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1.  Interactions of Chromatin Context, Binding Site Sequence Content, and Sequence Evolution in Stress-Induced p53 Occupancy and Transactivation 
PLoS Genetics  2015;11(1):e1004885.
Cellular stresses activate the tumor suppressor p53 protein leading to selective binding to DNA response elements (REs) and gene transactivation from a large pool of potential p53 REs (p53REs). To elucidate how p53RE sequences and local chromatin context interact to affect p53 binding and gene transactivation, we mapped genome-wide binding localizations of p53 and H3K4me3 in untreated and doxorubicin (DXR)-treated human lymphoblastoid cells. We examined the relationships among p53 occupancy, gene expression, H3K4me3, chromatin accessibility (DNase 1 hypersensitivity, DHS), ENCODE chromatin states, p53RE sequence, and evolutionary conservation. We observed that the inducible expression of p53-regulated genes was associated with the steady-state chromatin status of the cell. Most highly inducible p53-regulated genes were suppressed at baseline and marked by repressive histone modifications or displayed CTCF binding. Comparison of p53RE sequences residing in different chromatin contexts demonstrated that weaker p53REs resided in open promoters, while stronger p53REs were located within enhancers and repressed chromatin. p53 occupancy was strongly correlated with similarity of the target DNA sequences to the p53RE consensus, but surprisingly, inversely correlated with pre-existing nucleosome accessibility (DHS) and evolutionary conservation at the p53RE. Occupancy by p53 of REs that overlapped transposable element (TE) repeats was significantly higher (p<10−7) and correlated with stronger p53RE sequences (p<10−110) relative to nonTE-associated p53REs, particularly for MLT1H, LTR10B, and Mer61 TEs. However, binding at these elements was generally not associated with transactivation of adjacent genes. Occupied p53REs located in L2-like TEs were unique in displaying highly negative PhyloP scores (predicted fast-evolving) and being associated with altered H3K4me3 and DHS levels. These results underscore the systematic interaction between chromatin status and p53RE context in the induced transactivation response. This p53 regulated response appears to have been tuned via evolutionary processes that may have led to repression and/or utilization of p53REs originating from primate-specific transposon elements.
Author Summary
It is well established that p53 binds DNA elements near p53 target genes to regulate the response to cellular stress. To assess factors influencing binding to response elements and subsequent gene expression, we have analyzed 2932 p53-occupied response elements (p53REs) in the context of genome-wide chromatin state, DNA accessibility and dynamics, and considered roles for binding-sequence specificity and evolutionary conservation. While p53 occupancy level shows little apparent direct relationship to gene expression change, after grouping expressed genes by their chromatin status at baseline, a relationship between occupancy of p53REs and gene expression change emerged. Analysis of p53RE sequences demonstrated that p53 occupancy was strongly correlated with sequence similarity to p53RE consensus, but surprisingly, was inversely correlated with nucleosome accessibility (DHS) and evolutionary conservation. These data revealed a systematic interaction between p53RE content and chromatin context that affects both quantitative p53 occupancy and the induced transactivation response to exposure. Moreover, this interaction appears to have been tuned via evolutionary events involving transposable elements, which strongly bind p53, but in only a few instances affect gene expression levels. Models of p53-regulated gene expression response that consider both chromatin state and sequence context may prove useful in guiding strategies for cancer prevention or therapy.
PMCID: PMC4287438  PMID: 25569532
3.  A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection 
Cell  2013;155(2):410-422.
The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.
PMCID: PMC4171736  PMID: 24120139
4.  Knemidocoptic Mange in Wild Golden Eagles, California, USA 
Emerging Infectious Diseases  2014;20(10):1716-1718.
During 2012–2013 in California, USA, 3 wild golden eagles were found with severe skin disease; 2 died. The cause was a rare mite, most closely related to Knemidocoptes derooi mites. Cautionary monitoring of eagle populations, habitats, and diseases is warranted.
PMCID: PMC4193178  PMID: 25271842
ectoparasite; electron microscopy; golden eagle; Knemidocoptes sp.; mange; raptor; skin disease; wild; parasites
5.  Electronic health information exchange in underserved settings: examining initiatives in small physician practices & community health centers 
Health information exchange (HIE) is an important tool for improving efficiency and quality and is required for providers to meet Meaningful Use certification from the United States Centers for Medicare and Medicaid Services. However widespread adoption and use of HIE has been difficult to achieve, especially in settings such as smaller-sized physician practices and federally qualified health centers (FQHCs). We assess electronic data exchange activities and identify barriers and benefits to HIE participation in two underserved settings.
We conducted key-informant interviews with stakeholders at physician practices and health centers. Interviews were recorded, transcribed, and then coded in two waves: first using an open-coding approach and second using selective coding to identify themes that emerged across interviews, including barriers and facilitators to HIE adoption and use.
