Browsing by Subject "Cluster Analysis"
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Item Open Access Adding Physical Impairment to Risk Stratification Improved Outcome Prediction in Low Back Pain.(Physical therapy, 2020-09-24) Beneciuk, Jason M; George, Steven ZOBJECTIVE:Identifying subgroups of low back pain (LBP) has the potential to improve prediction of clinical outcomes. Risk stratification is one such strategy that identifies similar characteristics indicative of a common clinical outcome trajectory. The purpose of this study was to determine if an empirically derived subgrouping approach based on physical impairment measures improves information provided from the STarT Back Tool (SBT). METHODS:At baseline in this secondary analysis of a cohort study, patients (N = 144) receiving physical therapy for LBP completed the SBT and tests (active lumbar flexion, extension, lateral bending, and passive straight-leg-raise) from a validated physical impairment index. Clinical outcomes were assessed at 4 weeks and included the Numerical Pain Rating Scale (NPRS) and Oswestry Disability Index (ODI). Exploratory hierarchical agglomerative cluster analysis identified empirically derived subgroups based on physical impairment measures. Independent samples t testing and chi-square analysis assessed baseline subgroup differences in demographic and clinical measures. Spearman rho correlation coefficient was used to assess baseline SBT risk and impairment subgroup relationships, and a 3-way mixed-model ANOVA was used to assessed SBT risk and impairment subgroup relationships with clinical outcomes at 4 weeks. RESULTS:Two physical impairment-based subgroups emerged from cluster analysis: (1) Low-Risk Impairment (n = 119, 81.5%), characterized by greater lumbar mobility and (2) High-Risk Impairment (n = 25, 17.1%), characterized by less lumbar mobility. A weak, positive relationship was observed between baseline SBT risk and impairment subgroups (rs = .170). An impairment-by-SBT risk-by-time interaction effect was observed for ODI scores but not for NPRS scores at 4 weeks. CONCLUSIONS:Physical impairment subgroups were not redundant with SBT risk categories and could improve prediction of 4-week LBP disability outcomes. Physical impairment subgroups did not improve the prediction of 4-week pain intensity scores. IMPACT:Subgroups based on physical impairment and psychosocial risk could lead to better prediction of LBP disability outcomes and eventually allow for treatment options tailored to physical and psychosocial risk.Item Open Access Artificial intelligence clustering of adult spinal deformity sagittal plane morphology predicts surgical characteristics, alignment, and outcomes.(European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society, 2021-08) Durand, Wesley M; Lafage, Renaud; Hamilton, D Kojo; Passias, Peter G; Kim, Han Jo; Protopsaltis, Themistocles; Lafage, Virginie; Smith, Justin S; Shaffrey, Christopher; Gupta, Munish; Kelly, Michael P; Klineberg, Eric O; Schwab, Frank; Gum, Jeffrey L; Mundis, Gregory; Eastlack, Robert; Kebaish, Khaled; Soroceanu, Alex; Hostin, Richard A; Burton, Doug; Bess, Shay; Ames, Christopher; Hart, Robert A; Daniels, Alan H; International Spine Study Group (ISSG)Purpose
AI algorithms have shown promise in medical image analysis. Previous studies of ASD clusters have analyzed alignment metrics-this study sought to complement these efforts by analyzing images of sagittal anatomical spinopelvic landmarks. We hypothesized that an AI algorithm would cluster preoperative lateral radiographs into groups with distinct morphology.Methods
This was a retrospective review of a multicenter, prospectively collected database of adult spinal deformity. A total of 915 patients with adult spinal deformity and preoperative lateral radiographs were included. A 2 × 3, self-organizing map-a form of artificial neural network frequently employed in unsupervised classification tasks-was developed. The mean spine shape was plotted for each of the six clusters. Alignment, surgical characteristics, and outcomes were compared.Results
Qualitatively, clusters C and D exhibited only mild sagittal plane deformity. Clusters B, E, and F, however, exhibited marked positive sagittal balance and loss of lumbar lordosis. Cluster A had mixed characteristics, likely representing compensated deformity. Patients in clusters B, E, and F disproportionately underwent 3-CO. PJK and PJF were particularly prevalent among clusters A and E. Among clusters B and F, patients who experienced PJK had significantly greater positive sagittal balance than those who did not.Conclusions
