Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis. In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs−). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable
The rapidly expanding arsenal of chemotherapeutic agents approved in the past 5 years represents significant progress in the field. However, this poses a challenge for oncologists to choose which drug or combination of drugs is best for any individual. Because only a fraction of patients respond to any drug, efforts have been made to devise strategies to personalize care. The majority of efforts have involved development of predictive biomarkers. While there are notable successes, there are no predictive biomarkers for most drugs. Moreover, predictive biomarkers enrich the cohort of individuals likely to benefit; they do not guarantee benefit. There is a need to devise alternate strategies to tailor cancer care. One alternative approach is to enhance the current adaptive approach, which involves administration of a drug and cessation of treatment once progression is documented. This currently involves radiographic tests for the most part, which are expensive, inconvenient and imperfect in their ability
Recent advances in biomedical and sequencing technologies have revealed the genomic landscape of common forms of human cancer in unprecedented detail. Of the genes that drive tumorigenesis when altered, for most cancers it is believed that there exist a small number of
Cancer prevention has advanced tremendously in the past few decades, driven primarily by greater insights into the mechanisms of early stages of neoplastic development as well as progress in the screening, early detection, and surgical removal of precancerous lesions and cancer. The area of chemoprevention, however, has seen slower and less steady progress. Though we now have refined insights into disease pathogenesis, successful risk assessments and new risk models, as well as the established efficacy of 13 agents approved for the treatment of precancerous lesions and cancer risk reduction (1), progress has been hindered by a lack of validated biomarkers of risk and interventive response. The identification and development of accurate, reliable, and easily measurable risk and response biomarkers within the field of cancer prevention could dramatically alter our approach to the disease. Confirmed risk biomarkers would allow us to more precisely predict who will develop cancer and, therefore, who ...
Tissue imaging of treatment-induced metabolic changes is useful for optimizing cancer therapies, but commonly used methods require trade-offs between assay sensitivity and spatial resolution. Nanostructure-Initiator Mass Spectrometry imaging (NIMS) permits quantitative co-localization of drugs and treatment response biomarkers in cells and tissues with relatively high resolution. The present feasibility studies use NIMS to monitor phosphorylation of 3′-deoxy-3′-fluorothymidine (FLT) to FLT-MP in lymphoma cells and solid tumors as an indicator of drug exposure and pharmacodynamic responses. NIMS analytical sensitivity and spatial resolution were examined in cultured Burkitts lymphoma cells treated briefly with Rapamycin or FLT. Sample aliquots were dispersed on NIMS surfaces for single cell imaging and metabolic profiling, or extracted in parallel for LC-MS/MS analysis. Docetaxel-induced changes in FLT metabolism were also monitored in tissues and tissue extracts from mice bearing drug-sensitive
Purpose: Despite major progress in the molecular characterization of ovarian cancers (OC), women with recurrent, advanced stage OC continue to be treated with cytotoxic chemotherapy agents that have poor overall response rates. This contrasts with the treatment paradigm for other cancers, where outcomes have been improved by selecting treatment based upon actionable genomic alteration(s) that are in drug-targetable pathways. There is a need to determine if molecular profiling for OC patients can improve treatment outcomes. Such a profile should comprehensively identify actionable genetic aberrations as well as measure expression levels of proteins that are drug targets/response biomarkers.. Methods: The presence of mutations or alterations [e.g., copy number (CN)] in ~200 genes was determined using a validated exon-capture sequencing platform (Foundation Medicine, Inc) and protein levels of ERBB2, EGFR, ESR1, cMET, PTEN, RB1, and p16 were measured by IHC (Caris Life Sciences and Clarient, ...
Different drugs elicit a different response depending on the patient; understanding the reasons for this may not only improve treatment, but the development of future anti-cancer drugs. Tailoring treatment to the individual ensures the optimum patient response, reducing disease progression and drug toxicity. Currently, using biomarkers to tailor cancer therapy focuses on the prognosis and prediction of disease.. A review by Shahil Amin and Oliver Bathe discusses the potential of using biomarkers in an alternative way, to assess a patients response to treatment. The authors explore the implications of treatment response biomarkers which, they argue, may not only benefit individual patients, by minimizing exposure to drugs which may be ineffective or toxic, but could also revolutionize how drugs are developed and clinical trials are conducted.. Significant dose-response relationship between alcohol consumption and prostate cancer risk. A meta-analysis and systematic review by Zhao et al. ...
