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Development and application of a diagnostic algorithm for posttraumatic stress disorder

James, Lisa M; Belitskaya-Levy, Ilana; Lu, Ying; Wang, Hui; Engdahl, Brian E; Leuthold, Arthur C; Georgopoulos, Apostolos P
Intact cognitive functions rely on synchronous neural activity; conversely, alterations in synchrony are thought to underlie psychopathology. We recently demonstrated that anomalies in synchronous neural interactions (SNI) determined by magnetoencephalography represent a putative PTSD biomarker. Here we develop and apply a regression-based diagnostic algorithm to further validate SNI as a PTSD biomarker in 432 veterans (235 controls; 138 pure PTSD; 59 PTSD plus comorbid disorders). Correlation coefficients served as proximities in multidimensional scaling (MDS) to obtain a two-dimensional representation of the data. In addition, least absolute shrinkage and selection operator (LASSO) regression was used to derive a diagnostic algorithm for PTSD. Performance of this algorithm was assessed by the area under the receiver operating characteristic (ROC) curves, sensitivity, and specificity in 1000 randomly divided testing and validation datasets and in independent samples. MDS revealed that individuals with PTSD, regardless of comorbid psychiatric conditions, are highly distinct from controls. Similarly, application of the LASSO regression-derived prediction model demonstrated remarkable classification accuracy (AUCs>/=0.93 for men, AUC=0.82 for women). Neural functioning in individuals with PTSD, regardless of comorbid psychiatric diagnoses, can be used as a diagnostic test to determine patient disease status, further validating SNI as a PTSD biomarker.
PMID: 25433425
ISSN: 0165-1781
CID: 1462972

P-values in genomics: Apparent precision masks high uncertainty

Lazzeroni, L C; Lu, Y; Belitskaya-Levy, I
Scientists often interpret P-values as measures of the relative strength of statistical findings. This is common practice in large-scale genomic studies where P-values are used to choose which of numerous hypothesis test results should be pursued in subsequent research. In this study, we examine P-value variability to assess the degree of certainty P-values provide. We develop prediction intervals for the P-value in a replication study given the P-value observed in an initial study. The intervals depend on the initial value of P and the ratio of sample sizes between the initial and replication studies, but not on the underlying effect size or initial sample size. The intervals are valid for most large-sample statistical tests in any context, and can be used in the presence of single or multiple tests. While P-values are highly variable, future P-value variability can be explicitly predicted based on a P-value from an initial study. The relative size of the replication and initial study is an important predictor of the P-value in a subsequent replication study. We provide a handy calculator implementing these results and apply them to a study of Alzheimer's disease and recent findings of the Cross-Disorder Group of the Psychiatric Genomics Consortium. This study suggests that overinterpretation of very significant, but highly variable, P-values is an important factor contributing to the unexpectedly high incidence of non-replication. Formal prediction intervals can also provide realistic interpretations and comparisons of P-values associated with different estimated effect sizes and sample sizes.
PMCID:4255087
PMID: 24419042
ISSN: 1359-4184
CID: 1360142

Defining the genomic signature of the parous breast

Peri, Suraj; de Cicco, Ricardo Lopez; Santucci-Pereira, Julia; Slifker, Michael; Ross, Eric A; Russo, Irma H; Russo, Patricia A; Arslan, Alan A; Belitskaya-Levy, Ilana; Zeleniuch-Jacquotte, Anne; Bordas, Pal; Lenner, Per; Ahman, Janet; Afanasyeva, Yelena; Johansson, Robert; Sheriff, Fathima; Hallmans, Goran; Toniolo, Paolo; Russo, Jose
BACKGROUND: It is accepted that a woman's lifetime risk of developing breast cancer after menopause is reduced by early full term pregnancy and multiparity. This phenomenon is thought to be associated with the development and differentiation of the breast during pregnancy. METHODS: In order to understand the underlying molecular mechanisms of pregnancy induced breast cancer protection, we profiled and compared the transcriptomes of normal breast tissue biopsies from 71 parous (P) and 42 nulliparous (NP) healthy postmenopausal women using Affymetrix Human Genome U133 Plus 2.0 arrays. To validate the results, we performed real time PCR and immunohistochemistry. RESULTS: We identified 305 differentially expressed probesets (208 distinct genes). Of these, 267 probesets were up- and 38 down-regulated in parous breast samples; bioinformatics analysis using gene ontology enrichment revealed that up-regulated genes in the parous breast represented biological processes involving differentiation and development, anchoring of epithelial cells to the basement membrane, hemidesmosome and cell-substrate junction assembly, mRNA and RNA metabolic processes and RNA splicing machinery. The down-regulated genes represented biological processes that comprised cell proliferation, regulation of IGF-like growth factor receptor signaling, somatic stem cell maintenance, muscle cell differentiation and apoptosis. CONCLUSIONS: This study suggests that the differentiation of the breast imprints a genomic signature that is centered in the mRNA processing reactome. These findings indicate that pregnancy may induce a safeguard mechanism at post-transcriptional level that maintains the fidelity of the transcriptional process.
PMCID:3487939
PMID: 23057841
ISSN: 1755-8794
CID: 222832

