Improvement of experimental testing and network training conditions with genome-wide microarrays for more accurate predictions of drug gene targets

BACKGROUND: Genome-wide microarrays have been useful for predicting chemical-genetic interactions at the gene level. However, interpreting genome-wide microarray results can be overwhelming due to the vast output of gene expression data combined with off-target transcriptional responses many times induced by a drug treatment. This study demonstrates how experimental and computational methods can interact with each other, to arrive at more accurate predictions of drug-induced perturbations. We present a two-stage strategy that links microarray experimental testing and network training conditions to predict gene perturbations for a drug with a known mechanism of action in a well-studied organism. RESULTS: S. cerevisiae cells were treated with the antifungal, fluconazole, and expression profiling was conducted under different biological conditions using Affymetrix genome-wide microarrays. Transcripts were filtered with a formal network-based method, sparse simultaneous equation models and Lasso regression (SSEM-Lasso), under different network training conditions. Gene expression results were evaluated using both gene set and single gene target analyses, and the drug’s transcriptional effects were narrowed first by pathway and then by individual genes. Variables included: (i) Testing conditions – exposure time and concentration and (ii) Network training conditions – training compendium modifications. Two analyses of SSEM-Lasso output – gene set and single gene – were conducted to gain a better understanding of how SSEM-Lasso predicts perturbation targets. CONCLUSIONS: This study demonstrates that genome-wide microarrays can be optimized using a two-stage strategy for a more in-depth understanding of how a cell manifests biological reactions to a drug treatment at the transcription level. Additionally, a more detailed understanding of how the statistical model, SSEM-Lasso, propagates perturbations through a network of gene regulatory interactions is achieved.Published versio

Finding Solutions to Institutional Corruption: Lessons from Cognitive Dissonance Theory

The American Psychiatric Association and academic psychiatry in the United States have two conflicts of interest that may affect their assessment of psychiatric drugs and their development of diagnostic and clinical care guidelines: payments from pharmaceutical companies and guild interests. Until recently, the proposed solution to industry-academic relationships has been transparency. However, cognitive dissonance research reveals that disclosure is not a solution because cognitive biases are commonplace and difficult to eradicate. Indeed, bias is most often manifest in subtle ways unbeknownst to the researcher or clinician, and thus is usually implicit and unintentional. Also, recent studies suggest that disclosure of financial conflicts of interest may actually worsen bias. In this paper we discuss the implications of cognitive dissonance theory for understanding why disclosure or even management of financial conflicts of interest are not robust enough solutions to guarantee objectivity and prevent bias. We suggest that as a gold standard commercial ties should be eliminated in settings where new drugs are being tested and assessed, or clinical guidelines are being developed. This solution will require the use of multidisciplinary teams to do the tasks, including methodologists in addition to psychiatrists

Book Review - Promoting Law Student and Lawyer Well-Being in Australia and Beyond

Promoting Law Student and Lawyer Well-Being in Australia and Beyond is a book on how to alleviate pathological levels of psychological distress (‘distress’) in people who choose to study law for legal practice (‘legal profession’). The book showcases the Australian Wellness For Law Network’s normative orthodoxy, that the entire legal academic community must be, or become, responsible for law students’ mental health

Psychiatric Taxonomy, Psychopharmacology and Big Pharma

Clinicians practicing today need to be aware of the ways in which the current industry-dominated climate may undermine the integrity of the scientific process and, thus, may compromise patient care. In the mental health field, corporate sponsorship bias can affect psychiatric taxonomy and clinical Practice Guidelines (CPG). Financial conflicts of interest (FCOI) can occur when there are financial associations between researchers, authors, or panel members developing psychiatric diagnostic and treatment guidelines, and the pharmaceutical industry, or when randomized clinical trials (RCTs) are industry funded. Therefore, clinicians need to be especially vigilant about the informed consent process when patients are prescribed psychotropic medications

Expanding Disease Definitions in Guidelines and Expert Panel Ties to Industry:A Cross-sectional Study of Common Conditions in the United States

BACKGROUND: Financial ties between health professionals and industry may unduly influence professional judgments and some researchers have suggested that widening disease definitions may be one driver of over-diagnosis, bringing potentially unnecessary labeling and harm. We aimed to identify guidelines in which disease definitions were changed, to assess whether any proposed changes would increase the numbers of individuals considered to have the disease, whether potential harms of expanding disease definitions were investigated, and the extent of members' industry ties. METHODS AND FINDINGS: We undertook a cross-sectional study of the most recent publication between 2000 and 2013 from national and international guideline panels making decisions about definitions or diagnostic criteria for common conditions in the United States. We assessed whether proposed changes widened or narrowed disease definitions, rationales offered, mention of potential harms of those changes, and the nature and extent of disclosed ties between members and pharmaceutical or device companies. Of 16 publications on 14 common conditions, ten proposed changes widening and one narrowing definitions. For five, impact was unclear. Widening fell into three categories: creating “pre-disease”; lowering diagnostic thresholds; and proposing earlier or different diagnostic methods. Rationales included standardising diagnostic criteria and new evidence about risks for people previously considered to not have the disease. No publication included rigorous assessment of potential harms of proposed changes. Among 14 panels with disclosures, the average proportion of members with industry ties was 75%. Twelve were chaired by people with ties. For members with ties, the median number of companies to which they had ties was seven. Companies with ties to the highest proportions of members were active in the relevant therapeutic area. Limitations arise from reliance on only disclosed ties, and exclusion of conditions too broad to enable analysis of single panel publications. CONCLUSIONS: For the common conditions studied, a majority of panels proposed changes to disease definitions that increased the number of individuals considered to have the disease, none reported rigorous assessment of potential harms of that widening, and most had a majority of members disclosing financial ties to pharmaceutical companies. Please see later in the article for the Editors' Summar

The American Psychiatric Association’s Guideline for Major Depressive Disorder: A Commentary

The American Psychiatric Association (APA) published a new guideline for Major Depressive Disorder (MDD) which will undoubtedly be used by many practitioners to guide clinical decision-making. In fact, it is non-psychiatrist clinicians who prescribe the majority of antidepressants (AD). We review the APA’s most recent guideline on MDD and report on our observations

Industry’s Colonization of Psychiatry: Ethical and Practical Implications of Financial Conflicts of Interest in the DSM-5

The revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM), scheduled for publication in May 2013 by the American Psychiatric Association (APA), has created a firestorm of controversy because of questions about undue industry influence. Specifically, concerns have been raised about financial conflicts of interest between DSM-5 panel members and the pharmaceutical industry. The authors argue that current approaches to the management of these relationships, particularly transparency of them, are insufficient solutions to the problem of industry’s capture of organized psychiatry. The conceptual framework of institutional corruption is used to understand psychiatry’s dependence on the pharmaceutical industry and to identify the epistemic assumptions that ground the DSM’s biopsychiatric discourse. APA’s rationale for including Premenstrual Dysphoric Disorder (PMDD) in the DSM-5 as a Mood Disorder is reviewed and discussed