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The Emerging Role of Electronic Medical Records in Pharmacogenomics
- Christian Wiggins
- 3 years ago
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1 nature publishing group state The Emerging Role of Electronic Medical Records in Pharmacogenomics RA Wilke 1, H Xu 2, JC Denny 2, DM Roden 1, RM Krauss 3, CA McCy 4, RL Davis 5, T Skaar 6, J Lamba 7 and G Savova 8,9,10 Health-care information technology and genotyping technology are both advancing rapidly, creating new opportunities for medical and scientific discovery. The convergence of these two technologies is now facilitating genetic association studies of unprecedented size within the context of routine clinical care. As a result, the medical community will soon be presented with a number of novel opportunities to bring functional genomics to the bedside in the area of pharmacotherapy. By linking biological material to comprehensive medical records, large multi-institutional biobanks are now poised to advance the field of pharmacogenomics through three distinct mechanisms: (i) retrospective assessment of previously known findings in a clinical practice-based setting, (ii) discovery of new associations in huge observational cohorts, and (iii) prospective application in a setting capable of providing real-time decision support. This review explores each of these translational mechanisms within a historical framework. Although the field of pharmacogenomics has the potential to transform the clinical practice of medicine, gene-based drug prescribing currently occurs rather infrequently. The Clinical Pharmacogenomics Implementation Consortium has been organized to move research findings into routine practice ( Personalized gene-based healthcare delivery may therefore soon shift the allocation of medical resources away from reactive treatment of disease toward a more proactive approach based upon interindividual variations. 1,2 It is likely that electronic medical records (EMRs) will play a pivotal role in this transformation. Before 2008, only ~10% of all US physicians were using a basic electronic health-care record. 3 Although the proportion of US hospitals implementing a basic EMR system was similarly low (7.6%) before 2008, 4 the application of EMRs has subsequently been expanding rapidly in both the inpatient and outpatient settings. 5 Nearly half of all large multispecialty group practices now utilize a comprehensive electronic record ( computerworld.com). Through the Patient Protection and Affordable Care Act of 2010, federal legislators have set an aggressive timeline to encourage the widespread implementation of EMRs. 5 Providers who roll out EMRs by 2015 will receive additional incentives for the care of Medicare patients, but only if the application is determined to fulfill prespecified meaningful use criteria. The meaningful use rules for 2011 and 2012 were released by the US Depment of Health and Human Services on 13 July 2010 ( A two-track approach has been established, containing criteria that are both mandatory (e.g., maintenance of active medication lists) and optional (e.g., decision-support software capable of flagging drug drug interactions). To date, EMR deployment not only has improved patient care, but has also established large, practice-based longitudinal data sets ideal for the conduct of observational research. 6,7 These data sets are rich in clinical information and available in both structured and unstructured formats. Structured data include diagnoses, clinical laboratory results, diagnostic imaging results, procedures ordered and performed, medications ordered and dispensed, and physician order entry. Structured medication data, in picular, have been used for a large variety of pharmacoepidemiology, pharmacoeconomic, and service-related health-care investigations. 8 1 Depment of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; 2 Depment of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA; 3 Depment of Atherosclerosis Research, Center for Nutrition and Metabolism, Children s Hospital Oakland Research Institute, Oakland, California, USA; 4 Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA; 5 Center for Health Research Southeast, Kaiser Permanente, Atlanta, Georgia, USA; 6 Depment of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA; 7 Depment of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA; 8 Depment of Biomedical Informatics, Mayo Clinic, Rochester, Minnesota, USA; 9 Children s Hospital Informatics Program, Children s Hospital Boston, Boston, Massachusetts, USA; 10 Depment of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. Correspondence: RA Wilke Received 26 June 2010; accepted 30 September 2010; advance online publication 19 January doi: /clpt Clinical pharmacology & Therapeutics VOLUME 89 NUMBER 3 march
2 When unstructured medication data are embedded in free-text clinical notes, natural language processing (NLP) algorithms have proven useful in the accurate reconstruction of comprehensive drug-exposure histories. 9 NLP-based phenotyping approaches have been used successfully to identify genetic determinants of drug outcome in the context of toxicity and efficacy. 10 As a community, our ability to characterize the genetic architecture underlying treatment outcomes also continues to improve because of advances in genotyping technology. Increases in throughput and decreases in cost are allowing investigators to move from searches for candidate genes (pharmacogenetics) to genome-wide SNP scanning (pharmacogenomics) in cohorts of increasing size. 11 It is likely that entire genomic sequences will soon be linked to individual EMRs. 1,2 Because the convergence of these two rapidly expanding technologies (i.e., biomedical informatics and high-throughput genotyping) represents an unprecedented opportunity to bring functional genomics to the bedside, many large medical centers are constructing DNA biobanks in the context of routine clinical practice These biobanks offer the advantages of scale, cost efficiency, and extremely dense longitudinal health-care data. Many models have emerged for the construction of biobanks, including models based on recruitment and enrollment of subjects from a specific geographic region or practice community. Other approaches have employed novel informatics strategies for total de-identification of EMRs. The latter approach optimizes security while allowing the de-identified samples to be linked to archived biological material in a cost-effective manner Electronic medical record data Notes, text reports Clinical messaging Labs, structured data ICD9, CPT CPOE De-identification DNA from discarded blood samples Linked through a one-directional hash algorithm De-identified research data set Synthetic derivative Biobank genetic data Figure 1 One approach to the construction of a biobank for pharmacogenomic research. Electronic medical records (EMRs) typically contain a combination of unstructured text reports and structured data. Structured data include most laboratory values, vital signs, and information such as computerized provider order entry (CPOE) records. In addition, administrative billing codes (ICD9, CPT) form valuable components for electronic phenotyping. These data can then be de-identified using algorithms to remove personal health identifiers from text through a combination of statistical and pattern-matching techniques. 