Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Descriptive ethics: a qualitative study of local research ethics committees in Mexico.

OBJECTIVE: To describe how local research ethics committees (LRECs) consider and apply research ethics in the evaluation of biomedical research proposals. DESIGN: A qualitative study was conducted using purposeful sampling, focus groups and a grounded theory approach to generate data and to analyse the work of the LRECs. SETTING AND PARTICIPANTS: 11 LRECs of the Mexican Institute of Social Security (IMSS). RESULTS: LRECs considered ethics to be implicit in all types of research, but that ethics reviews were only necessary for projects that included the direct participation of human beings. The LRECs appeared to understand the importance of consent, as in the completion of a consent form, but did not emphasise the importance of the process of acquiring 'informed' consent. The committees considered their main roles or functions to be: (a) to improve the methodological quality of research and to verify - if applicable - the ethical aspects; (b) to encourage personnel to undergo research training; (c) to follow-up research to oversee the adherence to norms and compliance with a specified research timetable. CONCLUSIONS: This study provides a valuable insight into how these LRECs understand the ethical review process. The emphasis of the committees was on rules, regulations, improving research methodology and research training, rather than a focus on efforts to protect the rights and well being of research subjects. The results encourage further normative and descriptive lines of investigation concerning education and the development of LRECs

Who's afraid Of Thomas Bayes?

Sometimes direct evidence is so strong that a prescription for practice is decreed. Usually, things are not that simple—leaving aside the possibility that important trade offs may be involved, direct comparative data may be imprecise (especially in crucial sub-groups) or subject to possible bias, or there may be no direct comparative evidence; but still decisions have to be made. In these circumstances, indirect evidence—the plausibility of effects—enters the frame. But how should we describe the extent of plausibility and, having done so, how can this be integrated with any direct evidence that might exist. Also, how can allowance be made in a transparent (that is, explicit) way for perceptions of the size of bias in the direct evidence. Enter the Reverend Thomas Bayes; plausibility (however derived—laboratory experiment, qualitative study or just "experience") is captured numerically as degrees of belief ("prior" to the direct data) and updated (by the direct evidence) to yield "posterior" probabilities for use in decision making. The mathematical model used for this purpose must explicitly take account of assumptions about bias in the direct data. This paradigm bridges theory and practice, and provides the intellectual scaffold for those who recognise that (numerically definable) probabilities, and values (also numerically definable) underlie decisions, but who also realise that subjectivity is ineluctable in science.


Keywords: Bayesian statistics; research methods; decisions; Cochrane lectur