The Astounding Breadth of Health Disparity: Phenome-Wide Effects of Race on Disease Risk

ObjectiveWe conducted a phenotype-wide association study (PheWAS) to compare diagnoses among Blacks with those of Whites in one health center in Tennessee using data from 1,883,369 patients.MethodsWe used our deidentified EHR, the Synthetic Derivative, to assess risk of diagnoses associated with Black as compared with White race using Firth logistic regression with covariates including age, sex, and density of clinical encounters.ResultsThere were anchoring associations in both directions, including the highest increased risk for Blacks of having sickle cell anemia, and strongest decreased risk of basal cell carcinoma. Results included established areas of disparity and many novel associations.ConclusionsPheWAS is a viable tool for calculating risk associated with any biomarker. The current analysis provide a new approach to generating hypotheses and understanding the breadth of health disparities. Future analyses will further explore causality, risk factors, and potential confounders not accounted for here.     

Performance of Older Depressed Patients on Two Cognitive Malingering Tests: False Positive Rates for the Rey 15-item Memorization and Dot Counting Tests

To our knowledge, no investigations have been undertaken to determine whether depression impacts performance on two commonly used tests to detect malingering of cognitive symptoms, the Rey 15-item Memorization Test and the Rey Dot Counting Test. This is a critical issue because of the high rate of depressive symptoms in patients with neurological conditions. It was hypothesized that depressed individuals, especially those with more severe depression, might be at risk for failing the tests, because these patients exhibit mild deficits in mental speed, visual perceptual/spatial skills, and visual memory, abilities required for successful completion of the malingering tests. However, examination of test performance in 64 older participants with major depression generally revealed very low false positive rates for most test scores, and severity of depression was unrelated to test scores. These results add to accumulating data supporting the validity of these cognitive malingering tests by documenting few false positive identifications.     

The prevalence of use,dependency and harms of legal ‘party pills’ containing benzylpiperazine (BZP) and trifluorophenylmethylpiperazine (TFMPP) in New Zealand

Piperazine‐based ‘party pills’ containing 1‐benzylpiperazine (BZP) and 1‐(m‐trifluorophenylmethylphenyl)piperazine (TFMPP) have become increasingly popular in New Zealand and many other countries. The aim of this study was to collect data on the population prevalence and related harm from legal party pill use in New Zealand. A national household sample of 2010 people aged 13–45 years old was collected using a computer‐assisted telephone interviewing (CATI) facility. Twenty per cent of the sample had tried legal party pills and 15% had used them in the previous year. Approximately 40% of males aged 18–24 years old had used legal party pills in the past year. While most users reported fairly minor problems from use, such as insomnia (50% of last year users), some users reported potentially more serious physical problems, such as ‘vomiting’ (12%), ‘inability to urinate’ (10%), ‘chest pains’ (4%) and ‘seizures’ (0.8%). Users also reported a range of psychological problems from use such as visual hallucinations (9%), paranoia (8%) and depression (8%). Two per cent of last year users were classified as dependent on legal party pills using a short dependency scale. The extent of harms and incidences of more serious problems, suggest that stricter regulation of the sale and use of legal party pills in New Zealand may be appropriate.     

Explicit scoring criteria for the Rey-Osterrieth and Taylor complex figures

Explicit scoring criteria based on the Taylor-Osterrieth method were developed for the Rey-Osterrieth and Taylor Complex Figure Tests. Without such criteria, clinicians and researchers are left to develop their own idiographic scoring systems, leading to low interrater reliability, especially in the middle range of scores. Criteria were applied to the copy and 30-min recall protocols of 101 subjects infected with HIV. Results indicate that the criteria presented are reliable across a wide range of scores, making them useful for tracking subtle changes over time. Independent raters were within two points of each other on 90.1 % of the copy and 88.1% of recall scores, with a maximum disagreement of five points on two copy protocols. The Taylor figure was also found to be more easily remembered than the Rey-Osterrieth, calling into question their interchangeability. Explicit criteria are particularly useful in research settings. They ensure interrater reliability over time and across examiners in longitudinal studies, enhance the detection of subtle differences within the normal range, and allow comparison of results obtained by different investigators.     

Intramolecular allosteric communication in dopamine D2 receptor revealed by evolutionary amino acid covariation