Primary Objective To determine the MTD and/or RD of SNS-062 Secondary Objectives To characterize the safety profile of SNS-062 To characterize the PK profile of SNS-062 To characterize the antitumor activity of SNS-062 To assess the preliminary effect of SNS-062 on the QTc interval Exploratory Objectives To evaluate changes in pharmacodynamic markers of BTK pathway activation To evaluate the potential effects of CYP (cytochrome P450) genotype on pharmacokinetics To evaluate the effect of SNS-062 on overall survival. ...
The immune landscape of head and neck squamous cell carcinoma in pretreated areas remains poorly documented. We aimed to assess the tumor microenvironment for biomarkers of antitumor immune responses in tumors in previously irradiated areas compared with de novo tumors. This retrospective monocentric study analyzed 100 paraffin‑embedded surgical samples of invasive head and neck squamous cell carcinoma (oral cavity, oropharynx, larynx, hypopharynx) from patients who underwent surgery between January 2010 and November 2017. We compared the immune microenvironment in 50 de novo tumors and 50 tumors recurring within irradiated areas. We used immunohistochemistry to assess p16 status, CD3+/CD8+ tumor‑infiltrating lymphocytes (TILs), and programmed death‑ligand 1 (PD‑L1) expression on tumor and immune cells in stromal and intratumoral components. CD3+ TIL counts were significantly lower in intratumoral and stromal components (P=0.003 and P=0.020, respectively) in the irradiated area cohort; ...
0128]The LRP-1 or LRP-2 molecules are also useful as pharmacodynamic markers. As used herein, a pharmacodynamic marker is an objective biochemical marker which correlates specifically with drug effects. The presence or quantity of a pharmacodynamic marker is not related to the disease state or disorder for which the drug is being administered; therefore, the presence or quantity of the marker is indicative of the presence or activity of the drug in a subject. For example, a pharmacodynamic marker can be indicative of the concentration of the drug in a biological tissue, in that the marker is either expressed or transcribed or not expressed or transcribed in that tissue in relationship to the level of the drug. In this fashion, the distribution or uptake of the drug can be monitored by the pharmacodynamic marker. Similarly, the presence or quantity of the pharmacodynamic marker can be related to the presence or quantity of the metabolic product of a drug, such that the presence or quantity of ...
I think youve missed an important point about Bayesian statistics--essentially, choosing a prior lets the statistician to formally incorporate information we already know into the analysis. This prior knowledge could come from other research papers on the topic, prior stages in the same experiment (very useful in clinical trials) or maybe just intuitive logic. Frequentists do exactly the same thing, but the difference is that they arent supposed to--it technically invalidates their results. Consider for example a placebo-controlled clinical trial. The treatment and placebo groups are never truly random--ethics dictate that we balance the two groups to look as similar as possible, because this will increase the statistical power and help us identify potential risks of treatment much sooner, potentially saving lives. At the end of the trial we get a frequentist p-value of, say, 0.05, but in reality this is wrong--we are pretty sure that because of balancing the two groups the real p-value is ...
I think youve missed an important point about Bayesian statistics--essentially, choosing a prior lets the statistician to formally incorporate information we already know into the analysis. This prior knowledge could come from other research papers on the topic, prior stages in the same experiment (very useful in clinical trials) or maybe just intuitive logic. Frequentists do exactly the same thing, but the difference is that they arent supposed to--it technically invalidates their results. Consider for example a placebo-controlled clinical trial. The treatment and placebo groups are never truly random--ethics dictate that we balance the two groups to look as similar as possible, because this will increase the statistical power and help us identify potential risks of treatment much sooner, potentially saving lives. At the end of the trial we get a frequentist p-value of, say, 0.05, but in reality this is wrong--we are pretty sure that because of balancing the two groups the real p-value is ...
