (11.3-38.7), 17.0 (11.0-23.5) and 19.5 (7.7-32.6) in diarrhoea hospitalisations on a TAV95, TAV99, D95 and D99 heat wave day, respectively. At lags of 3 days, we noticed a negative association indicating a 'harvesting' effect. Our findings suggest that heat wave was a significant risk factor for diarrhoea hospitalisation in Dhaka. Further research is needed to elucidate the causal pathways and identify the preventive measures necessary to mitigate the impacts of heat waves on diarrhoea. Given that no heat wave definitions exist for Dhaka, these results may help to define heat waves for Dhaka and trigger public health interventions including heat alerts to prevent heat-related morbidity in Dhaka, Bangladesh
Blood RNA biomarkers for tuberculosis screening in people living with HIV before antiretroviral therapy initiation: a diagnostic accuracy study.
Get PDFBACKGROUND: Undiagnosed tuberculosis remains a major threat for people living with HIV. Multiple blood transcriptomic biomarkers have shown promise for tuberculosis diagnosis. We sought to evaluate their diagnostic accuracy and clinical utility for systematic pre-antiretroviral therapy (ART) tuberculosis screening. METHODS: We enrolled consecutive adults (age ≥18 years) referred to start ART at a community health centre in Cape Town, South Africa, irrespective of symptoms. Sputa were obtained (using induction if required) for two liquid cultures. Whole-blood RNA samples underwent transcriptional profiling using a custom Nanostring gene panel. We measured the diagnostic accuracy of seven candidate RNA signatures (one single gene biomarker [BATF2] and six multigene biomarkers) for the reference standard of Mycobacterium tuberculosis culture status, using area under the receiver-operating characteristic curve (AUROC) analysis, and sensitivity and specificity at prespecified thresholds (two standard scores above the mean of healthy controls; Z2). Clinical utility was assessed by calculating net benefit in decision curve analysis. We compared performance with C-reactive protein (CRP; threshold ≥5 mg/L), WHO four-symptom screen (W4SS), and the WHO target product profile for tuberculosis triage tests. FINDINGS: A total of 707 people living with HIV (407 [58%] female and 300 [42%] male) were included, with median CD4 count 306 cells per mm3 (IQR 184-486). Of 676 participants with available sputum culture results, 89 (13%) had culture-confirmed tuberculosis. The seven RNA signatures were moderately to highly correlated (Spearman rank coefficients 0·42-0·93) and discriminated tuberculosis culture positivity with similar AUROCs (0·73-0·80), but none statistically better than CRP (AUROC 0·78, 95% CI 0·72-0·83). Diagnostic accuracy was similar across CD4 count strata, but lower among participants with negative W4SS (AUROCs 0·56-0·65) compared with positive (AUROCs 0·75-0·84). The RNA biomarker with the highest AUROC point estimate was a four-gene signature (Suliman4; AUROC 0·80, 95% CI 0·75-0·86), with sensitivity 83% (95% CI 74-90) and specificity 59% (55-63) at the Z2 threshold. In decision curve analysis, Suliman4 and CRP had similar clinical utility to guide confirmatory tuberculosis testing, but both had higher net benefit than W4SS. In exploratory analyses, an approach combining CRP (≥5 mg/L) and Suliman4 (≥Z2) had sensitivity of 80% (70-87), specificity of 70% (66-74), and higher net benefit than either biomarker alone. INTERPRETATION: RNA biomarkers showed better clinical utility to guide confirmatory tuberculosis testing for people living with HIV before ART initiation than symptom-based screening, but their performance did not exceed that of CRP and fell short of WHO recommended targets. Interferon-independent approaches might be required to improve accuracy of host-response biomarkers to support tuberculosis screening before ART initiation. FUNDING: South African Medical Research Council, European and Developing Countries Clinical Trials Partnership 2, National Institutes of Health National Institute of Allergy and Infectious Diseases, The Wellcome Trust, National Institute for Health and Care Research, Royal College of Physicians London