We interviewed 24 providers, administrators and office staff from 16 locations in two states. They identified barriers to HIE use at three levels—regional (e.g., lack of area-level exchanges; partner organizations), inter-organizational (e.g., strong relationships with exchange partners; achieving a critical mass of users), and intra-organizational (e.g., type of electronic medical record used; integration into organization’s workflow). A major perceived benefit of HIE use was the improved care-coordination clinicians could provide to patients as a direct result of the HIE information. Utilization and perceived benefit of the exchange systems differed based on several practice- and clinic-level factors.
The adoption and use of HIE in underserved settings appears to be impeded by regional, inter-organizational, and intra-organizational factors and facilitated by perceived benefits largely at the intra-organizational level. Stakeholders should consider factors both internal and external to their organization, focusing efforts in changing modifiable factors and tailoring HIE efforts based on all three categories of factors. Collective action between organizations may be needed to address inter-organizational and regional barriers. In the interest of facilitating HIE adoption and use, the impact of interventions at various levels on improving the use of electronic health data exchange should be tested.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6963-14-415) contains supplementary material, which is available to authorized users.
PMCID: PMC4181433  PMID: 25240718
6.  Effect of electronic prescribing with formulary decision support on medication tier, copayments, and adherence 
Medication non-adherence is prevalent. We assessed the effect of electronic prescribing (e-prescribing) with formulary decision support on preferred formulary tier usage, copayment, and concomitant adherence.
We retrospectively analyzed 14,682 initial pharmaceutical claims for angiotensin receptor blocker and inhaled steroid medications among 14,410 patients of 2189 primary care physicians (PCPs) who were offered e-prescribing with formulary decision support, including 297 PCPs who adopted it. Formulary decision support was initially non-interruptive, such that formulary tier symbols were displayed adjacent to medication names. Subsequently, interruptive formulary decision support alerts also interrupted e-prescribing when preferred-tier alternatives were available. A difference in differences design was used to compare the pre-post differences in medication tier for each new prescription attributed to non-adopters, low user (<30% usage rate), and high user PCPs (>30% usage rate). Second, we modeled the effect of formulary tier on prescription copayment. Last, we modeled the effect of copayment on adherence (proportion of days covered) to each new medication.
Compared with non-adopters, high users of e-prescribing were more likely to prescribe preferred-tier medications (vs. non-preferred tier) when both non-interruptive and interruptive formulary decision support were in place (OR 1.9 [95% CI 1.0-3.4], p = 0.04), but no more likely to prescribe preferred-tier when only non-interruptive formulary decision support was in place (p = 0.90). Preferred-tier claims had only slightly lower mean monthly copayments than non-preferred tier claims (angiotensin receptor blocker: $10.60 versus $11.81, inhaled steroid: $14.86 versus $16.42, p < 0.0001). Medication possession ratio was 8% lower for each $1.00 increase in monthly copayment to the one quarter power (p < 0.0001). However, we detected no significant direct association between formulary decision support usage and adherence.
Interruptive formulary decision support shifted prescribing toward preferred tiers, but these medications were only minimally less expensive in the studied patient population. In this context, formulary decision support did not significantly increase adherence. To impact cost-related non-adherence, formulary decision support will likely need to be paired with complementary drug benefit design. Formulary decision support should be studied further, with particular attention to its effect on adherence in the setting of different benefit designs.
PMCID: PMC4236533  PMID: 25167807
Clinical decision support; Electronic prescribing; Medication adherence
7.  Drug–drug interactions that should be non-interruptive in order to reduce alert fatigue in electronic health records 
Alert fatigue represents a common problem associated with the use of clinical decision support systems in electronic health records (EHR). This problem is particularly profound with drug–drug interaction (DDI) alerts for which studies have reported override rates of approximately 90%. The objective of this study is to report consensus-based recommendations of an expert panel on DDI that can be safely made non-interruptive to the provider's workflow, in EHR, in an attempt to reduce alert fatigue.
We utilized an expert panel process to rate the interactions. Panelists had expertise in medicine, pharmacy, pharmacology and clinical informatics, and represented both academic institutions and vendors of medication knowledge bases and EHR. In addition, representatives from the US Food and Drug Administration and the American Society of Health-System Pharmacy contributed to the discussions.
Recommendations and considerations of the panel resulted in the creation of a list of 33 class-based low-priority DDI that do not warrant being interruptive alerts in EHR. In one institution, these accounted for 36% of the interactions displayed.
Development and customization of the content of medication knowledge bases that drive DDI alerting represents a resource-intensive task. Creation of a standardized list of low-priority DDI may help reduce alert fatigue across EHR.
Future efforts might include the development of a consortium to maintain this list over time. Such a list could also be used in conjunction with financial incentives tied to its adoption in EHR.