This study clustered preoperative lateral radiographs of ASD patients into groups with highly distinct overall spinal morphology and association with sagittal alignment parameters, baseline HRQOL, and surgical characteristics. The relationship between SVA and PJK differed by cluster. This study represents significant progress toward incorporation of computer vision into clinically relevant classification systems in adult spinal deformity.Level of evidence iv
Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.Item Open Access Automatic annotation of spatial expression patterns via sparse Bayesian factor models.(PLoS Comput Biol, 2011-07) Pruteanu-Malinici, Iulian; Mace, Daniel L; Ohler, UweAdvances in reporters for gene expression have made it possible to document and quantify expression patterns in 2D-4D. In contrast to microarrays, which provide data for many genes but averaged and/or at low resolution, images reveal the high spatial dynamics of gene expression. Developing computational methods to compare, annotate, and model gene expression based on images is imperative, considering that available data are rapidly increasing. We have developed a sparse Bayesian factor analysis model in which the observed expression diversity of among a large set of high-dimensional images is modeled by a small number of hidden common factors. We apply this approach on embryonic expression patterns from a Drosophila RNA in situ image database, and show that the automatically inferred factors provide for a meaningful decomposition and represent common co-regulation or biological functions. The low-dimensional set of factor mixing weights is further used as features by a classifier to annotate expression patterns with functional categories. On human-curated annotations, our sparse approach reaches similar or better classification of expression patterns at different developmental stages, when compared to other automatic image annotation methods using thousands of hard-to-interpret features. Our study therefore outlines a general framework for large microscopy data sets, in which both the generative model itself, as well as its application for analysis tasks such as automated annotation, can provide insight into biological questions.Item Open Access Can unsupervised cluster analysis identify patterns of complex adult spinal deformity with distinct perioperative outcomes?(Journal of neurosurgery. Spine, 2023-05) Lafage, Renaud; Fourman, Mitchell S; Smith, Justin S; Bess, Shay; Shaffrey, Christopher I; Kim, Han Jo; Kebaish, Khaled M; Burton, Douglas C; Hostin, Richard; Passias, Peter G; Protopsaltis, Themistocles S; Daniels, Alan H; Klineberg, Eric O; Gupta, Munish C; Kelly, Michael P; Lenke, Lawrence G; Schwab, Frank J; Lafage, Virginie; International Spine Study GroupObjective
The objective of this study was to use an unsupervised cluster approach to identify patterns of operative adult spinal deformity (ASD) and compare the perioperative outcomes of these groups.Methods
A multicenter data set included patients with complex surgical ASD, including those with severe deformities, significant surgical complexity, or advanced age who underwent a multilevel fusion. An unsupervised cluster analysis allowing for 10% outliers was used to identify different deformity patterns. The perioperative outcomes of these clusters were then compared using ANOVA, Kruskal-Wallis, and chi-square tests, with p values < 0.05 considered significant.Results
Two hundred eighty-six patients were classified into four clusters of deformity patterns: hyper-thoracic kyphosis (hyper-TK), severe coronal, severe sagittal, and moderate sagittal. Hyper-TK patients had the lowest disability (mean Oswestry Disability Index [ODI] 32.9 ± 17.1) and pain scores (median numeric rating scale [NRS] back score 6, leg score 1). The severe coronal cluster had moderate functional impairment (mean physical component score 34.4 ± 12.3) and pain (median NRS back score 7, leg score 4) scores. The severe sagittal cluster had the highest levels of disability (mean ODI 49.3 ± 15.6) and low appearance scores (mean 2.3 ± 0.7). The moderate cluster (mean 68.8 ± 7.8 years) had the highest pain interference subscores on the Patient-Reported Outcomes Measurement Information System (mean 65.2 ± 5.8). Overall 30-day adverse events were equivalent among the four groups. Fusion to the pelvis was most common in the moderate sagittal (89.4%) and severe sagittal (97.5%) clusters. The severe coronal cluster had more osteotomies per case (median 11, IQR 6.5-14) and a higher rate of 30-day implant-related complications (5.5%). The severe sagittal and hyper-TK clusters had more three-column osteotomies (43% and 32.3%, respectively). Hyper-TK patients had shorter hospital stays.Conclusions