13 Finally, de-identified medical records are linked to DNA samples, using research-unique identifiers that can be generated using a one-way hash algorithm that prevents discovery of the input number (e.g., a medical record number). CPT, current procedural terminology; ICD, International Classification of Disease. (as depicted in Figure 1). Early results indicate that biobanks constructed from completely de-identified EMRs are robust in their ability to replicate genetic associations previously identified in disease-specific cohorts. 15 This review explores potential methods through which existing EMRs may help facilitate the translation of pharmacogenomics into widespread clinical practice. Three distinct mechanisms are discussed: retrospective assessment of known findings in a clinical practice-based setting, discovery of novel associations in the context of gene environment interaction, and prospective application in a setting capable of providing real-time decision support through bioinformatics and pharmacovigilance. Each is presented in a historical context with an emphasis on future outlook. Historical Overview The clinical practice community began moving toward implementation of EMRs nearly half a century ago. 16 Although most early EMRs consisted primarily of billing codes, some contained diagnostic codes in site-specific lexicons. The majority of the early lexicons were rather cursory. Shortly thereafter, procedural codes and clinical laboratory data began to be archived in coded and easily extractable formats. 17 In most systems of care, clinical notes were entered as free text in a manner that was diverse, complex, and site specific. Medication data were typically unstructured and available only within free-text notes. More recently, computer-based prescribing has facilitated the entry of medication data in a format that is coded. National efforts are currently under way to harmonize both these data formats. 18 Early in the past decade, lack of structured medication data presented an obstacle to the routine use of EMRs in studies addressing the genetic determinants underlying treatment outcomes. Therefore, initial progress in the field of pharmacogenetics was limited primarily to cohorts enrolled in treatment trials. 19 However, as clinical interest in this field grew, investigators began manually interrogating clinical practice-based data sets for drug-exposed cohorts of limited sample sizes. 20 Within this setting, the process of case ascertainment was labor intensive and expensive. Nonetheless, such studies were ply successful, picularly when they focused on predictors of toxicity (rather than efficacy) for drugs associated with clinically severe adverse drug reactions (ADRs) and a narrow therapeutic index More recently, the electronic reconstruction of comprehensive medication histories has allowed the field of pharmacogenomics to gain considerable momentum within data sets that are derived from routine clinical practice. 9 Data derived from EMRs have proven to be highly accurate for quantifying disease phenotypes (onset and rate of progression) as well as treatment outcomes (efficacy and toxicity). Clinical diagnoses can be efficiently extracted from de-identified EMRs through the application of algorithms integrating diagnostic codes, clinical laboratory data, and medication histories, and these traits are robust in their ability to replicate known associations previously characterized in disease-specific research cohorts. 15 With the development of controlled vocabularies, their inclusion in 380 VOLUME 89 NUMBER 3 march
3 centralized terminology systems such as the Unified Medical Language System, and application of scalable information extraction strategies from the clinical narrative 24 ( ohnlp.org; investigators are now able to extend this work to the characterization of treatment outcomes using NLP software. 25 Standard evaluation metrics for the performance of NLP systems are shown in Eqs 1 4: True positives Recall = True positives + False negatives True positives Precision = True positives + False negatives ( ) ( ) 2 Precision Recall F-score = Precision + Recall True positives + True negatives Accuracy = True positives + False positives+ False negatives + True negatives Detailed medication information including strength of dose, route of administration, and frequency of administration can now be extracted from clinical text data. Jagannathan et al. 26 recently compared four commercial NLP engines and reported a high F-score of 93.2% for capturing drug names, but lower F-scores of 85.3, 80.3, and 48.3% for retrieving data on strength of dose, route of administration, and frequency of administration. Newer approaches can increase F-scores to >90% for strength, route, and frequency. 9 A recent NLP challenge in the Integrating Biology and the Bedside (i2b2) initiative focuses specifically on the extraction of drug signatures from clinical freetext documents ( Current Efforts Clearly, for pharmacogenetic and pharmacogenomic association studies to be successful within the context of EMRs, accurate drug-exposure histories need to be efficiently extracted and linked to treatment outcomes that are carefully defined. Methods used to quantify the toxicity of a given drug are typically quite different from those used to quantify its clinical efficacy. 27 As mentioned previously, many of the early findings in this field were related to toxicity EMRs and drug toxicity Data obtained from routine medical practice are uniquely suited for the investigation of genetic determinants underlying ADRs, whereas, in comparison, data obtained from clinical trials may be less useful for this task. 28 This discrepancy is due, in p, to the fact that clinical trials often have a run-in period, during which potential study subjects who show signs of drug intolerance are excluded before randomization. Patients with relevant comorbidities may also be actively excluded from clinical trials. This is not so in practice-based data sets. As a result, the prevalence of ADRs within the community is often higher (and more variable) than that observed within randomized trials. (1) (2) (3) (4) Consider the example of lipid-lowering therapy. HMG-CoA reductase inhibitors (statins) are the most commonly prescribed class of medications in the United States, and large multicenter trials have demonstrated unequivocally that these drugs reduce the risk of cardiovascular events in patients at risk. Although statin-related ADRs occur very infrequently in the context of monotherapy, the ADR event rate increases within the context of interacting medications. 29,30 Many of these drug drug interactions reflect alterations in pharmacokinetic processes. We have also observed that genetic variability in pharmacokinetic processes can contribute to the severity of statin-related ADRs. 20 However, patient-to-patient variability in phase I metabolism represents only a single component within any given patient s capacity for drug disposition. The entire process is better understood when each component is considered within the context of absorption, distribution, metabolism, and elimination. 31 For example, many statins undergo additional modification through phase II conjugation by enzymes within the UDP-glucuronosyltransferase (UGT) family. 32 UGT1A1 and UGT1A3 are both capable of converting atorvastatin acid to a lactone derivative, and perturbations in atorvastatin kinetics previously attributed to UGT1A1*28 may in fact be due to genetic variability in UGT1A3 (UGT1A3 haplotypes are in allelic association with UGT1A1*28). 33 Membrane transporters also markedly influence statin disposition. The SEARCH Collaborative Group recently reported that simvastatin-induced muscle toxicity is associated with genetic variability in statin uptake. 34 Other data suggest that variability in efflux may influence risk. 35 Efforts are under way to replicate these findings using EMRs. 30 The ability to resolve genetic determinants of drug toxicity depends on several factors. 22 Unless the toxicity end point is rigorously defined, such studies are subject to misclassification bias. Two important properties must be considered: the clinical severity of the ADR and the therapeutic index of the drug. The therapeutic index reflects the ratio of the dose known to cause half of the maximal toxicity to the dose known to deliver half of the maximal efficacy (TD 50 /ED 50 ). 31 Drugs with a wider therapeutic Effect Effect ED 50 TD 50 ED 50 TD 50 Drug dose Figure 2 Quantifying drug toxicity. Therapeutic index (TI) = TD 50 /ED 50. ED 50 = dose of a drug observed to yield half-maximal efficacy. TD 50 = dose of a drug observed to yield half-maximal toxicity. Clinical pharmacology & Therapeutics VOLUME 89 NUMBER 3 march