PMCID: PMC3628052  PMID: 23011124
clinical decision support; medication alerts; drug-drug interactions; alert fatigue; DDI alerts; computerized decision support systems
8.  pSCANNER: patient-centered Scalable National Network for Effectiveness Research 
This article describes the patient-centered Scalable National Network for Effectiveness Research (pSCANNER), which is part of the recently formed PCORnet, a national network composed of learning healthcare systems and patient-powered research networks funded by the Patient Centered Outcomes Research Institute (PCORI). It is designed to be a stakeholder-governed federated network that uses a distributed architecture to integrate data from three existing networks covering over 21 million patients in all 50 states: (1) VA Informatics and Computing Infrastructure (VINCI), with data from Veteran Health Administration's 151 inpatient and 909 ambulatory care and community-based outpatient clinics; (2) the University of California Research exchange (UC-ReX) network, with data from UC Davis, Irvine, Los Angeles, San Francisco, and San Diego; and (3) SCANNER, a consortium of UCSD, Tennessee VA, and three federally qualified health systems in the Los Angeles area supplemented with claims and health information exchange data, led by the University of Southern California. Initial use cases will focus on three conditions: (1) congestive heart failure; (2) Kawasaki disease; (3) obesity. Stakeholders, such as patients, clinicians, and health service researchers, will be engaged to prioritize research questions to be answered through the network. We will use a privacy-preserving distributed computation model with synchronous and asynchronous modes. The distributed system will be based on a common data model that allows the construction and evaluation of distributed multivariate models for a variety of statistical analyses.
PMCID: PMC4078293  PMID: 24780722
clinical data research network; comparative effectiveness research; patient-centered research; distributed analysis
9.  Electronic Health Record Impact on Work Burden in Small, Unaffiliated, Community-Based Primary Care Practices 
The use of electronic health records (EHR) is widely recommended as a means to improve the quality, safety and efficiency of US healthcare. Relatively little is known, however, about how implementation and use of this technology affects the work of clinicians and support staff who provide primary health care in small, independent practices.
To study the impact of EHR use on clinician and staff work burden in small, community-based primary care practices.
We conducted in-depth field research in seven community-based primary care practices. A team of field researchers spent 9–14 days over a 4–8 week period observing work in each practice, following patients through the practices, conducting interviews with key informants, and collecting documents and photographs. Field research data were coded and analyzed by a multidisciplinary research team, using a grounded theory approach.
All practice members and selected patients in seven community-based primary care practices in the Northeastern US.
The impact of EHR use on work burden differed for clinicians compared to support staff. EHR use reduced both clerical and clinical staff work burden by improving how they check in and room patients, how they chart their work, and how they communicate with both patients and providers. In contrast, EHR use reduced some clinician work (i.e., prescribing, some lab-related tasks, and communication within the office), while increasing other work (i.e., charting, chronic disease and preventive care tasks, and some lab-related tasks). Thoughtful implementation and strategic workflow redesign can mitigate the disproportionate EHR-related work burden for clinicians, as well as facilitate population-based care.
The complex needs of the primary care clinician should be understood and considered as the next iteration of EHR systems are developed and implemented.
PMCID: PMC3539023  PMID: 22926633
electronic health records; primary care; work burden; qualitative research
10.  Key principles for a national clinical decision support knowledge sharing framework: synthesis of insights from leading subject matter experts 
To identify key principles for establishing a national clinical decision support (CDS) knowledge sharing framework.
Materials and methods
As part of an initiative by the US Office of the National Coordinator for Health IT (ONC) to establish a framework for national CDS knowledge sharing, key stakeholders were identified. Stakeholders' viewpoints were obtained through surveys and in-depth interviews, and findings and relevant insights were summarized. Based on these insights, key principles were formulated for establishing a national CDS knowledge sharing framework.
Nineteen key stakeholders were recruited, including six executives from electronic health record system vendors, seven executives from knowledge content producers, three executives from healthcare provider organizations, and three additional experts in clinical informatics. Based on these stakeholders' insights, five key principles were identified for effectively sharing CDS knowledge nationally. These principles are (1) prioritize and support the creation and maintenance of a national CDS knowledge sharing framework; (2) facilitate the development of high-value content and tooling, preferably in an open-source manner; (3) accelerate the development or licensing of required, pragmatic standards; (4) acknowledge and address medicolegal liability concerns; and (5) establish a self-sustaining business model.
Based on the principles identified, a roadmap for national CDS knowledge sharing was developed through the ONC's Advancing CDS initiative.
The study findings may serve as a useful guide for ongoing activities by the ONC and others to establish a national framework for sharing CDS knowledge and improving clinical care.
PMCID: PMC3555314  PMID: 22865671
Knowledge management; clinical decision support systems; office of the national coordinator for health information technology; meaningful use; standards
11.  Targeted Deletion of Nrf2 Impairs Lung Development and Oxidant Injury in Neonatal Mice 
Antioxidants & Redox Signaling  2012;17(8):1066-1082.
