Background: Gene-set analysis evaluates the expression of biological pathways, or a priori defined gene sets, rather than that of individual genes, in association with a binary phenotype, and is of great biologic interest in many DNA microarray studies. Gene Set Enrichment Analysis (GSEA) has been applied widely as a tool for gene-set analyses. We describe here some critical problems with GSEA and propose an alternative method by extending the individual-gene analysis method, Significance Analysis of Microarray (SAM), to gene-set analyses (SAM-GS). Results: Using a mouse microarray dataset with simulated gene sets, we illustrate that GSEA gives statistical significance to gene sets that have no gene associated with the phenotype (null gene sets), and has very low power to detect gene sets in which half the genes are moderately or strongly associated with the phenotype (truly-associated gene sets). SAM-GS, on the other hand, performs very well. The two methods are also compared in the analyses of three real microarray datasets and relevant pathways, the diverging results of which clearly show advantages of SAM-GS over GSEA, both statistically and biologically. In a microarray study for identifying biological pathways whose gene expressions are associated with p53 mutation in cancer cell lines, we found biologically relevant performance differences between the two methods. Specifically, there are 31 additional pathways identified as significant by SAM-GS over GSEA, that are associated with the presence vs. absence of p53. Of the 31 gene sets, 11 actually involve p53 directly as a member. A further 6 gene sets directly involve the extrinsic and intrinsic apoptosis pathways, 3 involve the cell-cycle machinery, and 3 involve cytokines and/or JAK/STAT signaling. Each of these 12 gene sets, then, is in a direct, well-established relationship with aspects of p53 signaling. Of the remaining 8 gene sets, 6 have plausible, if less well established, links with p53. Conclusion: We conclude that GSEA has important limitations as a gene-set analysis approach for microarray experiments for identifying biological pathways associated with a binary phenotype. As an alternative statistically-sound method, we propose SAM-GS. A free Excel Add-In for performing SAM-GS is available for public use.

Little is known about the fertility desires of HIV infected individuals on highly active antiretroviral therapy (HAART). In order to contribute more knowledge to this topic we conducted a study to determine if HIV-infected persons on HAART have different fertility desires compared to persons not on HAART, and if the knowledge about HIV transmission from mother-to-child is different in the two groups.

As is the case elsewhere in sub-Saharan Africa, Ghana is experiencing a rapid increase in the population of older adults. Despite their rising numbers, the living conditions and wellbeing of older Ghanaians remain woefully understudied. This paper presents the results of a study exploring the quality of life (QoL) of older adults in two contrasting neighbourhoods in Accra, Ghana. The objectives of the study were to: (1) explore and compare the QoL of older slum and non-slum dwellers in Ghana; and (2) determine the extent of QoL disparities between slum and non-slum older adults. To accomplish these objectives, we undertook a cross-sectional survey of older adults (N = 603) residing in a slum and non-slum neighbourhood. QoL was self-assessed in four domains - physical, psychological, social, and environment - using the World Health Organization (WHO) QoL assessment tool (WHOQoL-BREF). Multivariable linear regression analyses of the data revealed no statistically significant difference between the slum and non-slum respondents in physical (coeff: 0.5; 95% CI: -1.7, 2.8; p = 0.642) and psychological (coeff: -0.2; 95% CI: -3.0, 2.6; p = 0.893) QoL. However, the slum respondents reported significantly higher social QoL than the non-slum respondents (coeff: -3.2; 95% CI: -5.6, -0.8; p = 0.010), while the reverse was true in environmental QoL (coeff: 4.2; 95% CI: 2.3, 6.2; p < 0.001). The existence of strong social support systems in the slum and better housing and neighbourhood environmental conditions in the non-slum may have accounted for the observed variation in social and environmental QoL. Thus, contrary to popular discourses that vilify slums as health-damaging milieus, these findings offer a more nuanced picture, and suggest that some features of slums may constitute important health resources for older adults.

