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

Perturbation Detection Through Modeling of Gene Expression on a Latent Biological Pathway Network: A Bayesian hierarchical approach

Cellular response to a perturbation is the result of a dynamic system of biological variables linked in a complex network. A major challenge in drug and disease studies is identifying the key factors of a biological network that are essential in determining the cell's fate. Here our goal is the identification of perturbed pathways from high-throughput gene expression data. We develop a three-level hierarchical model, where (i) the first level captures the relationship between gene expression and biological pathways using confirmatory factor analysis, (ii) the second level models the behavior within an underlying network of pathways induced by an unknown perturbation using a conditional autoregressive model, and (iii) the third level is a spike-and-slab prior on the perturbations. We then identify perturbations through posterior-based variable selection. We illustrate our approach using gene transcription drug perturbation profiles from the DREAM7 drug sensitivity predication challenge data set. Our proposed method identified regulatory pathways that are known to play a causative role and that were not readily resolved using gene set enrichment analysis or exploratory factor models. Simulation results are presented assessing the performance of this model relative to a network-free variant and its robustness to inaccuracies in biological databases

The role of phonological and semantic representations in verbal short-term memory and delayed retention

It has been suggested that phonological representations play a central role in verbal short-term memory, but when semantic knowledge has been investigated, it has also been shown to influence verbal short-term memory. Explaining this interaction between verbal short-term memory and the linguistic system has produced different theoretical positions: whether semantic knowledge is used to redintegrate phonological traces or if there is direct activation of both phonological and semantic knowledge upon encountering a word. The present study employed a new paradigm to systematically examine phonological and semantic representations in verbal short-term memory as well as long-term impacts. Across two experiments, a list of words was presented sequentially, followed by a probe word. Participants were to judge whether the probe word rhymed or was synonymous with any items on the list. Delayed memory was also tested. In Experiment 1, we found that immediate performance was better for synonym than rhyme judgements, and this continued to be the case after a brief delay. In Experiment 2, under a fast-encoding, running-span paradigm, we found similar activation of phonological and semantic knowledge. Nevertheless, accuracy was again higher for items probed with the semantic than rhyme cue in the long term. Results showed that indeed there are short-term semantic effects, in addition to phonological effects. Further, semantic processing can occur in a highly automatic and rapid manner, with strong influence on long-term memory. These findings provide a new perspective on viewing verbal short-term memory as operating more dynamically within the context of a complex linguistic system

U.S. Multinational Services Companies: Effects of Foreign Affiliate Activity on U.S. Employment

This working paper examines the effect that U.S. services firms’ establishment abroad has on domestic employment. Whereas many papers have explored the employment effects of foreign direct investment in manufacturing, few have explored the effects of services investment. We find that services multinationals’ activities abroad increase U.S. employment by promoting intrafirm exports from parent firms to their foreign affiliates. These exports support jobs at the parents’ headquarters and throughout their U.S. supply chains. Our findings are principally based on economic research and econometric analysis performed by Commission staff, services trade and investment data published by the Bureau of Economic Analysis, and employment data collected by the Bureau of Labor Statistics. In the aggregate, we find that services activities abroad support nearly 700,000 U.S. jobs. Case studies of U.S. multinationals in the banking, computer, logistics, and retail industries provide the global dimensions of U.S. MNC operations and identify domestic employment effects associated with foreign affiliate activity in each industry

Lung cancer screening: what do long-term smokers know and believe?

Objective To explore knowledge and beliefs of long-term smokers about lung cancer, associated risk factors and lung cancer screening. Design Qualitative study theoretically framed by the expanded Health Belief Model based on four focus group discussions. Content analysis was performed to identify themes of knowledge and beliefs about lung cancer, associated risk factors and lung cancer screening among long-term smokers' who had and had not been screened for lung cancer. Methods Twenty-six long-term smokers were recruited; two groups (n = 9; n = 3) had recently been screened and two groups (n = 7; n = 7) had never been screened. Results While most agreed lung cancer is deadly, confusion or inaccurate information exists regarding the causes and associated risk factors. Knowledge related to lung cancer screening and how it is performed was low; awareness of long-term smoking's association with lung cancer risk remains suboptimal. Perceived benefits of screening identified include: (i) finding lung cancer early; (ii) giving peace of mind; and (iii) motivation to quit smoking. Perceived barriers to screening identified include: (i) inconvenience; (ii) distrust; and (iii) stigma. Conclusions Perceived barriers to lung cancer screening, such as distrust and stigma, must be addressed as lung cancer screening becomes more widely implemented. Heightened levels of health-care system distrust may impact successful implementation of screening programmes. Perceived smoking-related stigma may lead to low levels of patient engagement with medical care and decreased cancer screening participation. It is also important to determine modifiable targets for intervention to enhance the shared decision-making process between health-care providers and their high-risk patients

Knowing Your Pharmacist's Name

Pharmacists are the most accessible health care providers to the general public. Pharmacists are experts in helping patients get the most out of today’s complicated medications. Pharmacists ensure safe and effective use of medications. The American Pharmacists Association pitched a campaign, “Know your medicine, know your pharmacist.” Before one can know their medicine, one must know their pharmacist. This study was conducted to see whether older or younger and male verse female patients knew their pharmacist’s name better in the Philadelphia area, as a pilot study.   Type: Commentar

Knowing Your Pharmacist's Name

Pharmacists are the most accessible health care providers to the general public. Pharmacists are experts in helping patients get the most out of today’s complicated medications. Pharmacists ensure safe and effective use of medications. The American Pharmacists Association pitched a campaign, “Know your medicine, know your pharmacist.” Before one can know their medicine, one must know their pharmacist. This study was conducted to see whether older or younger and male verse female patients knew their pharmacist’s name better in the Philadelphia area, as a pilot study.   Type: Commentar