Pregnancy-induced chromatin remodeling in the breast of postmenopausal women

Russo, J; Santucci-Pereira, J; de, Cicco RL; Sheriff, F; Russo, PA; Peri, S; Slifker, M; Ross, E; Mello, ML; Vidal, BC; Belitskaya-Levy, I; Arslan, A; Zeleniuch-Jacquotte, A; Bordas, P; Lenner, P; Ahman, J; Afanasyeva, Y; Hallmans, G; Toniolo, P; Russo, IH
Early pregnancy and multiparity are known to reduce the risk of women to develop breast cancer at menopause. Based on the knowledge that the differentiation of the breast induced by the hormones of pregnancy plays a major role in this protection, this work was performed with the purpose of identifying what differentiation-associated molecular changes persist in the breast until menopause. Core needle biopsies (CNB) obtained from the breast of 42 nulliparous (NP) and 71 parous (P) postmenopausal women were analyzed in morphology, immunocytochemistry and gene expression. Whereas in the NP breast, nuclei of epithelial cells were large and euchromatic, in the P breast they were small and hyperchromatic, showing strong methylation of histone 3 at lysine 9 and 27. Transcriptomic analysis performed using Affymetrix HG_U133 oligonucleotide arrays revealed that in CNB of the P breast, there were 267 upregulated probesets that comprised genes controlling chromatin organization, transcription regulation, splicing machinery, mRNA processing and noncoding elements including XIST. We concluded that the differentiation process induced by pregnancy is centered in chromatin remodeling and in the mRNA processing reactome, both of which emerge as important regulatory pathways. These are indicative of a safeguard step that maintains the fidelity of the transcription process, becoming the ultimate mechanism mediating the protection of the breast conferred by full-term pregnancy.
PMCID:3350833
PMID: 22025034
ISSN: 0020-7136
CID: 162482

Atypical ezrin localization as a marker of locally advanced breast cancer

Arslan, AA; Silvera, D; Arju, R; Giashuddin, S; Belitskaya-Levy, I; Formenti, SC; Schneider, RJ
Locally advanced breast cancer (LABC) was initially characterized as a large primary tumor (>/=5 cm), associated with or without skin or chest-wall involvement, fixed axillary lymph nodes, or disease spread to the ipsilateral internal mammary or supraclavicular nodes. Since 2002, LABC has been reclassified to include smaller stage IIB tumors (2 to <5 cm) with lymph node involvement, or stages IIIA-IIIB (>/=5 cm) with or without nodal involvement. Despite the rather common presentation of LABC, it remains a poorly understood and highly variable clinical presentation of breast cancer that is a challenge to treatment. Here, we characterized a panel of breast tumors of known stage, grade, and key clinical-pathological parameters for the expression of the protein ezrin, which is involved in promoting signaling of the PI3K-Akt-mTOR pathway in response to extracellular and tumor micro-environmental signals, and is involved in breast cancer invasion and metastasis. We show that ezrin, which resides primarily in the apical membrane in normal breast epithelium, relocalizes primarily to the cytoplasm in >80 % of traditional (T3) invasive ductal LABC tumors (>/=5 cm). Cytoplasmic ezrin is very strongly associated with a single characteristic in breast cancer-large tumor size. In contrast, in large non-malignant fibroadenomas, ezrin staining was similar to that of normal breast epithelium. Small (T1, 1 cm) invasive ductal carcinomas displayed largely apical membrane and perinuclear ezrin localization with weak cytoplasmic staining. Cytoplasmic ezrin localization was also associated with positive lymph node status, but no other clinical-pathological features, including hormone receptor status, histological or nuclear grade of tumor cell. The cytoplasmic relocalization of ezrin may therefore represent a novel marker for large malignant tumor size, reflecting the unique biology of LABC.
PMID: 22415480
ISSN: 0167-6806
CID: 162566

Endogenous knockdown of survivin improves chemotherapeutic response in ALL models

Morrison, D J; Hogan, L E; Condos, G; Bhatla, T; Germino, N; Moskowitz, N P; Lee, L; Bhojwani, D; Horton, T M; Belitskaya-Levy, I; Greenberger, L M; Horak, I D; Grupp, S A; Teachey, D T; Raetz, E A; Carroll, W L
Although the cure rate of newly diagnosed acute lymphoblastic leukemia (ALL) has improved over the past four decades, the outcome for patients who relapse remains poor. New therapies are needed for these patients. Our previous global gene expression analysis in a series of paired diagnosis-relapse pediatric patient samples revealed that the antiapoptotic gene survivin was consistently upregulated upon disease relapse. In this study, we demonstrate a link between survivin expression and drug resistance and test the efficacy of a novel antisense agent in promoting apoptosis when combined with chemotherapy. Gene-silencing experiments targeting survivin mRNA using either short-hairpin RNA (shRNA) or a locked antisense oligonucleotide (LNA-ON) specifically reduced gene expression and induced apoptosis in leukemia cell lines. When used in combination with chemotherapy, the survivin shRNA and LNA-ON potentiated the chemotherapeutic antileukemia effect. Moreover, in a mouse primary xenograft model of relapse ALL, the survivin LNA-ON decreased survivin expression in a subset of animals, and produced a statistically significant decrease in tumor progression. Taken together, these findings suggest that targeting endogenous levels of survivin mRNA by LNA-ON methods may augment the response to standard chemotherapy by sensitizing otherwise resistant tumor cells to chemotherapy.
PMCID:3833621
PMID: 21844871
ISSN: 0887-6924
CID: 159342