This cohort of patients with complex ASD surgeries contained four natural clusters of deformity, each with distinct perioperative outcomes.Item Open Access Classifying Patients Operated for Spondylolisthesis: A K-Means Clustering Analysis of Clinical Presentation Phenotypes.(Neurosurgery, 2021-11) Chan, Andrew K; Wozny, Thomas A; Bisson, Erica F; Pennicooke, Brenton H; Bydon, Mohamad; Glassman, Steven D; Foley, Kevin T; Shaffrey, Christopher I; Potts, Eric A; Shaffrey, Mark E; Coric, Domagoj; Knightly, John J; Park, Paul; Wang, Michael Y; Fu, Kai-Ming; Slotkin, Jonathan R; Asher, Anthony L; Virk, Michael S; Kerezoudis, Panagiotis; Alvi, Mohammed A; Guan, Jian; Haid, Regis W; Mummaneni, Praveen VBackground
Trials of lumbar spondylolisthesis are difficult to compare because of the heterogeneity in the populations studied.Objective
To define patterns of clinical presentation.Methods
This is a study of the prospective Quality Outcomes Database spondylolisthesis registry, including patients who underwent single-segment surgery for grade 1 degenerative lumbar spondylolisthesis. Twenty-four-month patient-reported outcomes (PROs) were collected. A k-means clustering analysis-an unsupervised machine learning algorithm-was used to identify clinical presentation phenotypes.Results
Overall, 608 patients were identified, of which 507 (83.4%) had 24-mo follow-up. Clustering revealed 2 distinct cohorts. Cluster 1 (high disease burden) was younger, had higher body mass index (BMI) and American Society of Anesthesiologist (ASA) grades, and globally worse baseline PROs. Cluster 2 (intermediate disease burden) was older and had lower BMI and ASA grades, and intermediate baseline PROs. Baseline radiographic parameters were similar (P > .05). Both clusters improved clinically (P < .001 all 24-mo PROs). In multivariable adjusted analyses, mean 24-mo Oswestry Disability Index (ODI), Numeric Rating Scale Back Pain (NRS-BP), Numeric Rating Scale Leg Pain, and EuroQol-5D (EQ-5D) were markedly worse for the high-disease-burden cluster (adjusted-P < .001). However, the high-disease-burden cluster demonstrated greater 24-mo improvements for ODI, NRS-BP, and EQ-5D (adjusted-P < .05) and a higher proportion reaching ODI minimal clinically important difference (MCID) (adjusted-P = .001). High-disease-burden cluster had lower satisfaction (adjusted-P = .02).Conclusion
We define 2 distinct phenotypes-those with high vs intermediate disease burden-operated for lumbar spondylolisthesis. Those with high disease burden were less satisfied, had a lower quality of life, and more disability, more back pain, and more leg pain than those with intermediate disease burden, but had greater magnitudes of improvement in disability, back pain, quality of life, and more often reached ODI MCID.Item Open Access Communication: Weakening the critical dynamical slowing down of models with SALR interactions.(The Journal of chemical physics, 2022-11) Zheng, Mingyuan; Tarzia, Marco; Charbonneau, PatrickIn systems with frustration, the critical slowing down of the dynamics severely impedes the numerical study of phase transitions for even the simplest of lattice models. In order to help sidestep the gelation-like sluggishness, a clearer understanding of the underlying physics is needed. Here, we first obtain generic insight into that phenomenon by studying one-dimensional and Bethe lattice versions of a schematic frustrated model, the axial next-nearest neighbor Ising (ANNNI) model. Based on these findings, we formulate two cluster algorithms that speed up the simulations of the ANNNI model on a 2D square lattice. Although these schemes do not eliminate the critical slowing own, speed-ups of factors up to 40 are achieved in some regimes.Item Open Access Complete genome sequencing and analysis of six enterovirus 71 strains with different clinical phenotypes.