There are two dominant approaches to statistics. Here, I explain why you need to choose one or the other, and link to resources to help you make your choice. Most ecologists use the frequentist approach. This approach focuses on P(D|H), the probability of the data, given the hypothesis. That is, this approach treats data as…
There are two dominant approaches to statistics. Here, I explain why you need to choose one or the other, and link to resources to help you make your choice. Most ecologists use the frequentist approach. This approach focuses on P(D|H), the probability of the data, given the hypothesis. That is, this approach treats data as…
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Poisson clearly distinguished between objective and subjective probabilities in 1837.[6] Soon thereafter a flurry of nearly simultaneous publications by Mill, Ellis (On the Foundations of the Theory of Probabilities[7] and Remarks on the Fundamental Principles of the Theory of Probabilities[8]), Cournot (Exposition de la théorie des chances et des probabilités)[9] and Fries introduced the frequentist view. Venn provided a thorough exposition (The Logic of Chance: An Essay on the Foundations and Province of the Theory of Probability (published editions in 1866, 1876, 1888))[10] two decades later. These were further supported by the publications of Boole and Bertrand. By the end of the 19th century the frequentist interpretation was well established and perhaps dominant in the sciences.[6] The following generation established the tools of classical inferential statistics (significance testing, hypothesis testing and confidence intervals) all based on frequentist ...
Natural Factors PGX 240 SoftgelsBy simply taking PGX before a meal, you can painlessly shed pounds without ever feeling starved, because PGX creates and maintains a satisfying sense of fullness. Based on sound clinical research, PGX helps to promote normal appetite regulation, eliminating the trap of yo-yo dieting. Incorporating PGX Daily Ultra Matrix Softgels into your diet can help you lose weight safely and gradually, even if you are not yet ready to make other positive diet and lifestyle changes at first. Taking PGX with food can reduce a meals glycemic index, promote healthy blood sugar levels* and create a sense of satiety (fullness). Naturally, the beneficial effects of PGX will be enhanced by a healthy diet and exercise, leading to incredible results. Suggested Usage: Start with 1-2 softgels per meal and slowly build up to the recommended dose of 3-6 softgels per meal. For best results take PGX Daily softgels before meals with a glass of water (8 oz), or as directed by a health professional.
The current treatment for Alzheimers disease (AD) is purely symptomatic, but medications interfering with underlying pathophysiological processes are being developed. To evaluate a possible disease-modifying effect, cerebrospinal fluid (CSF) biomark
A small percentage of people may initially experience minor digestive changes when taking PGX. Slowly work up to the full dose to give your body time to adjust. It is important to drink adequate amounts of water (8-16 oz. or 1-2 cups) after taking PGX. Consult your health professional before use if you are under 18 years of age or have any health concerns. If you are taking medication, take it one hour prior to two hours after taking PGX. As with any supplement, consult your health professional before use if you are pregnant, breastfeeding, or trying to conceive, or if you have a medical condition, or anticipate a surgery. Keep out of reach of children. Sealed for your protection. Do not use if seal is broken. For freshness, store in a cool, dry place. ...
The latest market report published by Credence Research, Inc. Global Pharmacogenomics Market - Growth, Share, Opportunities, Competitive Analysis, and Forecast, 2016 - 2023, the global pharmacogenomics market was valued at US$ 7,167.6 Mn in 2015, and is expected to reach US$ 11,938.8 Mn by 2024, expanding at a CAGR of 5.6% from 2016 to 2024.. Browse the full report Global Pharmacogenomics Market - Growth, Share, Opportunities, Competitive Analysis, and Forecast, 2016 - 2024 at http://www.credenceresearch.com/report/pharmacogenomic-market. Market Insights. Pharmacogenomics or personalized medicine is defined as the tailoring of medical treatment to the specific characteristics of each patient. This concept in reality involves the ability to classify individuals into subpopulations that are uniquely or disproportionately susceptible to a particular disease or responsive to a specific treatment. Personalized medicine emphasizes on paradigm shift in medicine from reaction to prevention. The ...
Lab tests can help you improve your future health. Knowing the predictive biomarkers can guide your lifestyle. Predictive biomarkers are tests that ca...