Exploring factors in diagnostic delays of head and neck cancer at a public hospital. [Meeting Abstract]

Lai, D. W.; Buckley, S. A.; Schmidt, B. L.; Viet, C.; Muggia, F.; Belitskaya-Levy, I.; Cohen, R. F.; DeLacure, M. D.; Sanfilippo, N.; Myssiorek, D.; Hirsch, D.; Seetharamu, N.
ISI:000208880301688
ISSN: 0732-183x
CID: 3159162

Impact of population genetic substructure on association studies and risk assessment for melanoma [Meeting Abstract]

Lobach, I.; Belitskaya-Levy, I.; Goldberg, J. D.; Ostrer, H.; Berman, R. S.; Pavlick, A. C.; Shapiro, R. L.; Osman, I.; Manga, P.
ISI:000208880302382
ISSN: 0732-183x
CID: 3159452

Lung nodules and patient characteristics in a high risk lung cancer screening cohort [Meeting Abstract]

Lu, F; Belitskaya-Levy, I; Owusu-Sarpong, Y; Walter, D; Rom, W N; Goldberg, J
Introduction The NYU Lung Cancer Biomarker Center recruited 1054 smokers (<=20 pack-years) between 03/2000 and 06/2010 and screened them with CT-scans and respiratory questionnaires. Questionnaires contained demographic characteristics, occupational exposures, lifestyle information including smoking history and alcohol use, personal and family medical history, and pulmonary symptoms. CT-scans showed the disease status and emphysema. We hypothesized that information collected in the questionnaires would be associated with the subject's disease status. Methods The 1054 Subjects were classified into 4 groups based on the results of enrollment CT-scans. This categorization showed 331 subjects with solid nodule(s) only, 95 with ground glass opacity (GGO) only, 126 with both solid nodule(s) and GGO(s), and the remaining 502 subjects with no nodules. Chi-squared tests were used to assess the relationship between disease category and each single predictor. Polytomous logistic regression was used to assess the association between disease category and multiple predictors. Forward/backward stepwise regression was used in model selection. Results Univariate analysis showed that gender (CMH =8.7092, p-value=0.0032), age (CMH=29.2219, p-value<0.0001), marijuana smoking (CMH=10.9024, p-value=0.0010), emphysema (CMH=9.0929, p-value=0.0026) and years of smoking (CMH=15.4712, p-value<0.0001) were significantly associated with disease categories. Further tests showed that years of smoking was highly associated with age, and did not contribute to prediction of disease category when age was included in the model, as shown by our multivariate analysis. In multivariate analysis, increasing age, gender (male) and history of emphysema were significant predictors of worsening disease class. Moreover, when we stratified by gender, the analysis indicated that in males, older men were more likely to develop solid nodules (OR=1.275, 95% CI [1.0063, 1.0490]) and more likely to have mixed nodules (OR= 1.0664, 95% CI= [1.0331, 1.1008]) than younger men. Males with emphysema were far more likely to have solid nodules compared with those without emphysema (OR= 1.9678, 95% CI= [1.3128, 2.9495]). Our analysis also revealed that in females, age was the only significant risk factor: older women were more likely to have mixed nodules than younger women (OR= 1.0593, 95% CI= [1.0274, 1.0922]). It is notable that all smoking related variables were not significantly associated with nodule class in our multivariable analysis. Conclusion Our analysis suggests that age, gender and emphysema play a critical role in the development of disease (solid nodule or GGO). Also, our analysis has shown that smoking is not likely to play a major role in the development of the disease in this high risk cohort
EMBASE:70851076
ISSN: 1073-449x
CID: 177180

Melanoma MicroRNA Signature Predicts Post-Recurrence Survival

Segura, Miguel F; Belitskaya-Levy, Ilana; Rose, Amy E; Zakrzewski, Jan; Gaziel, Avital; Hanniford, Douglas; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Osman, Iman; Hernando, Eva
PURPOSE: To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging criteria. EXPERIMENTAL DESIGN: Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria. RESULTS: We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into 'better' and 'worse' prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma. CONCLUSIONS: MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models. Clin Cancer Res; 16(5); 1577-86
PMCID:4662869
PMID: 20179230
ISSN: 1078-0432
CID: 107357