(Virol J, 2013-04-11) Wen, Hong-ling; Si, Lu-ying; Yuan, Xiao-jing; Hao, Shu-bin; Gao, Feng; Chu, Fu-lu; Sun, Cheng-xi; Wang, Zhi-yuBACKGROUND: Hand, foot and mouth diseases (HFMD) caused by enterovirus 71(EV71) presents a broad spectrum of clinical manifestations ranging from mild febrile disease to fatal neurolocal disease. However, the mechanism of virulence is unknown. METHODS: We isolated 6 strains of EV71 from HFMD patients with or without neurological symptoms, and sequenced the whole genomes of the viruses to reveal the virulence factors of EV71. RESULTS: Phylogenetic tree based on VP1 region showed that all six strains clustered into C4a of C4 sub-genotype. In the complete polypeptide, 298 positions were found to be variable in all strains, and three of these positions (Val(P814)/Ile(P814) in VP1, Val(P1148)/Ile(P1148) in 3A and Ala(P1728)/Cys)/Val(P1728) in 3C) were conserved among the strains with neurovirulence, but variable in strains without neurovirulence. In the 5'-UTR region, it showed that the first 10 nucleotides were mostly conserved, however from the 11th nucleotide, nucleotide insertions and deletions were quite common. The secondary structure prediction of 5'-UTR sequences showed that two of three strains without neurovirulence (SDLY11 and SDLY48) were almost the same, and all strains with neurovirulence (SDLY96, SDLY107 and SDLY153) were different from each other. SDLY107 (a fatal strain) was found different from other strains on four positions (C(P241)/T(P241), A(P571)/T(P571), C(P579)/T(P579) in 5'-UTR and T(P7335)/C(P7335) in 3'-UTR). CONCLUSIONS: The three positions (Val(P814)/Ile(P814) in VP1, Val(P1148)/Ile(P1148) in 3A and Ala(P1728)/Cys(P1728)/Val(P1728) in 3C), were different between two phenotypes. These suggested that the three positions might be potential virulent positions. And the three varied positions were also found to be conserved in strains with neurovirulence, and variable in strains without neurovirulence. These might reveal that the conservation of two of the three positions or the three together were specific for the strains with neurovirulence. Varation of secondary structure of 5'-UTR, might be correlated to the changes of viral virulence. SDLY107 (a fatal strain) was found different from other strains on four positions, these positions might be related with death.Item Open Access Correlations between physical and chemical defences in plants: tradeoffs, syndromes, or just many different ways to skin a herbivorous cat?(The New phytologist, 2013-04) Moles, Angela T; Peco, Begoña; Wallis, Ian R; Foley, William J; Poore, Alistair GB; Seabloom, Eric W; Vesk, Peter A; Bisigato, Alejandro J; Cella-Pizarro, Lucrecia; Clark, Connie J; Cohen, Philippe S; Cornwell, William K; Edwards, Will; Ejrnaes, Rasmus; Gonzales-Ojeda, Therany; Graae, Bente J; Hay, Gregory; Lumbwe, Fainess C; Magaña-Rodríguez, Benjamín; Moore, Ben D; Peri, Pablo L; Poulsen, John R; Stegen, James C; Veldtman, Ruan; von Zeipel, Hugo; Andrew, Nigel R; Boulter, Sarah L; Borer, Elizabeth T; Cornelissen, Johannes HC; Farji-Brener, Alejandro G; DeGabriel, Jane L; Jurado, Enrique; Kyhn, Line A; Low, Bill; Mulder, Christa PH; Reardon-Smith, Kathryn; Rodríguez-Velázquez, Jorge; De Fortier, An; Zheng, Zheng; Blendinger, Pedro G; Enquist, Brian J; Facelli, Jose M; Knight, Tiffany; Majer, Jonathan D; Martínez-Ramos, Miguel; McQuillan, Peter; Hui, Francis KCMost plant species have a range of traits that deter herbivores. However, understanding of how different defences are related to one another is surprisingly weak. Many authors argue that defence traits trade off against one another, while others argue that they form coordinated defence syndromes. We collected a dataset of unprecedented taxonomic and geographic scope (261 species spanning 80 families, from 75 sites across the globe) to investigate relationships among four chemical and six physical defences. Five of the 45 pairwise correlations between defence traits were significant and three of these were tradeoffs. The relationship between species' overall chemical and physical defence levels was marginally nonsignificant (P = 0.08), and remained nonsignificant after accounting for phylogeny, growth form and abundance. Neither categorical principal component analysis (PCA) nor hierarchical cluster analysis supported the idea that species displayed defence syndromes. Our results do not support arguments for tradeoffs or for coordinated defence syndromes. Rather, plants display a range of combinations of defence traits. We suggest this lack of consistent defence syndromes may be adaptive, resulting from selective pressure to deploy a different combination of defences to coexisting species.Item Open Access CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation.(Genome Biol, 2015-09-15) Wang, L; Oehlers, SH; Espenschied, ST; Rawls, JF; Tobin, DM; Ko, DCMeta-analyses of genome-wide association studies (GWAS) have demonstrated that the same genetic variants can be associated with multiple diseases and other complex traits. We present software called CPAG (Cross-Phenotype Analysis of GWAS) to look for similarities between 700 traits, build trees with informative clusters, and highlight underlying pathways. Clusters are consistent with pre-defined groups and literature-based validation but also reveal novel connections. We report similarity between plasma palmitoleic acid and Crohn's disease and find that specific fatty acids exacerbate enterocolitis in zebrafish. CPAG will become increasingly powerful as more genetic variants are uncovered, leading to a deeper understanding of complex traits. CPAG is freely available at www.sourceforge.net/projects/CPAG/.Item Open Access Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients.(BMC Med Genomics, 2011-03-28) Elashoff, Michael R; Wingrove, James A; Beineke, Philip; Daniels, Susan E; Tingley, Whittemore G; Rosenberg, Steven; Voros, Szilard; Kraus, William E; Ginsburg, Geoffrey S; Schwartz, Robert S; Ellis, Stephen G; Tahirkheli, Naheem; Waksman, Ron; McPherson, John; Lansky, Alexandra J; Topol, Eric JBACKGROUND: Alterations in gene expression in peripheral blood cells have been shown to be sensitive to the presence and extent of coronary artery disease (CAD). A non-invasive blood test that could reliably assess obstructive CAD likelihood would have diagnostic utility. RESULTS: Microarray analysis of RNA samples from a 195 patient Duke CATHGEN registry case:control cohort yielded 2,438 genes with significant CAD association (p < 0.05), and identified the clinical/demographic factors with the largest effects on gene expression as age, sex, and diabetic status. RT-PCR analysis of 88 CAD classifier genes confirmed that diabetic status was the largest clinical factor affecting CAD associated gene expression changes. A second microarray cohort analysis limited to non-diabetics from the multi-center PREDICT study (198 patients; 99 case: control pairs matched for age and sex) evaluated gene expression, clinical, and cell population predictors of CAD and yielded 5,935 CAD genes (p < 0.05) with an intersection of 655 genes with the CATHGEN results. Biological pathway (gene ontology and literature) and statistical analyses (hierarchical clustering and logistic regression) were used in combination to select 113 genes for RT-PCR analysis including CAD classifiers, cell-type specific markers, and normalization genes.RT-PCR analysis of these 113 genes in a PREDICT cohort of 640 non-diabetic subject samples was used for algorithm development. Gene expression correlations identified clusters of CAD classifier genes which were reduced to meta-genes using LASSO. The final classifier for assessment of obstructive CAD was derived by Ridge Regression and contained sex-specific age functions and 6 meta-gene terms, comprising 23 genes. This algorithm showed a cross-validated estimated AUC = 0.77 (95% CI 0.73-0.81) in ROC analysis. CONCLUSIONS: We have developed a whole blood classifier based on gene expression, age and sex for the assessment of obstructive CAD in non-diabetic patients from a combination of microarray and RT-PCR data derived from studies of patients clinically indicated for invasive angiography. CLINICAL TRIAL REGISTRATION INFORMATION: PREDICT, Personalized Risk Evaluation and Diagnosis in the Coronary Tree, http://www.clinicaltrials.gov, NCT00500617.Item Open Access Discrimination of vanadium from zinc using gene profiling in human bronchial epithelial cells.