4 The clinical narrative, mined using natural language processing Date: 8/10/2005 Patient Name and ID: Jones, Mha DOB 7/8/1969 CC: I have a second lump in my left breast. Patient is a 36 yo female who was ill 2 weeks ago with a summer cold. Rather than getting well she got worse several days ago. She has pain in the upper teeth on the right, blood tinged nasal discharge, and mild sore throat. She feels a bit better with Aspirin and Tylenol Mrs Jones underwent a lumpectomy to remove a mass from her right breast on the 30 May She was prescribed Tamoxifen 10 mg but states she Stopped Taking the medication about 9 months ago. Medication Dose Route Medication history extracted from prescription database Patient treatment profile Stage II breast cancer diagnosed Breast cancer progression (stage III) Patient not taking tamoxifen Patient undergoes complete mastectomy Advil (200 mg) Switched to femara Tamoxifen (10 mg) prescribed Tamoxifen (20 mg) prescribed Treatment history is clarified: tamoxifen followed by aromatase inhibitor Figure 3 Structured and unstructured data generate high-quality phenotypes. Upper left: recent advances in natural language processing (NLP) allow extremely accurate reconstruction of comprehensive medication histories. Upper right: structured medication data generated by computerized provider order entry software (e.g., name value pairs, such as medication = tamoxifen ) can be easier to collate and analyze. However, structured data must be normalized across diverse systems of care. The National Library of Medicine (NLM) has developed a terminology called RxNorm ( rxnorm), linking drug names (dose, ingredient, and formulation) to drug vocabularies commonly used in pharmacy management systems (e.g., First Databank, Micromedex, MediSpan, Gold Standard Alchemy, and Multum). Bottom: structured and unstructured data can be merged to yield high-quality drug-exposure phenotypes that facilitate pharmacogenomic studies using EMRs. (The hypothetical patient and clinical note featured above are completely fictitious.) index (e.g., statins) tend to have ADRs that are less susceptible to genetic (or environmental) perturbations in kinetic processes. This may explain, in p, why statin-related ADRs occur so rarely within the context of monotherapy. 22 Conversely, ADRs tend to occur more frequently with drugs that have a narrower TI (e.g., anticoagulants and antineoplastics). This principle is illustrated in Figure 2. To appreciate the importance of therapeutic index, one might consider the thromboembolic complications related to the use of tamoxifen, an antiestrogen used to treat breast cancer. Worldwide, it is the most common endocrine therapy for estrogen receptor positive breast cancer. Although aromatase inhibitors are also commonly prescribed for this indication, ~1.5 million tamoxifen prescriptions are still written in the United States each year. Tamoxifen reduces the risk of breast cancer recurrence by ~50%, but there is considerable variability in its efficacy and in its toxicity profile. Deep venous thromboses are rare but serious side effects linked to the use of tamoxifen. Because they are rare, there may not be enough events in typical clinical trials to conduct adequately powered genotype phenotype association studies. Therefore, in order to study this association, EMRs have recently been used to identify sufficient numbers of patients with breast cancer who experience deep venous thromboses while on tamoxifen. Through investigations using banked DNA from ADR case patients and frequency-matched tamoxifen-exposed controls, it was found that genetic variants in the estrogen receptor were associated with the occurrence of deep venous thromboses. 36 Studies are now under way to confirm these results, using additional EMRs linked to biobanks picipating in the National Institutes of Health funded emerge network ( php/main_page). EMRs and drug efficacy Tamoxifen is a moderately potent antiestrogen; however, it is metabolized into many metabolites that are known to be more potent than the parent compound. The most abundant of these high-potency metabolites is endoxifen (4-OH-N-desmethyltamoxifen). This active metabolite is formed primarily by cytochrome P450 2D6 (CYP2D6). As expected, patients have reduced concentrations of endoxifen in plasma if they have reduced CYP2D6 activity because of either the presence of genetic polymorphisms in CYP2D6 or the concurrent use of medications that inhibit CYP2D6 activity. Some association studies have shown a relationship between CYP2D6 activity and tamoxifen treatment outcome. In this context, EMRs have been used in recent efforts to determine whether the concurrent use 382 VOLUME 89 NUMBER 3 march
5 a LDL level (mg/dl) b E max M al e F e m a l e 50 ED Log 10 (dose) (mg) Percent Percent Distribution of efficacy in dose response E max (mg/dl) Figure 4 Quantifying drug efficacy within large populations, using electronic medical records (EMRs). (a) Dose response data for atorvastatin. LDL cholesterol plotted by dose. (b) Gender-stratified distribution for E max within an EMR biobank. of CYP2D6-inhibiting drugs (e.g., antidepressants) by patients taking tamoxifen is associated with an increase in the recurrence rates of breast cancer. These studies have drawn from breast cancer health records from Denmark, 37 the Netherlands, 38 Canada, 39 and other countries. Another study utilized records from the Medco, Inc., pharmacy benefits manager in the United States. 40 These studies have shown mixed results. In some of the studies, but not in others, CYP2D6 inhibitors were reported to be associated with recurrence rates of breast cancer. The discrepancy in results may be due to differences in the populations studied, sample sizes, and/or the methods used to mine the databases. This highlights the need for additional work focused on understanding the optimal and consistent use of EMRs. Within the National Institutes of Health funded Pharmacogenomics Research Network (PGRN) ( PharmGKB.org), in biobanks linked to EMRs, there are several ongoing efforts to construct and standardize comprehensive treatment histories of patients exposed to tamoxifen. Our group has recently applied automated NLP-based extraction and information merging within the EMR to quantify each patient s breast cancer treatment strategy within several Pharmacogenomics Research Network nodes. Sensitivity and specificity were % (positive and negative predictive values were %) as compared with a manually abstracted data set. Figure 3 illustrates how the combination of prescription database querying and NLP techniques applied to the clinical narrative can be merged to assemble an automated treatment classification. Similar efforts are under way in other systems of care 41 and for other drug gene interactions. 