Aims: Nrf2 is an essential transcription factor for protection against oxidant disorders. However, its role in organ development and neonatal disease has received little attention. Therapeutically administered oxygen has been considered to contribute to bronchopulmonary dysplasia (BPD) in prematurity. The current study was performed to determine Nrf2-mediated molecular events during saccular-to-alveolar lung maturation, and the role of Nrf2 in the pathogenesis of hyperoxic lung injury using newborn Nrf2-deficient (Nrf2−/−) and wild-type (Nrf2+/+) mice. Results: Pulmonary basal expression of cell cycle, redox balance, and lipid/carbohydrate metabolism genes was lower while lymphocyte immunity genes were more highly expressed in Nrf2−/− neonates than in Nrf2+/+ neonates. Hyperoxia-induced phenotypes, including mortality, arrest of saccular-to-alveolar transition, and lung edema, and inflammation accompanying DNA damage and tissue oxidation were significantly more severe in Nrf2−/− neonates than in Nrf2+/+ neonates. During lung injury pathogenesis, Nrf2 orchestrated expression of lung genes involved in organ injury and morphology, cellular growth/proliferation, vasculature development, immune response, and cell–cell interaction. Bioinformatic identification of Nrf2 binding motifs and augmented hyperoxia-induced inflammation in genetically deficient neonates supported Gpx2 and Marco as Nrf2 effectors. Innovation: This investigation used lung transcriptomics and gene targeted mice to identify novel molecular events during saccular-to-alveolar stage transition and to elucidate Nrf2 downstream mechanisms in protection from hyperoxia-induced injury in neonate mouse lungs. Conclusion: Nrf2 deficiency augmented lung injury and arrest of alveolarization caused by hyperoxia during the newborn period. Results suggest a therapeutic potential of specific Nrf2 activators for oxidative stress-associated neonatal disorders including BPD. Antioxid. Redox Signal. 00, 000–000.
PMCID: PMC3423869  PMID: 22400915
12.  Effects of Laboratory Data Exchange in the Care of Patients with HIV 
Electronic health record (EHR) systems are often modified through the addition of new features over time. Few studies have examined the specific effects of such changes. We examined whether implementation of a bidirectional laboratory interface for order entry and data reporting within an existing ambulatory EHR would result in more prompt responses to laboratory indications for antiretroviral therapy (ART) changes or in improved communication with HIV+ patients about relevant laboratory results.
We conducted a single-arm intervention study comparing the timeliness of ART regimen changes, HIV viral load (VL) outcomes and patient-reported assessments of care before and after implementation of a laboratory data exchange interface within an existing EHR, without changing the EHR ordering or results reporting user interface. Patient data was extracted from the EHR covering the period from 1 year before to 2 years after the intervention for a cohort of 1181 patients who had received care during the baseline year. The timeliness of ART changes was represented by the days from a laboratory-result “signal” (CD4 dropping below 350 or 200 or VL increasing by a half-log or to a value over 100,000) to an ART-change “response.” Patient assessments of care were collected by interviewing 100 anonymous patients at baseline and another 125 at 2 years post-intervention.
A total of 171 laboratory “signal” events were followed within 80 days by a change in ART therapy. The mean time from signal to therapy change (adjusted for clustering by patient) initially increased, from 37.7 days during the pre-intervention year to 48.2 days during the quarter immediately following activation of the lab intervention. It then declined to a mean of 31.4 days over the remaining 21 months of observation (P=0.03 for the 6-day improvement from the pre-period). A majority of patients (65%) achieved undetectable VL values by the end of the observation period; faster signal-response times were not associated with greater achievement of undetectable VL. Patients rated communication about laboratory tests more highly after implementation of the interface (91 vs. 83 on a 100-point scale, P=0.01); ratings were not higher for other aspects of care.
Adding laboratory data exchange interfaces within existing EHRs holds promise for improving HIV care, both in the timeliness of responses to important laboratory results and in the quality of provider communication about lab tests. However, the benefits from this incremental change may be modest unless more extensive redesign of laboratory follow-up workflows is undertaken, with support from enhanced user interfaces that take advantage of the laboratory information delivered. Providers should also consider increased staffing to compensate for dips in follow-up performance during the initial post-implementation months.
PMCID: PMC3477872  PMID: 22906370
HIV Infections/prevention & control; Computer Communication Networks; Ambulatory Care Information Systems; Clinical Laboratory Information Systems; Medical Order Entry Systems; Electronic Health Records; Communication; Evaluation Studies
13.  Comorbid Chronic Illness and the Diagnosis and Treatment of Depression in Safety Net Primary Care Settings 
To estimate the impact of chronic medical conditions on depression diagnosis, treatment, and follow-up care in primary care settings.
This was a cross-sectional study that used interviewer-administered surveys and medical record reviews. Three hundred fifteen participants were recruited from 3 public primary care clinics. Depression diagnosis, guideline-concordant treatment, and follow-up care were the primary outcomes examined in individuals with depression alone compared with individuals with depression and chronic medical conditions measured using the Charlson Comorbidity Index (CCI).
