Exon Array Biomarkers for the Differential Diagnosis of Schizophrenia and Bipolar Disorder.

This study developed potential blood-based biomarker tests for diagnosing and differentiating schizophrenia (SZ), bipolar disorder type I (BD), and normal control (NC) subjects using mRNA gene expression signatures. A total of 90 subjects (n = 30 each for the three groups of subjects) provided blood samples at two visits. The Affymetrix exon microarray was used to profile the expression of over 1.4 million probesets. We selected potential biomarker panels using the temporal stability of the probesets and also back-tested them at two different visits for each subject. The 18-gene biomarker panels, using logistic regression modeling, correctly differentiated the three groups of subjects with high accuracy across the two different clinical visits (83-88% accuracy). The results are also consistent with the actual data and the "leave-one-out" analyses, indicating that the models should be predictive when applied to independent data cohorts. Many of the SZ and BD subjects were taking antipsychotic and mood stabilizer medications at the time of blood draw, raising the possibility that these drugs could have affected some of the differential transcription signatures. Using an independent Illumina data set of gene expression data from antipsychotic medication-free SZ subjects, the 18-gene biomarker panels produced a receiver operating characteristic curve accuracy greater than 0.866 in patients that were less than 30 years of age and medication free. We confirmed select transcripts by quantitative PCR and the nCounter® System. The episodic nature of psychiatric disorders might lead to highly variable results depending on when blood is collected in relation to the severity of the disease/symptoms. We have found stable trait gene panel markers for lifelong psychiatric disorders that may have diagnostic utility in younger undiagnosed subjects where there is a critical unmet need. The study requires replication in subjects for ultimate proof of the utility of the differential diagnosis.

Performance comparison of single-view digital breast tomosynthesis plus single-view digital mammography with two-view digital mammography.

OBJECTIVE: To determine the performance of combined single-view mediolateral oblique (MLO) digital breast tomosynthesis (DBT) plus single-view cranio-caudal (CC) mammography (MX) compared with that of standard two-view digital mammography. METHODS: A multi-reader multi-case (MRMC) receiver-operating characteristic (ROC) study was conducted, involving six breast radiologists. Two hundred fifty patients underwent bilateral MX and DBT imaging. MX and DBT images with the adjunct of the CC-MX view from 469 breasts were evaluated and rated independently by six readers. Differences in mean areas under the ROC curves (AUCs), mean sensitivity and mean specificity were analysed by analysis of variance (ANOVA) to assess clinical performance. RESULTS: The combined technique was found to be non-inferior to standard two-view mammography (MX((CC+MLO))) in mean AUC (difference: +0.021;95 % LCL = -0.011), but was not statistically significant for superiority (P = 0.197). The combined technique had equivalent sensitivity to standard mammography (76.2 % vs. 72.8 %, P = 0.269) and equivalent specificity (84.9 % vs. 83.0 %, P = 0.130). Specificity for benign lesions was significantly higher with the combination of techniques versus mammography (45.6 % vs. 36.8 %, P = 0.002). CONCLUSION: In this enriched study population, the combination of single-view MLO tomosynthesis plus single-view CC mammography was non-inferior to that of standard two-view digital mammography in terms of ROC curve area, sensitivity and specificity.

Identification of a novel gene set in human cumulus cells predictive of an oocyte's pregnancy potential.

OBJECTIVE: To identify a gene expression signature in human cumulus cells (CCs) predictive of pregnancy outcome across multiple clinics, taking into account the clinic and patient variations inherent in IVF practice. DESIGN: Retrospective analysis of single human cumulus-oocyte complexes with the use of a combined microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) approach. SETTING: Multiple private IVF clinics. PATIENT(S): Fifty-eight patients. Samples from 55 patients underwent qRT-PCR analysis, and samples from 27 patients resulted in live birth. INTERVENTION(S): Gene expression analysis for correlation with pregnancy outcome on individual human CCs collected immediately after oocyte retrieval. Pregnancy prediction analysis used leave-one-out cross-validation with weighted voting. MAIN OUTCOME MEASURE(S): Combinatorial expression of 12 genes in 101 samples from 58 patients. RESULT(S): We found a set of 12 genes predictive of pregnancy outcome based on their expression levels in CCs. This pregnancy prediction model had an accuracy of 78%, a sensitivity of 72%, a specificity of 84%, a positive predictive value of 81%, and a negative predictive value of 76%. Receiver operating characteristic analysis found an area under the curve of 0.763 ± 0.079, significantly greater than 0.5 (random chance prediction). CONCLUSION(S): Gene expression analysis in human CCs should be considered in identifying oocytes with a high potential to lead to pregnancy in IVF-ET.

Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial.

BACKGROUND: Preliminary work suggests that single-pulse transcranial magnetic stimulation (sTMS) could be effective as a treatment for migraine. We aimed to assess the efficacy and safety of a new portable sTMS device for acute treatment of migraine with aura. METHODS: We undertook a randomised, double-blind, parallel-group, two-phase, sham-controlled study at 18 centres in the USA. 267 adults aged 18-68 years were enrolled into phase one. All individuals had to meet international criteria for migraine with aura, with visual aura preceding at least 30% of migraines followed by moderate or severe headache in more than 90% of those attacks. 66 patients dropped out during phase one. In phase two, 201 individuals were randomly allocated by computer to either sham stimulation (n=99) or sTMS (n=102). We instructed participants to treat up to three attacks over 3 months while experiencing aura. The primary outcome was pain-free response 2 h after the first attack, and co-primary outcomes were non-inferiority at 2 h for nausea, photophobia, and phonophobia. Analyses were modified intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00449540. FINDINGS: 37 patients did not treat a migraine attack and were excluded from outcome analyses. 164 patients treated at least one attack with sTMS (n=82) or sham stimulation (n=82; modified intention-to-treat analysis set). Pain-free response rates after 2 h were significantly higher with sTMS (32/82 [39%]) than with sham stimulation (18/82 [22%]), for a therapeutic gain of 17% (95% CI 3-31%; p=0.0179). Sustained pain-free response rates significantly favoured sTMS at 24 h and 48 h post-treatment. Non-inferiority was shown for nausea, photophobia, and phonophobia. No device-related serious adverse events were recorded, and incidence and severity of adverse events were similar between sTMS and sham groups. INTERPRETATION: Early treatment of migraine with aura by sTMS resulted in increased freedom from pain at 2 h compared with sham stimulation, and absence of pain was sustained 24 h and 48 h after treatment. sTMS could be a promising acute treatment for some patients with migraine with aura. FUNDING: Neuralieve.

Computerized pharmaceutical algorithm reduces medication administration errors during simulated resuscitations.

OBJECTIVE: Medication errors involving intravenous medications continue to be a significant problem, particularly in the pediatric population due to the high rate of point-of-care and weight-adjusted dosing. The pharmaceutical algorithm computerized calculator (pac2) assists in converting physician medication orders to correct volumes and rates of administration for intravenous medications. This study was designed to assess the efficacy of the pac2 in simulated clinical scenarios of point-of-care dosing. METHODS: The study design was a within-subject controlled study in which 33 nurses from pediatrics, pediatric critical care, or critical care (mean nursing experience of 10.9 years) carried out various point-of-care medication-dosing scenarios with and without the aid of the pac2. RESULTS: Use of the pac2 resulted in a significantly higher percentage (mean [95% CI]) of medication volumes calculated and drawn accurately (91% [87-95%] versus 61% [52-70%], p<0.0001), a higher percentage of correct recall of essential medication information (97% [95-99%] versus 45% [36-53%], p<0.0001), and better recognition of unsafe doses (93% [87-99%] versus 19% [12-27%], p<0.0001) as compared to usual practice. The pac2 also significantly reduced average medication calculation times (1.5 minutes [1.3-1.7 minutes] versus 1.9 minutes [1.6-2.2 minutes], p=0.0028) as compared to usual practice. CONCLUSIONS: The pac2 significantly improved the performance of drug calculations by pediatric and critical care nurses during simulated clinical scenarios designed to mimic point-of-care dosing. These results suggest that the pac2 addresses an area of safety vulnerability for point-of-care dosing practices and could be a useful addition to a hospital's overall program to minimize medication errors.

