Information Discovery on Electronic Health Records Using Authority Flow Techniques

<p>Abstract</p> <p>Background</p> <p>As the use of electronic health records (EHRs) becomes more widespread, so does the need to search and provide effective information discovery within them. Querying by keyword has emerged as one of the most effective paradigms for searching. Most work in this area is based on traditional Information Retrieval (IR) techniques, where each document is compared individually against the query. We compare the effectiveness of two fundamentally different techniques for keyword search of EHRs.</p> <p>Methods</p> <p>We built two ranking systems. The traditional BM25 system exploits the EHRs' content without regard to association among entities within. The Clinical ObjectRank (CO) system exploits the entities' associations in EHRs using an authority-flow algorithm to discover the most relevant entities. BM25 and CO were deployed on an EHR dataset of the cardiovascular division of Miami Children's Hospital. Using sequences of keywords as queries, sensitivity and specificity were measured by two physicians for a set of 11 queries related to congenital cardiac disease.</p> <p>Results</p> <p>Our pilot evaluation showed that CO outperforms BM25 in terms of sensitivity (65% vs. 38%) by 71% on average, while maintaining the specificity (64% vs. 61%). The evaluation was done by two physicians.</p> <p>Conclusions</p> <p>Authority-flow techniques can greatly improve the detection of relevant information in EHRs and hence deserve further study.</p

Genetic regulation of pituitary gland development in human and mouse

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans

Association of the Type 2 Diabetes Mellitus Susceptibility Gene, TCF7L2, with Schizophrenia in an Arab-Israeli Family Sample

Many reports in different populations have demonstrated linkage of the 10q24–q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24–q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p = 7.01×10−6) and of the nearby intergenic SNP, rs1033772, (p = 6.59×10−6) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required

Proteomic Analysis of Pathways Involved in Estrogen-Induced Growth and Apoptosis of Breast Cancer Cells

Estrogen is a known growth promoter for estrogen receptor (ER)-positive breast cancer cells. Paradoxically, in breast cancer cells that have been chronically deprived of estrogen stimulation, re-introduction of the hormone can induce apoptosis.Here, we sought to identify signaling networks that are triggered by estradiol (E2) in isogenic MCF-7 breast cancer cells that undergo apoptosis (MCF-7:5C) versus cells that proliferate upon exposure to E2 (MCF-7). The nuclear receptor co-activator AIB1 (Amplified in Breast Cancer-1) is known to be rate-limiting for E2-induced cell survival responses in MCF-7 cells and was found here to also be required for the induction of apoptosis by E2 in the MCF-7:5C cells. Proteins that interact with AIB1 as well as complexes that contain tyrosine phosphorylated proteins were isolated by immunoprecipitation and identified by mass spectrometry (MS) at baseline and after a brief exposure to E2 for two hours. Bioinformatic network analyses of the identified protein interactions were then used to analyze E2 signaling pathways that trigger apoptosis versus survival. Comparison of MS data with a computationally-predicted AIB1 interaction network showed that 26 proteins identified in this study are within this network, and are involved in signal transduction, transcription, cell cycle regulation and protein degradation.G-protein-coupled receptors, PI3 kinase, Wnt and Notch signaling pathways were most strongly associated with E2-induced proliferation or apoptosis and are integrated here into a global AIB1 signaling network that controls qualitatively distinct responses to estrogen

Comparative genomics reveals functional transcriptional control sequences in the Prop1 gene

Mutations in PROP1 are a common genetic cause of multiple pituitary hormone deficiency (MPHD). We used a comparative genomics approach to predict the transcriptional regulatory domains of Prop1 and tested them in cell culture and mice. A BAC transgene containing Prop1 completely rescues the Prop1 mutant phenotype, demonstrating that the regulatory elements necessary for proper PROP1 transcription are contained within the BAC. We generated DNA sequences from the PROP1 genes in lemur, pig, and five different primate species. Comparison of these with available human and mouse PROP1 sequences identified three putative regulatory sequences that are highly conserved. These are located in the PROP1 promoter proximal region, within the first intron of PROP1, and downstream of PROP1. Each of the conserved elements elicited orientation-specific enhancer activity in the context of the Drosophila alcohol dehydrogenase minimal promoter in both heterologous and pituitary-derived cells lines. The intronic element is sufficient to confer dorsal expansion of the pituitary expression domain of a transgene, suggesting that this element is important for the normal spatial expression of endogenous Prop1 during pituitary development. This study illustrates the usefulness of a comparative genomics approach in the identification of regulatory elements that may be the site of mutations responsible for some cases of MPHD

TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders

TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n=596) and healthy controls (n=385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative-symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment

The different use dependences of tocainide and benzocaine are correlated with different effects on sodium channel inactivation

To study the mechanism of use dependence, we investigated the influence of 0.5 mM tocainide on the amplitude of sodium currents elicited by membrane depolarizations with standard test pulses in voltage-clamped human myoballs. For comparison, the experiments were also conducted with 1 mM benzocaine, a drug with almost no use dependence. These concentrations were so chosen that without stimulation and at a holding potential of -135 mV, either drug blocked about 50% of the channels (tonic block). With repetitive stimulation at 1 Hz, tocainide blocked about 75% of the channels that had remained open in the rested state (phasic block), while benzocaine had little such effect. The potential dependence of steady-state inactivation (h∞ curves) of the sodium channels in these myoballs depended on the duration of the prepotential indicating that they possess at least two states of inactivation: fast and intermediate. The two drugs differed in their effects on these two states. Benzocaine always produced a left-shift of the h∞ curve, no matter whether the duration of the conditioning pulse was short (8 ms) or long (512 ms) indicating that it can bind when the channel is in the state of fast inactivation. Tocainide shifted the h∞ curve only with long prepulses, i.e. when the sodium channels were in the state of intermediate inactivation. The recovery from inactivation, a process governed by two time constants in the absence of drugs, was also differently influenced by the two drugs. In the presence of tocainide, the channels mainly recovered with the slow time constant and this time constant was significantly increased, whereas benzocaine did not substantially modify this biphasic process. The results are in agreement with the hypothesis that drug binding depends on the state of the channel. The different use dependences of tocainide and benzocainide are explained by the fact that they bind favourably to the sodium channels when they are in the states of intermediate and fast inactivation, respectively