(Environmental health perspectives, 2005-12) Li, Zhuowei; Stonehuerner, Jackie; Devlin, Robert B; Huang, Yuh-Chin TWe hypothesized that gene expression profiling may discriminate vanadium from zinc in human bronchial epithelial cells (HBECs). RNA from HBECs exposed to vehicle, V (50 microM), or Zn (50 microM) for 4 hr (n = 4 paired experiments) was hybridized to Affymetrix Hu133A chips. Using one-class t-test with p < 0.01, we identified 140 and 76 genes with treatment:control ratios > or = 2.0 or < or = 0.5 for V and Zn, respectively. We then categorized these genes into functional pathways and compared the number of genes in each pathway between V and Zn using Fisher's exact test. Three pathways regulating gene transcription, inflammatory response, and cell proliferation distinguished V from Zn. When genes in these three pathways were matched with the 163 genes flagged by the same statistical filtration for V:Zn ratios, 12 genes were identified. The hierarchical clustering analysis showed that these 12 genes discriminated V from Zn and consisted of two clusters. Cluster 1 genes (ZBTB1, PML, ZNF44, SIX1, BCL6, ZNF450) were down-regulated by V and involved in gene transcription, whereas cluster 2 genes (IL8, IL1A, PTGS2, DTR, TNFAIP3, CXCL3) were up-regulated and linked to inflammatory response and cell proliferation. Also, metallothionein 1 genes (MT1F, MT1G, MT1K) were up-regulated by Zn only. Thus, using microarray analysis, we identified a small set of genes that may be used as biomarkers for discriminating V from Zn. The novel genes and pathways identified by the microarray may help us understand the pathogenesis of health effects caused by environmental V and Zn exposure.Item Open Access Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States.(PLoS Pathog, 2010-04-22) Byrnes 3rd, EJ; Li, W; Lewit, Y; Ma, H; Voelz, K; Ren, P; Carter, DA; Chaturvedi, V; Bildfell, RJ; May, RC; Heitman, JCryptococcus gattii causes life-threatening disease in otherwise healthy hosts and to a lesser extent in immunocompromised hosts. The highest incidence for this disease is on Vancouver Island, Canada, where an outbreak is expanding into neighboring regions including mainland British Columbia and the United States. This outbreak is caused predominantly by C. gattii molecular type VGII, specifically VGIIa/major. In addition, a novel genotype, VGIIc, has emerged in Oregon and is now a major source of illness in the region. Through molecular epidemiology and population analysis of MLST and VNTR markers, we show that the VGIIc group is clonal and hypothesize it arose recently. The VGIIa/IIc outbreak lineages are sexually fertile and studies support ongoing recombination in the global VGII population. This illustrates two hallmarks of emerging outbreaks: high clonality and the emergence of novel genotypes via recombination. In macrophage and murine infections, the novel VGIIc genotype and VGIIa/major isolates from the United States are highly virulent compared to similar non-outbreak VGIIa/major-related isolates. Combined MLST-VNTR analysis distinguishes clonal expansion of the VGIIa/major outbreak genotype from related but distinguishable less-virulent genotypes isolated from other geographic regions. Our evidence documents emerging hypervirulent genotypes in the United States that may expand further and provides insight into the possible molecular and geographic origins of the outbreak.Item Open Access Expression signatures of TP53 mutations in serous ovarian cancers.(BMC Cancer, 2010-05-26) Bernardini, Marcus Q; Baba, Tsukasa; Lee, Paula S; Barnett, Jason C; Sfakianos, Gregory P; Secord, Angeles Alvarez; Murphy, Susan K; Iversen, Edwin; Marks, Jeffrey R; Berchuck, AndrewBACKGROUND: Mutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease. METHODS: The TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage. RESULTS: Missense or chain terminating (null) mutations in TP53 were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict TP53 status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers. CONCLUSIONS: This represents the first attempt to define a genomic signature of TP53 mutation in ovarian cancer. Patterns of gene expression characteristic of TP53 mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of TP53 mutation in breast cancer.Item Open Access Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.(PLoS Comput Biol, 2010-10-07) Gnanakaran, S; Daniels, MG; Bhattacharya, T; Lapedes, AS; Sethi, A; Li, M; Tang, H; Greene, K; Gao, H; Haynes, BF; Cohen, MS; Shaw, GM; Seaman, MS; Kumar, A; Gao, F; Montefiori, DC; Korber, BA steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.Item Open Access Genome-wide direct target analysis reveals a role for SHORT-ROOT in root vascular patterning through cytokinin homeostasis.