42 McAlpine and colleagues have effectively scanned EMR data to quantify drug exposure (including dose) as p of an investigation to determine the strength of association between genetic variability in CYP2D6 and therapeutic response to antidepressants. By altering drug concentration levels in the circulation (or within a tissue microenvironment), many genetic predictors of toxicity are also known to alter drug efficacy (e.g., variable drug oxidation by cytochromes P450). Genetic variability in phase I metabolism of some statins not only influences the severity of ADRs (as mentioned earlier) but also affects the degree to which these drugs decrease low-density lipoprotein cholesterol levels. 43 Given that the impact of size appears to be relatively small (<10 mg/dl difference in cholesterol lowering per copy of the minor allele), the clinical significance of these findings remains uncertain. 43 Variability in pharmacodynamic candidate genes can have similar effects. Variants in HMG-CoA reductase clearly influence the lipid-lowering efficacy of statins. 44 Large, multicenter studies are now under way to identify additional genes that influence the efficacy of statins; this research is being carried out primarily through the retrospective genotyping of archived biological materials obtained during prior randomized clinical trials. 11 However, restricting these efforts to treatment trials would produce only very limited information because most efficacy data obtained during trials are limited to a single dose. Complete characterization of drug response requires a consideration of potency (ED 50 ) as well as of maximal efficacy. These properties can be determined only in patients who are exposed to multiple drug doses and may best be derived from real-life, clinical practice based data. Without a complete characterization of efficacy in subjects exposed to drugs across a wide range of doses, clinical phenotypes cannot be fully characterized. To begin identifying genetic markers associated with the low-density lipoprotein cholesterol lowering effect of atorvastatin across multiple doses, we previously interrogated EMR data from a large population-based biobank. 27 NLP software was used to generate comprehensive retrospective drug-exposure histories for the entire database (n = 20,000). For statin exposure, these algorithms were 100% sensitive and 96% specific, with an initial positive predictive value of 87%. Through manual ch abstraction, these algorithms were optimized using programming that corrected for dosing discrepancies attributed to pill splitting; the final positive predictive value was 95%. Full dose response relationships were then constructed for all biobank picipants exposed to atorvastatin. The result was a nested cohort of 3,710 individuals for whom we subsequently derived rigorous phenotypic parameters for atorvastatin potency (ED 50 ) and maximal atorvastatin efficacy (E max ). 27 The distribution of these traits is shown in Figure 4. The application of algorithms rigorously characterizing efficacy within EMR data is now being expanded to other classes of drugs across diverse systems of care. Through an initiative led by the PGRN ( pgrnresources/pgpop_profile.jsp), these approaches are being Clinical pharmacology & Therapeutics VOLUME 89 NUMBER 3 march
6 explored for the accurate characterization of treatment outcomes within multiple nodes of the HMO Research Network. Network members include Harvard Pilgrim and Fallon Healthcare (in the northeastern United States); Kaiser Permanente Georgia (in the southeastern United States); HealthPners, Henry Ford, and Marshfield Clinic (in the midwestern United States); and Group Health Cooperative, Lovelace Clinic, Kaiser Permanente Colorado, Kaiser Permanente Northwest, Kaiser Permanente Hawaii, Kaiser Permanente Southern California, and Kaiser Permanente Northern California (in the western United States). These institutions provide care to more than 10 million individuals. 8 Cross-network consortia are currently being established, and more than 250,000 DNA samples are already in hand. Kaiser Permanente Northern California, in picular, has recently embarked on one of the most ambitious biobanking efforts ever undertaken. As biological materials are linked to additional EMRs in these and other systems of care, the resulting data will advance the field of pharmacogenomics in two distinct ways: first, by enabling assessment of the generalizability of previously identified drug response genes within the community, and second, by facilitating discovery of previously unrecognized determinants of drug outcome in the context of clinical covariates. Vision For the Future The knowledge base relating variable outcomes in drug therapy to genomic variations is rapidly expanding. As noted above, the construction and integration of biobanks linked to EMRs can follow a variety of designs. Biobanks that enroll subjects through the process of informed consent must comply with laws regarding privacy at the local, state, and federal levels. 10,12 Clinical data and biological materials that are de-identified in accordance with the provisions of 45 CFR 46 may be used for research with nonhuman subjects. 15 As these and other EMR-based data sources are merged for large-scale pharmacogenomic studies, all such efforts must be subject to ongoing oversight by institutional review boards, internal and external ethics committees, community advisory boards, legal depments, and the Federal Office of Human Research Protection. Data security and privacy are paramount. The Safe Harbor provision of the HIPAA Privacy Rule requires the removal of 18 personal identifiers (including demographic data) before any form of public disclosure. Additional layers of security are being developed and tested as the clinical and scientific communities manage increasingly complex genomic data sets. 45 Decision support As efforts to merge biobanks grow, there is increasing difficulty in envisioning how pharmacogenomic knowledge can be brought to the bedside in the absence of advanced informatics tools that would include examination of the levels of evidence as well as advice on how to manage individual subjects. The scientific and clinical communities have only begun to leverage the wide variety of phenotypic data available in EMRs to optimize studies of drug outcomes. Medication information from the structured (e.g., electronic prescribing systems) and free-text components (e.g., from clinical notes) of each EMR will need to be merged, as shown in Figure 3. Additional data sources will allow assessment of adherence to medication regimens. Pharmacy claim data have been standardized for many years and are widely used in health services research, especially for Pharmacy Benefit Management programs, Medicaid, and, recently, P D of Medicare. Data normalization strategies (using locally adopted formats and terminologies) need to be shared across large healthcare networks. The mapping of clinically relevant terms to community-vetted and -adopted ontologies will ensure semantic interoperability and ease of study replication. Extending the example developed in Figure 3, variations in the terms indicating exposure to tamoxifen can be mapped to the same RxNORM code (10324) so that investigators may avoid the creation of exhaustive lists of terms referring to the same phenotypic data element. Normalization procedures such as these will enable the establishment of large patient registries, with unique biological and clinical characteristics, across institutions. Supported by