Alternatively, the frequentist multivariate solutions contain approximations and assumptions that are not stated explicitly or confirmed when the strategies are applied (see discussion on meta-analysis designs over). As an example, the mvmeta bundle for Stata allows community meta-analysis inside of a frequentist framework.[63] Nevertheless, if there isnt a prevalent comparator while in the network, then this should be managed by augmenting the dataset with fictional arms with higher variance, which isnt pretty objective and involves a call as to what constitutes a adequately large variance ...
Few doctors are familiar with both the genetics and pharmacology of drug response, pharmacogenomic reporting is not useful without explaining care implications
Implements various mainstream and specialised changepoint methods for finding single and multiple changepoints within data. Many popular non-parametric and frequentist methods are included. The cpt.mean(), cpt.var(), cpt.meanvar() functions should be your first point of call.. ...
|strong|The Power of Predictive|/strong||a href=http://www.perque.com/Biomarkers_IP_Email/||img class= wp-image-4482 alignleft title=BiomarkersAd ...
Understanding the impact of BRAF signaling inhibition in human melanoma on key disease mechanisms is important for developing biomarkers of therapeutic response and combination strategies to improve long term disease control. This work investigates the downstream metabolic consequences of BRAF inhibition with vemurafenib, the molecular and biochemical processes that underpin them, their significance for antineoplastic activity and potential as non-invasive imaging response biomarkers.1H NMR spectroscopy showed that vemurafenib decreases the glycolytic activity of BRAF mutant (WM266.4 and SKMEL28) but not BRAFWT (CHL-1 and D04) human melanoma cells. In WM266.4 cells, this was associated with increased acetate, glycine and myo-inositol levels and decreased fatty acyl signals, while the bioenergetic status was maintained. 13C NMR metabolic flux analysis of treated WM266.4 cells revealed inhibition of de novo lactate synthesis and glucose utilization, associated with increased oxidative and ...
PGX (PolyGlycopleX) is a precise blend of naturally occurring water-soluble polysaccharides (fibers) that together, have highly unique and desirable properties for weight loss and overall good health. PGX is the result of extensive research by the University of Toronto and the Canadian Center for Functional Medicine. PGX is the worlds most viscous soluble fiber blend. What does viscous mean? Simply to thicken. Once PGX is added to water or food it thickens or becomes viscous. The viscosity of soluble fiber is important as it relates directly to the overall health benefits. The most important advantage of PGX over other soluble fiber products is that significantly less PGX is required to obtain the same important health benefits, including appetite control and reduced food cravings. Why take PGX? PGX has been clinically proven to: - Reduce appetite comfortably and safely - Reduce food cravings - Balance metabolism - Improve regularity - Maintain glucose levels already within normal range
PGX, the short-form of PolyGlycopleX, is a form of fiber that is sold either on its own or as a supplement for weight loss in many major stores.
Press Release issued Dec 22, 2014: One of the major breakthroughs that genetic testing has paved way for includes Personalized Medicine. Personalized medicine is the use of new methods of molecular analysis for better management of a patients disease or predisposition towards a disease. PGx, the study of variations of DNA and RNA characteristics as related to drug response, is one of the most exciting areas of personalized medicine today. Patients typically have variability in response to many drugs that are currently available. PGx seeks to understand how differences in genes and their expression affect the bodys response to medications. Such approaches promise the advent of Personalized Medicine in which drugs and drug combinations are optimized for each individuals unique genetic makeup.
Bayesian probability represents a level of certainty relating to a potential outcome or idea. This is in contrast to a frequentist probability that represents the frequency with which a particular outcome will occur over any number of trials. An event with Bayesian probability of .6 (or 60%) should be interpreted as stating With confidence 60%, this event contains the true outcome, whereas a frequentist interpretation would view it as stating Over 100 trials, we should observe event X approximately 60 times. The difference is more apparent when discussing ideas. A frequentist will not assign probability to an idea, either it is true or false and it cannot be true 6 times out of 10. ...