Physician diagnosis of depression (32.6%), guideline-concordant depression treatment (32.7%), and guideline-concordant follow-up care (16.3%) were all low. Logistic regression analysis showed no significant difference in the likelihood of depression diagnosis, guideline-concordant treatment, or follow-up care in individuals with depression alone compared with those with both depression and chronic medical conditions. Participants with severe depression were, however, twice as likely to receive a diagnosis of depression as participants with moderate depression. In addition, participants with moderately severe and severe depression received much less appropriate follow-up care than participants with moderate depression. Among participants receiving a depression diagnosis, 74% received guideline-concordant treatment.
Physician depression care in primary care settings is not influenced by competing demands for care for other comorbid medical conditions.
PMCID: PMC3782997  PMID: 19264935
14.  Correction: CSF1 Is a Novel p53 Target Gene Whose Protein Product Functions in a Feed-Forward Manner to Suppress Apoptosis and Enhance p53-Mediated Growth Arrest 
PLoS ONE  2013;8(9):10.1371/annotation/8deafa94-628f-4b03-9dbc-2ec78f5bf737.
PMCID: PMC3779272
15.  CSF1 Is a Novel p53 Target Gene Whose Protein Product Functions in a Feed-Forward Manner to Suppress Apoptosis and Enhance p53-Mediated Growth Arrest 
PLoS ONE  2013;8(9):e74297.
The p53 tumor suppressor gene has a common polymorphism at codon 72 that alters its function. We previously reported that the proline 72 polymorphic variant of p53 (P72) demonstrates increased ability to transactivate a subset of genes, relative to arginine 72 (R72); one of these genes is macrophage colony stimulating factor (CSF1). At present, the mechanism(s) underlying the increased transcriptional activity of P72 toward genes like CSF1 have not been completely elucidated. Additionally, the consequences of increased transcription of genes like CSF1 by the P72 variant to the downstream p53 pathway are unknown. In this report, we address these issues. We show that the CSF1 gene contains a conserved binding site for p53, and interestingly that the P72 variant shows increased ability to bind to this site. Moreover, we show that increased CSF1/CSF1R signaling in P72 cells feeds back on the p53 pathway to enhance p53 phosphorylation, levels, and transactivation of target genes, particularly the cyclin-dependent kinase inhibitor p21 (CDKN1A). This leads to an increase in p53-mediated growth arrest, along with a concomitant decrease in apoptosis. Notably, the CSF1/CSF1R signaling axis is overexpressed in several epithelial cancers, and there is clinical evidence that this pathway plays a role in radio-resistance of some cancers. We show that cells expressing CSF1 and CSF1R are indeed radio-resistant, and further, that this effect requires p53. These combined data are the first to implicate the CSF1/CSF1R pathway in the decision between p53-mediated growth arrest and apoptosis. They are also the first to highlight a cytokine as influential in cell fate determined by p53 in epithelial cells. Finally, these data may explain the association of the P72 variant and the CSF1/CSF1R pathway with increased senescence and radio-resistance in some epithelial tumor types.
PMCID: PMC3760869  PMID: 24019961
16.  High-priority drug–drug interactions for use in electronic health records 
To develop a set of high-severity, clinically significant drug–drug interactions (DDIs) for use in electronic health records (EHRs).
A panel of experts was convened with the goal of identifying critical DDIs that should be used for generating medication-related decision support alerts in all EHRs. Panelists included medication knowledge base vendors, EHR vendors, in-house knowledge base developers from academic medical centers, and both federal and private agencies involved in the regulation of medication use. Candidate DDIs were assessed by the panel based on the consequence of the interaction, severity levels assigned to them across various medication knowledge bases, availability of therapeutic alternatives, monitoring/management options, predisposing factors, and the probability of the interaction based on the strength of evidence available in the literature.
Of 31 DDIs considered to be high risk, the panel approved a final list of 15 interactions. Panelists agreed that this list represented drugs that are contraindicated for concurrent use, though it does not necessarily represent a complete list of all such interacting drug pairs. For other drug interactions, severity may depend on additional factors, such as patient conditions or timing of co-administration.
The panel provided recommendations on the creation, maintenance, and implementation of a central repository of high severity interactions.
A set of highly clinically significant drug-drug interactions was identified, for which warnings should be generated in all EHRs. The panel highlighted the complexity of issues surrounding development and implementation of such a list.
PMCID: PMC3422823  PMID: 22539083
Alerts; Medication-related decision support; electronic health records; alert fatigue; Office of the National Coordinator for health information Technology; drug-drug interaction; clinical decision support; medical informatics; knowledge bases; knowledge acquisition and knowledge management; knowledge representations; uncertain reasoning and decision theory; designing usable (responsive) resources and systems; personal health records and self-care systems; knowledge acquisition and knowledge management; demonstrating return on it investment; other specific EHR applications (results review); medication administration; disease progression; patient safety; decision support; data exchange
17.  Criteria for assessing high-priority drug-drug interactions for clinical decision support in electronic health records 
High override rates for drug-drug interaction (DDI) alerts in electronic health records (EHRs) result in the potentially dangerous consequence of providers ignoring clinically significant alerts. Lack of uniformity of criteria for determining the severity or validity of these interactions often results in discrepancies in how these are evaluated. The purpose of this study was to identify a set of criteria for assessing DDIs that should be used for the generation of clinical decision support (CDS) alerts in EHRs.