National Institutes of Health funding, many medical centers are already applying NLP techniques for extracting information from the clinical narrative to investigate rare medication side effects prospectively. Although the need for NLP analysis can be reduced by an increase in structured data entry in EMRs, novel approaches to the characterization of free text will continue to be essential. For example, although structured applications in medical oncology now automatically encode the chemotherapy regimens ordered (and medications actually delivered to a patient), free-text interrogation is still needed to understand why divergence occurs, in some cases, between the medications ordered and those actually delivered. The rapid advancements in electronic phenotyping approaches, described earlier, have occurred in parallel with equally robust progress in the area of genotyping technologies. Genome-wide SNP scanning arrays have become increasingly dense (currently containing more than 1 million SNPS) and increasingly cost effective over the past decade. As a result, more genetic information is available at lower cost. Exome scanning (i.e., a focused approach that sequences all exons for all genes) is being conducted in cohorts of increasing sample sizes, and it seems inevitable that entire genomes will soon be included in each patient s EMR. 1,2 Ultimately, the clinical utility of this phenotypic and genotypic information will depend on biomedical informatics application platforms that provide efficient real-time decision support at the point of care. Furthermore, the expansion of knowledge generated by ongoing genotype phenotype association studies will make it imperative that decision-support platforms be flexible enough to incorporate future knowledge. Decision-support software must allow reinterpretation of clinical genetic data in the light of information that may emerge from future discoveries. 46 There is also a considerable need to educate and train health-care professionals in the use of these data. A recent survey carried out by the 384 VOLUME 89 NUMBER 3 march
7 American Medical Association in collaboration with Medco Health Solutions, Inc., found that, although 98% of provider picipants agreed about the utility of genetic testing in drug therapy, only 10% actually felt that they had been adequately informed about the process. Only 26% had received some form of formalized training ( com/community/ pharmacogenomics/physicansurvey). This stands in strong contrast to interview data that clearly indicate that most patients expect health-care professionals to explain the clinical utility of pharmacogenetic tests. 47 Clinical implementation To ease the transition of this information into routine clinical practice, Gardner et al. have proposed the addition of genetic information to an existing drug interaction database so as to further enhance clinical decision support and optimize patient safety. 48 This approach is appealing from a clinical viewpoint. Relevant genetic data can be formatted as an Extensible Markup Language document, and the additional information can be added using tags and implemented through existing software. Such software is already in place at many large medical centers. The real challenge will be in deciding when and how to use this information. Potential application paradigms include (i) gene-based drug selection, (ii) gene-based drug dosing, (iii) medication reconciliation, (iv) push phenotyping, and (v) pharmacovigilance. Warfarin provides a good example of the use of genetic information in determining drug dosing. Clearly an individual s maintenance dose of warfarin is strongly influenced by variability in the pharmacodynamics and pharmacokinetics of the drug induced by the presence of specific candidate genes, and this relationship can be utilized to inform the process of gene-based drug dosing. Although similar strategies are being developed for managing the effect of pharmacokinetics-altering candidate genes on the efficacy of clopidogrel, gene-based drug selection (e.g., prescribing another thienopyridine in place of clopidogrel) is a suitable alternative. It is important to note, however, that these strategies need not be limited to the period of drug initiation. Both can be applied, in the context of a variety of drugs, during the process of medication reconciliation, picularly when patients move from a system of care without an EMR to one with an EMR. 49 Furthermore, even in the absence of genetic information, EMRs can facilitate gene-based drug dosing by flagging in real-time the data of patients who appear to be developing an ADR and by prompting providers to consider genotyping such patients in an effort to optimize risk assessment. EMRs can also be used at the population level to identify trends in the development of new ADRs; that is, EMRs may enhance pharmacovigilance, especially during the postmarketing period. For instance, there are now compelling data to support the claim that cardiovascular ADRs related to the use of highly potent COX-2 inhibitors might have been identified earlier using such an EMR-based approach. 50 In 2007, the US Congress passed the Food and Drug Administration Amendments Act, directing the agency to increase the postmarket monitoring of drug safety. In order to accomplish this, the Food and Drug Administration established the Sentinel Initiative with the goal of detecting drug safety related signals earlier and more accurately. This is now being accomplished through real-time monitoring of EMRs and medical claims databases. The monitoring of multiple databases throughout the health-care system requires the sophisticated integration of diverse EMR databases. Although many crossinstitutional networks have already been constructed to facilitate this process (e.g., the PGRN, the emerge network, and the HMO Research Network), it is likely that new funding initiatives and patient advocacy groups will drive the implementation of even larger consortia. Such efforts will generate the data needed to define the role of EMRs in pharmacogenomics and drug safety. Outlook Data on pharmacogenetic associations of various effect sizes are streaming into the literature at an increasing rate. It is not possible for individual practitioners to keep track of these relationships without assistance from information technology systems. However, with electronic decision support, clinical practitioners now have the ability to utilize this information. Genetic data will likely soon be deposited preemptively into each patient s EMR, and robust biomedical informatics platforms will be positioned to interrogate this information during the process of clinical decision making in real time. It appears that EMRs have brought personalized medicine to our doorstep. Acknowledgments This work was supported by the following NIH grants: R01DK080007, U01HL069757, U01HG004608, U01 HL65962, RC2GM092618, R01CA139246, NCI DCCPS supplement to U01 HG 04599, UO1GM61388, Breast SPORE CA , U54LM008748, R01GM088076, U01GM061373, and UL1 RR Conflict of Interest The authors declared no conflict of interest American Society for Clinical Pharmacology and Therapeutics 1. Ashley, E.A. et al. Clinical assessment incorporating a personal genome. Lancet 375, (2010). 2. Lifton, R.P. Individual genomes on the horizon. N. Engl. J. Med. 362, (2010). 3. DesRoches, C.M. et al. Electronic health records in ambulatory care a national survey of physicians. N. Engl. J. 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This weekend saw the third annual charity walk for Susan (Scanlon) Bradley, who passed away far too early from a brain tumor.