The latest market report published by Credence Research, Inc. Global Pharmacogenomics Market - Growth, Share, Opportunities, Competitive Analysis, and Forecast, 2016 - 2023, the global pharmacogenomics market was valued at US$ 7,167.6 Mn in 2015, and is expected to reach US$ 11,938.8 Mn by 2024, expanding at a CAGR of 5.6% from 2016 to 2024.. Browse the full report Global Pharmacogenomics Market - Growth, Share, Opportunities, Competitive Analysis, and Forecast, 2016 - 2024 at http://www.credenceresearch.com/report/pharmacogenomic-market. Market Insights. Pharmacogenomics or personalized medicine is defined as the tailoring of medical treatment to the specific characteristics of each patient. This concept in reality involves the ability to classify individuals into subpopulations that are uniquely or disproportionately susceptible to a particular disease or responsive to a specific treatment. Personalized medicine emphasizes on paradigm shift in medicine from reaction to prevention. The ...
Given its ability to detect a disease in its very early stage, consequently improving clinical outcomes, pharmacogenomic testing is slowly gaining greater acceptance across Europe.
Pharmacogenomics is the science of understanding the role of genes in determining the response a person may have when given a drug.
First, let me take a minute to make fun of frequentists. According to conventional hypothesis testing, the data from the scouting report is not statistically significant. If the null hypothesis is that Monty has the same chance of blinking regardless of the location of the car, the p-value of the sample we saw is 0.27 (I used Fishers exact test, computed using this online calculator). We cant reject the null hypothesis, so if we play by the rules of conventional hypothesis testing, I guess that means we cant take advantage of Montys tell. If you are a committed frequentist, you should stop reading now ...
Dr Ascierto talks to ecancertv at ITOC-3 about PD-L1 checkpoint inhibition. In particular, he discusses whether or not it can be truly considered a
A new dating site promises to match users according to genetic capability, requiring a saliva sample to test DNA for two key markers.
Allergic Asthma functional & Pharmaco-genomics for Early and Late Phase Response Biomarkers --- Biomarkers of a Sympathetic Anti-inflammatory Pathway, Neuro-regulation of Sympathetic Anti-inflammatory Activity --- Clinical Investigator Collaborative (CIC) --- Development of a Microarray Genotyping Chip for Clinical Trials --- Environmental impact, inflammation and the role of IL-13 receptor a2 --- Genetics of the early and late responses to AllerGen challenge --- Hemopoietic stem cell biomarkers in the diagnosis and prediction of allergic inflammation and disease --- Metabolomics --- Strengthening the Case for Ongoing Reduction of Exposure to Traffic-Related Air Pollution (SCORE-TRAP) --- The Clinical Investigator Collaborative (CIC)-Allergic Asthma (AA) --- Thymic Stromal Lymphopoitin-induced Cord Blood Hemopoietic Progenitors: Biomarkers for the Development of Atopy and Asthma --- Urine NMR-based Metabolomics for Asthma Diagnosis -- Predictive Biomarkers of the Late-Phase Response -- Urine ...
By simply taking PGX® before a meal‚ you can shed pounds without ever feeling starved‚ because PGX creates and maintains a satisfying sense of fullness. Based on sound clinical research‚ PGX helps to promote normal appetite regulation‚ eliminating the trap of yo-yo dieting. Incorporating PGX Daily Ultra Matrix Softgels into your diet can help you lose weight safely and gradually‚ even if you are not yet ready to make other positive diet and lifestyle changes at first. Taking PGX with food can reduce a meals glycemic index‚ promote healthy blood sugar levels already within normal range and create a sense of satiety (fullness). Naturally‚ the beneficial effects of PGX will be enhanced by a healthy diet and exercise‚ leading to incredible results.. These statements have not been evaluated by the Food and Drug Administration (FDA). These products are not meant to diagnose‚ treat or cure any disease or medical condition. Please consult your doctor before starting any exercise or ...
This category is for sites about the closely related fields of pharmacogenetics and pharmacogenomics. Both involve themselves with the variation in drug reaction and expression in individuals with different genetic makeup; pharmacogenetics considers the influence of one or several individual genes, whereas pharmacogenomics deals with the entire genome.
Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.. ...
Pharmacogenomics is the mixture of pharmaceuticals and genetics. This field has very bright future. It provides methods of drug insertion by knowing the variations in the structures of proteins and DNA.
Biomarkers are widely employed as biochemical indicators of health and disease states and processes. We have expanded our coverage of Biomarkers in Vizit.
A unique approach to connecting people and ideas in the life sciences, creating a space for probing conversations and deep insight into the topics and trends shaping our future.
Innovative genomic test for amantadin personalised pharmacogenomic analysis to explore how your genes can affect and modulate your response to amantadin ...
Innovative genomic test for butamirate personalised pharmacogenomic analysis to explore how your genes can affect and modulate your response to butamirate ...
uBiome gone? - posted in Biomarkers & Genes: Now that uBiome is defunct, where/how does one get their test results/data? I have several test results that I can no longer access since their site is no longer.
TY - JOUR. T1 - Response-driven imaging biomarkers for predicting radiation necrosis of the brain. AU - Zadeh, Mohammad Reza Nazem. AU - Chapman, Christopher H.. AU - Chenevert, Thomas. AU - Lawrence, Theodore S.. AU - Ten Haken, Randall K.. AU - Tsien, Christina I.. AU - Cao, Yue. PY - 2014/5/21. Y1 - 2014/5/21. N2 - Radiation necrosis is an uncommon but severe adverse effect of brain radiation therapy (RT). Current predictive models based on radiation dose have limited accuracy. We aimed to identify early individual response biomarkers based upon diffusion tensor (DT) imaging and incorporated them into a response model for prediction of radiation necrosis. Twenty-nine patients with glioblastoma received six weeks of intensity modulated RT and concurrent temozolomide. Patients underwent DT-MRI scans before treatment, at three weeks during RT, and one, three, and six months after RT. Cases with radiation necrosis were classified based on generalized equivalent uniform dose (gEUD) of whole brain ...
wikilink,Bayesian probability}} {{arbitallink,https://arbital.com/p/bayes_rule_probability/,Bayes rule: Probability form}} Bayesian probability represents a level of certainty relating to a potential outcome or idea. This is in contrast to a [[Wikipedia:Frequentist_inference,frequentist]] probability that represents the frequency with which a particular outcome will occur over any number of trials. An [[Wikipedia:Event (probability theory),event]] with Bayesian probability of .6 (or 60%) should be interpreted as stating With confidence 60%, this event contains the true outcome, whereas a frequentist interpretation would view it as stating Over 100 trials, we should observe event X approximately 60 times. The difference is more apparent when discussing ideas. A frequentist will not assign probability to an idea; either it is true or false and it cannot be true 6 times out of 10. ==Blog posts== *[http://lesswrong.com/lw/1to/what_is_bayesianism/ What is Bayesianism?] ...
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Pharmacogenomics Testing Services for doctors, clinics, hospitals, and more in Fort Worth. Texas Genetic Testing, LLC. (855) 306-8347
Thesis, English, The Emerging Role Of Pharmacogenomics In The Treatment Of Patients With Hypertension for Shabeb Reda Abd Elazeem Mohammed
This article is an attempt to summarize basic material [/lw/kh/explainers_shoot_high_aim_low/], and thus probably wont have anything new for the hard core posting crowd. Itd be interesting to know whether you think theres anything essential I missed, though. Youve probably seen the word Bayesian used a lot on this site, but may be a bit uncertain of what exactly we mean by that. You may have read the intuitive explanation [http://www.yudkowsky.net/rational/bayes/], but that only seems to explain a certain math formula. Theres a wiki entry about Bayesian [http://wiki.lesswrong.com/wiki/Bayesian], but that doesnt help much. And the LW usage seems different from just the Bayesian and frequentist statistics thing, too. As far as I can tell, theres no article explicitly defining whats meant by Bayesianism. The core ideas are sprinkled across a large amount of posts, Bayesian has its own tag [/tag/bayesian/], but theres not a single post that explicitly comes out to make the connections and
This Editorial article provides an insight into how pharmacogenomics can assist in guided dosing of fentanyl for the treatment of pain.