We conducted a 20-year systematic literature review of MEDLINE and EMBASE to identify characteristics of high-priority DDIs. These criteria were validated by an expert panel consisting of medication knowledge base vendors, EHR vendors, in-house knowledge base developers from academic medical centers, and both federal and private agencies involved in the regulation of medication use.
Forty-four articles met the inclusion criteria for assessing characteristics of high-priority DDIs. The panel considered five criteria to be most important when assessing an interaction- Severity, Probability, Clinical Implications of the interaction, Patient characteristics, and the Evidence supporting the interaction. In addition, the panel identified barriers and considerations for being able to utilize these criteria in medication knowledge bases used by EHRs.
A multi-dimensional approach is needed to understanding the importance of an interaction for inclusion in medication knowledge bases for the purpose of CDS alerting. The criteria identified in this study can serve as a first step towards a uniform approach in assessing which interactions are critical and warrant interruption of a provider’s workflow.
PMCID: PMC3706355  PMID: 23763856
Clinical decision support; Drug-drug interaction; Medication-related decision support system; Electronic health record; Alerts
18.  Provider Views about Responsibility for Medication Adherence and Content of Physician-Older Patient Discussions 
To investigate provider opinions about responsibility for medication adherence and examine physician-patient interactions to illustrate how adherence discussions are initiated.
Focus group discussions with healthcare providers and audiotaped outpatient office visits with a separate group of providers.
Focus group participants were recruited from multi-specialty practice groups in New Jersey and Washington, D.C. Outpatient office visits were conducted in primary care offices in Northern California.
Twenty-two healthcare providers participated in focus group discussions. One hundred patients aged 65 and older and 28 primary care physicians had their visits audiotaped.
Inductive content analysis of focus groups and audiotaped encounters.
Focus group analyses indicated that providers feel responsible for assessing medication adherence during office visits and for addressing mutable factors underlying nonadherence. However, they believed that patients are ultimately responsible for taking medications and voiced reluctance about confronting patients about nonadherence. The 100 patients participating in audio taped encounters were taking a total of 410 medications. Of these, 254 (62%) were discussed in a way that might touch upon adherence; physicians made simple inquiries about current patient medication use for 31.5%, but they made in-depth inquiries about adherence for only 4.3%. Of 39 identified instances of nonadherence, patients spontaneously disclosed 51%.
The lack of intrusive questions about medication taking during actual office visits may reflect poor provider recognition of the questions needed to fully assess adherence. Alternatively, provider beliefs about patient responsibility for adherence may hinder detailed queries. A paradigm of joint provider-patient responsibility may be needed to better guide discussions about medication adherence.
PMCID: PMC3381510  PMID: 22646818
medication adherence; patient-physician relationship; provider-patient communication; prescription medication
19.  Novel Hematopoietic Target Genes in the NRF2-Mediated Transcriptional Pathway 
Nuclear factor- (erythroid-derived 2) like 2 (NFE2L2, NRF2) is a key transcriptional activator of the antioxidant response pathway and is closely related to erythroid transcription factor NFE2. Under oxidative stress, NRF2 heterodimerizes with small Maf proteins and binds cis-acting enhancer sequences found near oxidative stress response genes. Using the dietary isothiocyanate sulforaphane (SFN) to activate NRF2, chromatin immunoprecipitation sequencing (ChIP-seq) identified several hundred novel NRF2-mediated targets beyond its role in oxidative stress. Activated NRF2 bound the antioxidant response element (ARE) in promoters of several known and novel target genes involved in iron homeostasis and heme metabolism, including known targets FTL and FTH1, as well as novel binding in the globin locus control region. Five novel NRF2 target genes were chosen for followup: AMBP, ABCB6, FECH, HRG-1 (SLC48A1), and TBXAS1. SFN-induced gene expression in erythroid K562 and lymphoid cells were compared for each target gene. NRF2 silencing showed reduced expression in lymphoid, lung, and hepatic cells. Furthermore, stable knockdown of NRF2 negative regulator KEAP1 in K562 cells resulted in increased NQO1, AMBP, and TBXAS1 expression. NFE2 binding sites in K562 cells revealed similar binding profiles as lymphoid NRF2 sites in all potential NRF2 candidates supporting a role for NRF2 in heme metabolism and erythropoiesis.
PMCID: PMC3677633  PMID: 23766848
20.  450K Epigenome-Wide Scan Identifies Differential DNA Methylation in Newborns Related to Maternal Smoking during Pregnancy 
Environmental Health Perspectives  2012;120(10):1425-1431.
Background: Epigenetic modifications, such as DNA methylation, due to in utero exposures may play a critical role in early programming for childhood and adult illness. Maternal smoking is a major risk factor for multiple adverse health outcomes in children, but the underlying mechanisms are unclear.
Objective: We investigated epigenome-wide methylation in cord blood of newborns in relation to maternal smoking during pregnancy.