Pattern of antioxidant and DNA repair gene expression in normal airway epithelium associated with lung cancer diagnosis.

In previous studies, we reported that key antioxidant and DNA repair genes are regulated differently in normal bronchial epithelial cells of lung cancer cases compared with non-lung cancer controls. In an effort to develop a biomarker for lung cancer risk, we evaluated the transcript expressions of 14 antioxidant, DNA repair, and transcription factor genes in normal bronchial epithelial cells (HUGO names CAT, CEBPG, E2F1, ERCC4, ERCC5, GPX1, GPX3, GSTM3, GSTP1, GSTT1, GSTZ1, MGST1, SOD1, and XRCC1). A test comprising these 14 genes accurately identified the lung cancer cases in two case-control studies. The receiver operating characteristic-area under the curve was 0.82 (95% confidence intervals, 0.68-0.91) for the first case-control set (25 lung cancer cases and 24 controls), and 0.87 (95% confidence intervals, 0.73-0.96) for the second set (18 cases and 22 controls). For each gene included in the test, the key difference between cases and controls was altered distribution of transcript expression among cancer cases compared with controls, with more lung cancer cases expressing at both extremes among all genes (Kolmorogov-Smirnov test, D = 0.0795; P = 0.041). A novel statistical approach was used to identify the lower and upper boundaries of transcript expression that optimally classifies cases and controls for each gene. Based on the data presented here, there is an increased prevalence of lung cancer diagnosis among individuals that express a threshold number of key antioxidant, DNA repair, and transcription factor genes at either very high or very low levels in the normal airway epithelium.

Quality-controlled measurement methods for quantification of variations in transcript abundance in whole blood samples from healthy volunteers.

BACKGROUND: Transcript abundance (TA) measurement in whole blood frequently is conducted to identify potential biomarkers for disease risk and to predict or monitor drug response. Potential biomarkers discovered in this way must be validated by quantitative technology. In this study we assessed the use of standardized reverse transcription PCR (StaRT-PCR) to validate potential biomarkers discovered through whole blood TA profiling. METHODS: For each of 15 healthy volunteers, 6 blood samples were obtained, including 3 samples at each of 2 separate visits. Total variation in TA for each gene was partitioned into replicate, sample, visit, study participant, and residual components. RESULTS: Variation originating from technical processing was <5% of total combined variation and was primarily preanalytical. Interindividual biological sample variation was larger than technical variation. For 12 of 19 tests, the distribution of measured values was gaussian (Shapiro-Wilks test). CONCLUSION: For control or diseased population groups with variation rates as low as those observed in this control group, 17 individuals per group would be required to detect 1 SD change with 80% power with a 2-sided alpha = 0.05 statistical test for mean differences.

Evaluation of DNA microarray results with quantitative gene expression platforms.

We have evaluated the performance characteristics of three quantitative gene expression technologies and correlated their expression measurements to those of five commercial microarray platforms, based on the MicroArray Quality Control (MAQC) data set. The limit of detection, assay range, precision, accuracy and fold-change correlations were assessed for 997 TaqMan Gene Expression Assays, 205 Standardized RT (Sta)RT-PCR assays and 244 QuantiGene assays. TaqMan is a registered trademark of Roche Molecular Systems, Inc. We observed high correlation between quantitative gene expression values and microarray platform results and found few discordant measurements among all platforms. The main cause of variability was differences in probe sequence and thus target location. A second source of variability was the limited and variable sensitivity of the different microarray platforms for detecting weakly expressed genes, which affected interplatform and intersite reproducibility of differentially expressed genes. From this analysis, we conclude that the MAQC microarray data set has been validated by alternative quantitative gene expression platforms thus supporting the use of microarray platforms for the quantitative characterization of gene expression.