Her family has been staging a charity walk in her honor every year to help raise money for a scholarship and keep her legacy alive.
On Sunday, more than 200 people turned out to walk in what was arguably the nicest weather the event has seen in its three years.
Mucho mileage was logged around the track at Notre Dame Academy in Tyngsboro by the hearty and healthy walkers.
Sue's brother, Barry, opened things up with a thank you to all who contributed to the scholarship fund
And then Sue's husband Tim led his children out for the first lap of many around the track!
Sue passed away from a Glioblastoma, a type of malignant brain tumor. The third annual walk was organized as a way to remember and honor all the wonderful things she did for so many, while also allowing her family to give back to the community.
Susan was a big advocate of education her entire life. She worked in the school systems for 25 years and was also very involved in the schools her children attended. The funds raised at the walk will be applied toward the Susan Bradley Scholarship set up at the Academy of Notre Dame so that even in her absence, she will continue to give back to others.
Over the span of the three years of the walk, her family has raised more than $25,000!!!
Here, Barry and Scott recreate their performance on the power lines stretch of the Merrimack River trail race
The ladies in Barry's life
One incredible aspect of the walk is that every year, it draws in people who also attended St. Joseph's Regional High School (Sue's alma mater) back in the day.
Always great to reunite with friends from nearly FOUR DECADES AGO!
This year saw a record number of dogs taking part in the walk. Though truth be told, from what I saw, most of them ended up being carried, or just calling it a day and laying down on the field.
Selfies abounded this day. This one, along with several other pics on this post, comes courtesy of Marcia Cassidy
The Brothers Scanlon, counting down the minutes to the prize raffle, always an exciting event! Especially for Sean and Jill's children
My Number One Walking Buddy. Any day, every day.
Best buds coming up on 45 YEARS!
Looks like the walk itself may be winding down. John, of course, always knows where the camera is. Andrew must be slipping.
Yeah, I think it's time to declare this puppy over.
A group pic of E Streeter Nation (absent a couple of participants who were busy taking care of clean-up details at the event)
As regular readers of the blog know, we're always honored to support charity causes, whether it be through road races, or special events.
But when it directly impacts one of our own as in this case, it always serves to remind us just how lucky we are to all still have one another and be able to get together like this to honor a loved one's life, and to celebrate the fact that we're all still together.
Friends and family. Don't take either of them for granted.

subset: commoncrawl


text:
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Posted by Milan Dec 20 2013, 12:23 pm
Dear Patrons and Supporters,
Thank you so much for a wonderful year of music, art and dance! We have been blessed to see many talented students, young and old, who worked with our wonderful faculty. We thank you for your patronage and trust. From all of us, we wish you peace and merriment for the holidays!
As you are making your year-end donations, we invite you to keep us in mind. As tuition and grants do not cover all the costs associated with running our programs, any gift makes a difference. To make an online gift (quickly and securely), click here.
Thank you and Happy Holidays!
Faculty and Staff,
Wyoming Fine Arts Center
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text:
Search Results:
Enter your search terms below. You can choose to filter your results by section by choosing from the drop-down menu below. Also, in some sections you can choose to filter by system as well!
Example: To search for Pac-Man in MAME ROMs type in "pac-man", choose "ROMs/ISOs/Games" as your Section and "M.A.M.E." as your system. It's just that simple!
You searched for "dessin" in All Sections:
2 Results FoundSwitch between ROMs, Emulators, Music, Scans, etc. by selecting the category tabs below!Save time. Add Emuparadise search to your browser search bar!
Synthetic Arts Dessin (1992)(Cybernetics)(fr) ROM
System: Atari ST Size: 96K
System: Atari ST Size: 96K


text:
GoConnect (ASX:GCN) has announced a new Asian-language IPTV joint venture with Victoria-based ISP Netbay Internet.
The arrangement will see the creation of an equally-owned company, Asia IPTV, which will initially serve up Cantonese and Mandarin language programming.
GoConnect, will be responsible for distribution across its various IPTV properties, which currently also includes programming such as music content from uctv.fm and The Business Show.
Netbay will host the programs and distribute them within its own broadband network.
The content is currently being offered by Netbay through its own MyiTV IPTV service, under license from the Australian subsidiary of TVB. TVB is a Hong Kong free to air broadcaster.
The joint company intends to eventually expand to include Korean, Indian, Chinese and Vietnamese language channels.
GoConnect executive chairman, Richard Li, said he foresaw a demand for the services.
"Australia is a nation of migrants and many Asian migrant households are already subscribers to satellite TV services provided by various networks from their countries of origin," he said.
He said he expected Asia IPTV to launch services in the second half of the year.
GCN shares fell 3.33 per cent on Wednesday to $0.029.