Methods: We examined maternal plasma cotinine (an objective biomarker of smoking) measured during pregnancy in relation to DNA methylation at 473,844 CpG sites (CpGs) in 1,062 newborn cord blood samples from the Norwegian Mother and Child Cohort Study (MoBa) using the Infinium HumanMethylation450 BeadChip (450K).
Results: We found differential DNA methylation at epigenome-wide statistical significance (p-value < 1.06 × 10–7) for 26 CpGs mapped to 10 genes. We replicated findings for CpGs in AHRR, CYP1A1, and GFI1 at strict Bonferroni-corrected statistical significance in a U.S. birth cohort. AHRR and CYP1A1 play a key role in the aryl hydrocarbon receptor signaling pathway, which mediates the detoxification of the components of tobacco smoke. GFI1 is involved in diverse developmental processes but has not previously been implicated in responses to tobacco smoke.
Conclusions: We identified a set of genes with methylation changes present at birth in children whose mothers smoked during pregnancy. This is the first study of differential methylation across the genome in relation to maternal smoking during pregnancy using the 450K platform. Our findings implicate epigenetic mechanisms in the pathogenesis of the adverse health outcomes associated with this important in utero exposure.
PMCID: PMC3491949  PMID: 22851337
epigenetics; epigenome-wide; in utero; maternal smoking; methylation
21.  A conceptual framework and protocol for defining clinical decision support objectives applicable to medical specialties 
The U.S. Centers for Medicare and Medicaid Services established the Electronic Health Record (EHR) Incentive Program in 2009 to stimulate the adoption of EHRs. One component of the program requires eligible providers to implement clinical decision support (CDS) interventions that can improve performance on one or more quality measures pre-selected for each specialty. Because the unique decision-making challenges and existing HIT capabilities vary widely across specialties, the development of meaningful objectives for CDS within such programs must be supported by deliberative analysis.
We developed a conceptual framework and protocol that combines evidence review with expert opinion to elicit clinically meaningful objectives for CDS directly from specialists. The framework links objectives for CDS to specialty-specific performance gaps while ensuring that a workable set of CDS opportunities are available to providers to address each performance gap. Performance gaps may include those with well-established quality measures but also priorities identified by specialists based on their clinical experience. Moreover, objectives are not constrained to performance gaps with existing CDS technologies, but rather may include those for which CDS tools might reasonably be expected to be developed in the near term, for example, by the beginning of Stage 3 of the EHR Incentive program. The protocol uses a modified Delphi expert panel process to elicit and prioritize CDS meaningful use objectives. Experts first rate the importance of performance gaps, beginning with a candidate list generated through an environmental scan and supplemented through nominations by panelists. For the highest priority performance gaps, panelists then rate the extent to which existing or future CDS interventions, characterized jointly as “CDS opportunities,” might impact each performance gap and the extent to which each CDS opportunity is compatible with specialists’ clinical workflows. The protocol was tested by expert panels representing four clinical specialties: oncology, orthopedic surgery, interventional cardiology, and pediatrics.
PMCID: PMC3536635  PMID: 22943497
22.  Evaluation of the NCPDP Structured and Codified Sig Format for e-prescriptions 
To evaluate the ability of the structure and code sets specified in the National Council for Prescription Drug Programs Structured and Codified Sig Format to represent ambulatory electronic prescriptions.
We parsed the Sig strings from a sample of 20 161 de-identified ambulatory e-prescriptions into variables representing the fields of the Structured and Codified Sig Format. A stratified random sample of these representations was then reviewed by a group of experts. For codified Sig fields, we attempted to map the actual words used by prescribers to the equivalent terms in the designated terminology.
Proportion of prescriptions that the Format could fully represent; proportion of terms used that could be mapped to the designated terminology.
The fields defined in the Format could fully represent 95% of Sigs (95% CI 93% to 97%), but ambiguities were identified, particularly in representing multiple-step instructions. The terms used by prescribers could be codified for only 60% of dose delivery methods, 84% of dose forms, 82% of vehicles, 95% of routes, 70% of sites, 33% of administration timings, and 93% of indications.
The findings are based on a retrospective sample of ambulatory prescriptions derived mostly from primary care physicians.
The fields defined in the Format could represent most of the patient instructions in a large prescription sample, but prior to its mandatory adoption, further work is needed to ensure that potential ambiguities are addressed and that a complete set of terms is available for the codified fields.
PMCID: PMC3168301  PMID: 21613642
23.  Advancing clinical decision support using lessons from outside of healthcare: an interdisciplinary systematic review 
Greater use of computerized decision support (DS) systems could address continuing safety and quality problems in healthcare, but the healthcare field has struggled to implement DS technology. This study surveys DS experience across multiple non-healthcare disciplines for new insights that are generalizable to healthcare provider decisions. In particular, it sought design principles and lessons learned from the other disciplines that could inform efforts to accelerate the adoption of clinical decision support (CDS).