Pakistan is one of the six countries estimated to contribute to over half of all maternal deaths worldwide. To address its high maternal mortality rate, in particular the inequities in access to maternal health care services, the government of Pakistan created a new cadre of community-based midwives (CMW). A key expectation is that the CMWs will improve access to skilled antenatal and intra-partum care for the poor and disadvantaged women. A critical gap in our knowledge is whether this cadre of workers, operating in the private health care context, will meet the expectation to provide care to the poorest and most marginalized women. There is an inherent paradox between the notions of fee-for-service and increasing access to health care for the poorest who, by definition, are unable to pay.

In 2007, the Government of Pakistan introduced a new cadre of community midwives (CMWs) to address low skilled birth attendance rates in rural areas; this workforce is located in the private-sector. There are concerns about the effectiveness of the programme for increasing skilled birth attendance as previous experience from private-sector programmes has been sub-optimal. Indonesia first promoted private sector midwifery care, but the initiative failed to provide universal coverage and reduce maternal mortality rates. A clustered, stratified survey was conducted in the districts of Jhelum and Layyah, Punjab. A total of 1,457 women who gave birth in the 2 years prior to the survey were interviewed. χ2 analyses were performed to assess variation in coverage of maternal health services between the two districts. Logistic regression models were developed to explore whether differentials in coverage between the two districts could be explained by differential levels of development and demand for skilled birth attendance. Mean cost of childbirth care by type of provider was also calculated. Overall, 7.9% of women surveyed reported a CMW-attended birth. Women in Jhelum were six times more likely to report a CMW-attended birth than women in Layyah. The mean cost of a CMW-attended birth compared favourably with a dai-attended birth. The CMWs were, however, having difficulty garnering community trust. The majority of women, when asked why they had not sought care from their neighbourhood CMW, cited a lack of trust in CMWs’ competency and that they wanted a different provider. The CMWs have yet to emerge as a significant maternity care provider in rural Punjab. Levels of overall community development determined uptake and hence coverage of CMW care. The CMWs were able to insert themselves into the maternal health marketplace in Jhelum because of an existing demand. A lower demand in Layyah meant there was less ‘space’ for the CMWs to enter the market. To ensure universal coverage, there is a need to revisit the strategy of introducing a new midwifery workforce in the private sector in contexts of low demand and marketing the benefits of skilled birth attendance.

In Canada, reimbursement recommendations on drugs for common and rare diseases are overseen by the Canadian Agency for Drugs and Technologies in Health (CADTH) and made through the pan-Canadian Oncology Drug Review (pCODR) and the Common Drug Review (CDR). While the agency specifies information requirements for the review of drug submissions, how that information is used by each process to formulate final reimbursement recommendations, particularly on drugs for rare diseases (DRDs) in which per patient treatment costs are often high, is unclear. The purpose of this study was to determine which factors contribute to recommendation type for DRDs. Information was extracted from CDR and pCODR recommendations on drugs for diseases with a prevalence < 1 in 2000 from January 2012 to April 2018. Data were tabulated and multiple logistic regression was applied to explore the association between recommendation type and the following factors: condition/review process (cancer vs non-cancer), year, prevalence, clinical effectiveness (improvements in surrogate, clinical and patient reported outcomes), safety, quality of evidence (availability of comparative data, consistency between population in trial and indication, and bias), clinical need, treatment cost, and incremental cost-effective ratio (ICER). Two-way interactions were also explored. A total of 103 recommendations were included. Eleven were resubmissions, all of which received a positive recommendation. Among new submissions (n = 92), DRDs that were safe or offered improvements in clinical or patient reported outcomes were more likely to receive positive reimbursement recommendations. No associations between recommendation type and daily treatment cost, cost-effectiveness, or condition (cancer or non-cancer) were found. Clinical effectiveness, as opposed to economic considerations or whether the drug is indicated for cancer or non-cancer, determine the type of reimbursement recommendation.