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Alison Goodman defines a Talisman Book as "one of those novels that you read over and over again, a book that seems to resonate through you, that wards off the disappointments and insecurities of everyday life."
My Talisman Books are the ones I'd rescue from a burning building. For example:
— My dogeared paperback copy of 'Lord of the Rings'. This book – broken-spined, tattered, beloved – was probably one of the first thing that made me kneel at the altar of fantasy and begin SERIOUS worship there. Tolkien made me realise that the big epic dreams that crowded my imagination were FOR REAL, and were valuable. This book is the physical embodiment of that realization. It's a talisman not just because of its identity but because of what it represents, the kind of hugeness and wonder and awe and the way it made me cognisant of my place in this world.
— 'Tigana' by Guy Gavriel Kay, because it's one of the best BOOKS I've ever read. The writing and the story make this amazing for me and so does the visceral emotional connection I feel to the underlying themes of the book.
— 'Nine Princes in Amber,' the now out-of-print paperback edition that made Roger Zelazny lift his eyebrows in utter astonishment when I gave it to him to sign and ask me where on earth I'd got that copy because it had been out of print for YEARS.
– A volume of fairy tales by Hans Christian Andersen, because all stories live inside that book, and I could read them and dream up the rest of a lost world by his tropes.
– And because it's irreplaceable, a really ancient and ill-favored book with dull gray covers – a broken down book, loved well long before I had my hands on it, with scribbled commentary in the margins and on the bottom of the pages. This is the book that lived beside my grandfather's bed, the book that he read and re-read and re-read, the scribbles in the margins are his thoughts, and in his hand. He's been gone these twenty years. He'll never speak to me again except through this book, and I WOULD go through fire to get it.
Those are Talisman Books in the purest and most glittering sense of the word. There are many many books that I love, and have adored over the years.
— But forgive me if I add another to my Talisman Book list, a book that I wrote. A hardcover edition of "Secrets of Jin Shei", the book to remind me what I am, what the culmination is of all the gifts that all my other books have poured like gems into my waiting spirit. I'll take a copy with me and show it to people if I lose the power of speech and they ask me who or what I am. Because that is what I am. Will always be. I am the creator of THIS THING, this book, this collection of words, this story… this Talisman.
There were the books which drew my tears – "Les Miserables", Howard Spring's "My Son, My Son", Karl May's "Winnetou" (although it took me YEARS to unlearn all the "facts" I though I knew about the American Indian culture in general and the Apache in particular after I finished reading his work), Jack London's "Call of the Wild", almost ANYTHING by Ursula le Guin, a book not many people reading this will have heard of but whose title translates as "The Time of Death" by a writer of my own tongue and tribe by the name of Dobrica Cosic and another book by one of my own, Ivo Andric's "Bridge on the Drina".
Lest you should think that I spent my entire reading life weeping, there are books that drew my laughter – Jerome K. Jerome's "Three Men in a Boat", T. H. White's "Once and Future King".
And there are the comfort books I return to because I know I can find solace there – "Song of Arbonne", "Captain Corelli's Mandolin", Mary Stewart's Merlin books, "Shadow of the Moon" by M. M. Kaye or any fat historical novel by Sharon Penman (but particularly "Here Be Dragons"), Barbara Kingsolver's "Poisonwood Bible", lots of stuff by Pearl Buck, books by Henryk Sienkiewicz, John Galsworthy, Boris Pasternak, Nikos Kazantzakis, Daphne du Maurier. Of more recent vintage, Catherynne Valente whose poetic vision enthralls me or Neil Gaiman whose dark and sardonically twisted tales and characters draw me in and China Mieville whose surgical command of the English language leaves me breathless and humbled.
So – what are YOUR Talisman Books?


text:
There will be a brief intermission while I sort out the problem with the comment system. I (stupidly, without checking, because nothing ever goes wrong when you're on the bleeding edge of an upgrade, does it?) upgraded Hot Topic's WordPress underpinnings to the latest version — 4.0 — only to find that now comments don't display properly. I've tracked it down to a problem with the theme (the code that makes HT look the way it does), and I now have to work out how to fiddle with things to get them back. There may be a marked change in the site's appearance…
Category: Hot Topic
Hot Topic hiatus, or paws for thought?
Over the next week, my posting frequency trend line is going to take a sharp dip — mainly because if we choose tomorrow and a week hence as our end points — which, as we all know, is far too short to be blogologically significant — there will be a marked absence of posts. Having got the vineyard ready for netting (which will start happening at 8-30am tomorrow), I will be heading north to Nelson, there to board a boat for six days tootling around the Abel Tasman and D'Urville Island. I will check in from time to time when communication technologies allow, but if anybody thinks I'm going to disturb a few days fishing, swimming, walking and eating (and drinking good wine) by posting on climate matters then they are going to be royally disappointed. If you'd like to know a little more about where we're heading – try here.
Feel free to treat this as another open thread. (Image nicked from John "viral kitten" Cook at The Conversation)
Denial Tango 2014
Here's a new recording by Aussie group Men With Day Jobs of their climate classic The Denial Tango, accompanied by a rather striking video. Men With Day Jobs are Rod Crundwell, Stafford Sanders and Kim Constable (from left to right in the pix in the video) and their new album "Deep in Denial" is due for release early next year.
I'd go with Tony Abbott, It's just a load of crap
This round-the-world disaster is an evil greedy trap
'Cause everybody knows the world is flat
I posted the full lyrics back in 2011…
Santa Baby (and other views)
Christmas morning has dawned sunny and warm chez Hot Topic, and there's a pile of presents waiting to be opened. I doubt that any will be what Eartha Kitt had in mind when she recorded Santa Baby in 1953, but she makes a compelling case for Christmas largesse to be directed her way. This afternoon the weather is expected to turn to custard (or, perhaps, brandy butter) and when the rain sets in my mood may turn to match Eric Idle's rather more ascerbic (and sweary – definitely NSFW) take on the festive season:
And if you're feeling at all gloomy about prospects for the human race, then I have the perfect song for you. Peter Blegvad and Andy Partridge1 assure us that worse is on the way — a truth we will all have to live with.