Our systematic review drew broadly from non-healthcare databases in the basic sciences, social sciences, humanities, engineering, business, and defense: PsychINFO, BusinessSource Premier, Social Sciences Abstracts, Web of Science, and Defense Technical Information Center. Because our interest was in DS that could apply to clinical decisions, we selected articles that (1) provided a review, overview, discussion of lessons learned, or an evaluation of design or implementation aspects of DS within a non-healthcare discipline and (2) involved an element of human judgment at the individual level, as opposed to decisions that can be fully automated or that are made at the organizational level.
Clinical decisions share some similarities with decisions made by military commanders, business managers, and other leaders: they involve assessing new situations and choosing courses of action with major consequences, under time pressure, and with incomplete information. We identified seven high-level DS system design features from the non-healthcare literature that could be applied to CDS: providing broad, system-level perspectives; customizing interfaces to specific users and roles; making the DS reasoning transparent; presenting data effectively; generating multiple scenarios covering disparate outcomes (e.g., effective; effective with side effects; ineffective); allowing for contingent adaptations; and facilitating collaboration. The article provides examples of each feature. The DS literature also emphasizes the importance of organizational culture and training in implementation success. The literature contrasts “rational-analytic” vs. “naturalistic-intuitive” decision-making styles, but the best approach is often a balanced approach that combines both styles. It is also important for DS systems to enable exploration of multiple assumptions, and incorporation of new information in response to changing circumstances.
Complex, high-level decision-making has common features across disciplines as seemingly disparate as defense, business, and healthcare. National efforts to advance the health information technology agenda through broader CDS adoption could benefit by applying the DS principles identified in this review.
PMCID: PMC3524755  PMID: 22900537
24.  Hybridization among Arctic white-headed gulls (Larus spp.) obscures the genetic legacy of the Pleistocene 
Ecology and Evolution  2012;2(6):1278-1295.
We studied the influence of glacial oscillations on the genetic structure of seven species of white-headed gull that breed at high latitudes (Larus argentatus, L. canus, L. glaucescens, L. glaucoides, L. hyperboreus, L. schistisagus, and L. thayeri). We evaluated localities hypothesized as ice-free areas or glacial refugia in other Arctic vertebrates using molecular data from 11 microsatellite loci, mitochondrial DNA (mtDNA) control region, and six nuclear introns for 32 populations across the Holarctic. Moderate levels of genetic structure were observed for microsatellites (FST= 0.129), introns (ΦST= 0.185), and mtDNA control region (ΦST= 0.461), with among-group variation maximized when populations were grouped based on subspecific classification. Two haplotype and at least two allele groups were observed across all loci. However, no haplotype/allele group was composed solely of individuals of a single species, a pattern consistent with recent divergence. Furthermore, northernmost populations were not well differentiated and among-group variation was maximized when L. argentatus and L. hyberboreus populations were grouped by locality rather than species, indicating recent hybridization. Four populations are located in putative Pleistocene glacial refugia and had larger τ estimates than the other 28 populations. However, we were unable to substantiate these putative refugia using coalescent theory, as all populations had genetic signatures of stability based on mtDNA. The extent of haplotype and allele sharing among Arctic white-headed gull species is noteworthy. Studies of other Arctic taxa have generally revealed species-specific clusters as well as genetic structure within species, usually correlated with geography. Aspects of white-headed gull behavioral biology, such as colonization ability and propensity to hybridize, as well as their recent evolutionary history, have likely played a large role in the limited genetic structure observed.
PMCID: PMC3402200  PMID: 22833800
Genetic structure; hybridization; Larus; Pleistocene glacial refugia; white-headed gulls
25.  Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha 
Nucleic Acids Research  2012;40(15):7416-7429.
Cellular oxidative and electrophilic stress triggers a protective response in mammals regulated by NRF2 (nuclear factor (erythroid-derived) 2-like; NFE2L2) binding to deoxyribonucleic acid-regulatory sequences near stress-responsive genes. Studies using Nrf2-deficient mice suggest that hundreds of genes may be regulated by NRF2. To identify human NRF2-regulated genes, we conducted chromatin immunoprecipitation (ChIP)-sequencing experiments in lymphoid cells treated with the dietary isothiocyanate, sulforaphane (SFN) and carried out follow-up biological experiments on candidates. We found 242 high confidence, NRF2-bound genomic regions and 96% of these regions contained NRF2-regulatory sequence motifs. The majority of binding sites were near potential novel members of the NRF2 pathway. Validation of selected candidate genes using parallel ChIP techniques and in NRF2-silenced cell lines indicated that the expression of about two-thirds of the candidates are likely to be directly NRF2-dependent including retinoid X receptor alpha (RXRA). NRF2 regulation of RXRA has implications for response to retinoid treatments and adipogenesis. In mouse, 3T3-L1 cells’ SFN treatment affected Rxra expression early in adipogenesis, and knockdown of Nrf2-delayed Rxra expression, both leading to impaired adipogenesis.
PMCID: PMC3424561  PMID: 22581777

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