The structural basis of allosteric signaling in G protein-coupled receptors (GPCRs) is important in guiding design of therapeutics and understanding phenotypic consequences of genetic variation. The Evolutionary Trace (ET) algorithm previously proved effective in redesigning receptors to mimic the ligand specificities of functionally distinct homologs. We now expand ET to consider mutual information, with validation in GPCR structure and dopamine D2 receptor (D2R) function. The new algorithm, called ET-MIp, identifies evolutionarily relevant patterns of amino acid covariations. The improved predictions of structural proximity and D2R mutagenesis demonstrate that ET-MIp predicts functional interactions between residue pairs, particularly potency and efficacy of activation by dopamine. Remarkably, although most of the residue pairs chosen for mutagenesis are neither in the binding pocket nor in contact with each other, many exhibited functional interactions, implying at-a-distance coupling. The functional interaction between the coupled pairs correlated best with the evolutionary coupling potential derived from dopamine receptor sequences rather than with broader sets of GPCR sequences. These data suggest that the allosteric communication responsible for dopamine responses is resolved by ET-MIp and best discerned within a short evolutionary distance. Most double mutants restored dopamine response to wild-type levels, also suggesting that tight regulation of the response to dopamine drove the coevolution and intramolecular communications between coupled residues. Our approach provides a general tool to identify evolutionary covariation patterns in small sets of close sequence homologs and to translate them into functional linkages between residues.Identifying residues that coevolved to maintain or acquire fitness properties is critical for understanding protein structure, function, and evolution (1). Previous studies have shown that covarying residue pairs, those that exhibit correlated amino acid changes in large multiple sequence alignments, tend to form structural contacts (2–7), enhancing predictions of protein 3D structures (8–11). Covariation can also involve distal residues, but the function of these at-a-distance couplings is elusive and has been attributed to background noise, alternative protein conformations, or subunit interactions of protein homooligomers (5, 7, 12). Alternately, distal covarying residue pairs could indicate allosteric couplings (6, 13–18).The possibility of capturing intramolecular allosteric communication by amino acid covariation analysis of protein family sequences has not been extensively explored. Nonproximal thermodynamic coupling between correlated residue pairs was noted in 274 PDZ domains (14), but the relationship to allostery is still debated (19, 20). It may be that distinctive allosteric mechanisms, even among close homologs, limit the extraction of allosteric couplings from sequences (13). Our previous identification of residues important for allosteric signaling within G protein-coupled receptors (GPCRs) using Evolutionary Trace (ET) (21–24) and strong conservation of some of the residues implicated led us to ask whether ET could also uncover couplings among protein sequence positions not in direct contact.ET estimates the relative functional sensitivity of a protein to variations at each residue position using phylogenetic distances to account for the functional divergence among sequence homologs (25, 26). Similar ideas can be applied to pairs of sequence positions to recompute ET as the average importance of the couplings between a residue and its direct structural neighbors (27). To measure the evolutionary coupling information between residue pairs, we present a new algorithm, ET-MIp, that integrates the mutual information metric (MIp) (5) to the ET framework. We used dopamine D2 receptor (D2R), a target of drugs for neurological and psychiatric diseases (28), to test whether ET-MIp could elucidate the allosteric functional communications from amino acid covariation patterns and resolve the evolutionary distance at which the allosteric pathways of D2R homologs are sufficiently conserved to detect residue−residue coupling signatures. D2R is expressed in the central nervous system and responds to dopamine, the major catecholamine neurotransmitter. Canonical D2R signaling is effected by G_i/o class G proteins, which regulate ion channels (29, 30), MAPK kinases (31), phospholipase C (32), and inhibition of adenylyl cyclase (33). D1 class receptors (D1R and D5R) have lower affinities for dopamine (34–36) and activate adenylyl cyclase through G_s class G proteins. To characterize allosteric communication between covarying pairs of residues ranked as important by ET (ET residue pairs), we examined functional coupling for ligand binding affinities and downstream G_i activation induced by agonist-stimulated D2R.     

"Early-peak" carbon monoxide production in certain erythropoietic disorders

The "early-labeled" peak (ELP) of 14CO excretion following injection of glycine-2-14C was used to study erythropoiesis in a patient with sideroblastic anemia and in four subjects with myeloproliferative disorders. The ELP was greatly enlarged in all patients, as compared with a normal volunteer. The contour of the peaks from the hematologically abnormal subjects suggested the presence of increased erythroid heme degradation. In the patient with sideroblastic anemia, all hours of the early peak were significantly reduced after transfusion. This was interpreted to mean that even the earliest or "nonerythroid" phase of the peak is influenced by erythropoietic activity, at least under conditions of erythropoietic stress.     

Comparative trials of regimes for the treatment of urinary schistosomiasis in The Gambia

Alternative regimes for the treatment of Schistosoma haematobium infection were compared in two trials. Praziquantel at a dose of 40 mg kg-1 appeared to cure 63% of a random sample of heavily infected subjects; significantly more than the 18% cured by three fortnightly doses of metrifonate at 10 mg kg-1. However, praziquantel led to a greater incidence of mild, transient side-effects. A single dose of metrifonate was found to be an inadequate treatment in the same group of subjects as it left 53% with an egg count of at least 100 ova/10 ml. A combination of 10 mg kg-1 of metrifonate and 25 mg kg-1 of niridazole had a similar effect to that of a single dose of metrifonate alone and it had more side-effects. Reduced doses of praziquantel had less effect on egg counts than the standard regime, but the difference was not significant in the case of 20 mg kg-1. Although a combination of metrifonate and praziquantel, each at 10 mg kg-1, had a greater effect than either constituent alone, the difference was not significant. Factors affecting the choice of drug for use in mass treatment of urinary schistosomiasis in The Gambia are discussed. The present findings suggest that the standard regime of praziquantel should be used or, if this is not possible, a three-dose metrifonate regime.