Normal service will be resumed when the mince pies are finished.
Normal service will be resumed shortly
Something of a global warming (coverage) hiatus has hit Hot Topic in the last couple of days, courtesy of the rather dramatic gale that hit my part of New Zealand on Tuesday evening. We are all well, and suffered no damage to our house — but there's a hell of a lot of tidying up to do to damaged trees and fences, and we are still without power and mobile phone coverage. With luck we'll get reconnected in the next day or so. Normal bloggage will resume as soon as I finish chainsawing fallen branches and clearing debris.


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Developing quality content can be struggle for a lot of marketers, who often have many other things on their plates. They can't argue with the value in producing quality content, especially with Penguin 2.0. If you want quality link building, it boils down to creating quality content. So what does this mean? What are the standards when producing quality content?
The Content Marketing Institute (CMI) defines quality content as user-oriented and engaging. It also has a business purpose and is easy to find and share. In this post, I'll explain how you can develop user-oriented content that will be instrumental in making your content relevant. Relevancy goes hand-in-hand with quality.
There are two necessary steps to take when personalizing your content:
Dive into your data
Social media, Google Analytics, marketing automation (and more) will provide tons of valuable insight into your audience. In fact, in a recent edition of the Quarterly Digital Intelligence Briefing, Econsultancy found that only 6% of marketers use social graph data but of those, 88% give it high marks for ROI. It's always important to focus on demographics as well as behavioral data because both influence the decision-making process.
Develop Personas
Personas go deeper into the mindset of your audience. They should aim to identify wants, needs and pain points of your particular audience. Most likely your audience doesn't fit in one bucket; you should develop multiple personas with a variety of characteristics and buying behaviors. Understand how your product or service can help solve the problems that keep them up at night.
Quality content is content that resonates with the users and addresses their pain points and their place in the digital purchase funnel. Quality content is the most natural form of link-building. The higher the quality and more developed your content strategy, the more you can expect to earn visibility and links.


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Strona domowa ▸ Obrazki ▸ Obrazek #1081829
25,959 wyświetleń • 78 komentarzy • 368 ulubione • 12,970 punkty
Except where otherwise noted, pictures are licensed under a Creative Commons By-NC-ND License.
- Picture of the dayAug 24, 2014
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Komentarze78 komentarzy
Kousei ☆ ★ ☆
This would be perfect for people who don't want their NSFW figures on display when people come over.
I NEED this in my life!!
im late but what is this cabinet called? or where did you buy it from :D
I like this but I'd hate not being able to see them all at once.
wow that is cool. A clever way to display both types of figures, but if I had that much extra room in my house, I would want a secret room! or an extra closet LOL.
amazing this saves up a lot of space.
Gives me a lot of ideas. Like putting christmas related figs on one end for that time of the year and others on the other side.
Gives me a lot of ideas. Like putting christmas related figs on one end for that time of the year and others on the other side.
I needs that for my DVD and Blu ray collection!!
As in.. seriously!!
As in.. seriously!!
The nendoroids and that other figures don´t like me. but the idea of the cabinet is pretty cool! very original.
Wyświetl pozostałe komentarze
This is pretty neat. I don't know if I'd want something like this though. Just one wrong move and all your figures are gonna come crashing down. I'd probably get some glass installed in front of it just to make sure my figures are safe.


text: Hey yeah I'm lazy, took me a week to get around to posting this. I was bored last week, so I got a screwdriver and took apart my bass. I mean, I take apart all my stuff. Even my tv. I shocked myself haha. Oh well that's how ya learn... Anyway. I have a P/J setup. So I unscrewed both pups and put one of them underneat the strings one at a time...to see the tonal differences ya know? Then I noticed that when I took out the P pups...and put the J underneath the strings...it wasn't WORKING! I mean good god. All the wires are connected, everything seems ok. Course, I got it and a amp for $200 so whaddya expect. So basicly I'm only playing through a set of P pickups. Is this right? I mean...I should have bought that Fender J pup at the store just cuz I could have afforded it..but I didn't...damn shoulda done it!


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In recent days, the chairman of the Consumers Association of Ireland, James Doorley, has been critical of the proposal by the Department of Finance to scrap the Consumer Consultative Panel at the Financial Regulator once it's merged back into the Central Bank.
Mr. Doorley believes that scrapping this committee appointed by the Minister for Finance would have the effect of preventing "meaningful input into the system of financial regulation". According to Mr. Doorley:
those who pay should have a say and that the consumer voice should be at the heart of our new system of financial regulation, as it is consumers who are largely bearing the brunt of the financial crisis.
Mr. Doorley is speaking about a talking shop that didn't meet at all during some of the most devastating months of this financial crisis at the end of 2008. As first reported here on ValueIreland.com, the panel only met once between July 2008 and March 2009.
There was an interesting exchange in the Dail earlier this week in reference to the abolition of this talking shop. Thomas Byrne, Fianna Fail TD for Meath East (one of the local TDs for Mr. Doorley as it happens) made this appeal to the Minister for Finance:
Last night, the Minister for Finance stated that he is consulting the various representative associations and interest groups. I would be keen for him to consult the Consumers Association of Ireland on this legislation and, if possible, to retain the Central Bank's consumer panel in some form. It is included in the legislation in a different form, but perhaps it should be retained in a bid to keep the public's confidence. The public is confident that we are looking after the consumer and doing the right thing.
However, more telling of the attitude of Fianna Fail to regulation and consumer protection in general, in response to a retort to James Bannon TD, Deputy Byrne went on to say:
However, keeping the panel would be more image than reality, since the reality is evident in terms of the regulator's actions.
And there we have it. It's more important to be seen to do something rather than actually doing anything at all – as I've said many times here before, the modus operandi of the current Fianna Fail government.