(Plant Physiol, 2011-11) Cui, Hongchang; Hao, Yueling; Kovtun, Mikhail; Stolc, Viktor; Deng, Xing-Wang; Sakakibara, Hitoshi; Kojima, MikikoSHORT-ROOT (SHR) is a key regulator of root growth and development in Arabidopsis (Arabidopsis thaliana). Made in the stele, the SHR protein moves into an adjacent cell layer, where it specifies endodermal cell fate; it is also essential for apical meristem maintenance, ground tissue patterning, vascular differentiation, and lateral root formation. Much has been learned about the mechanism by which SHR controls radial patterning, but how it regulates other aspects of root morphogenesis is still unclear. To dissect the SHR developmental pathway, we have determined the genome-wide locations of SHR direct targets using a chromatin immunoprecipitation followed by microarray analysis method. K-means clustering analysis not only identified additional quiescent center-specific SHR targets but also revealed a direct role for SHR in gene regulation in the pericycle and xylem. Using cell type-specific markers, we showed that in shr, the phloem and the phloem-associated pericycle expanded, whereas the xylem and xylem-associated pericycle diminished. Interestingly, we found that cytokinin level was elevated in shr and that exogenous cytokinin conferred a shr-like vascular patterning phenotype in wild-type root. By chromatin immunoprecipitation-polymerase chain reaction and reverse transcription-polymerase chain reaction assays, we showed that SHR regulates cytokinin homeostasis by directly controlling the transcription of cytokinin oxidase 3, a cytokinin catabolism enzyme preferentially expressed in the stele. Finally, overexpression of a cytokinin oxidase in shr alleviated its vascular patterning defect. On the basis of these results, we suggest that one mechanism by which SHR controls vascular patterning is the regulation of cytokinin homeostasis.Item Open Access Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.(Aging Cell, 2013-04) Beekman, Marian; Blanché, Hélène; Perola, Markus; Hervonen, Anti; Bezrukov, Vladyslav; Sikora, Ewa; Flachsbart, Friederike; Christiansen, Lene; De Craen, Anton JM; Kirkwood, Tom BL; Rea, Irene Maeve; Poulain, Michel; Robine, Jean-Marie; Valensin, Silvana; Stazi, Maria Antonietta; Passarino, Giuseppe; Deiana, Luca; Gonos, Efstathios S; Paternoster, Lavinia; Sørensen, Thorkild IA; Tan, Qihua; Helmer, Quinta; van den Akker, Erik B; Deelen, Joris; Martella, Francesca; Cordell, Heather J; Ayers, Kristin L; Vaupel, James W; Törnwall, Outi; Johnson, Thomas E; Schreiber, Stefan; Lathrop, Mark; Skytthe, Axel; Westendorp, Rudi GJ; Christensen, Kaare; Gampe, Jutta; Nebel, Almut; Houwing-Duistermaat, Jeanine J; Slagboom, Pieternella Eline; Franceschi, Claudio; GEHA consortiumClear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.Item Open Access Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.(BMC medical genomics, 2014-06) Markunas, Christina A; Lock, Eric; Soldano, Karen; Cope, Heidi; Ding, Chien-Kuang C; Enterline, David S; Grant, Gerald; Fuchs, Herbert; Ashley-Koch, Allison E; Gregory, Simon GBackground
Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.Methods
A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.Results
All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.Conclusions
Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.Item Open Access Latent factor analysis to discover pathway-associated putative segmental aneuploidies in human cancers.(PLoS Comput Biol, 2010-09-02) Lucas, Joseph E; Kung, Hsiu-Ni; Chi, Jen-Tsan ATumor microenvironmental stresses, such as hypoxia and lactic acidosis, play important roles in tumor progression. Although gene signatures reflecting the influence of these stresses are powerful approaches to link expression with phenotypes, they do not fully reflect the complexity of human cancers. Here, we describe the use of latent factor models to further dissect the stress gene signatures in a breast cancer expression dataset. The genes in these latent factors are coordinately expressed in tumors and depict distinct, interacting components of the biological processes. The genes in several latent factors are highly enriched in chromosomal locations. When these factors are analyzed in independent datasets with gene expression and array CGH data, the expression values of these factors are highly correlated with copy number alterations (CNAs) of the corresponding BAC clones in both the cell lines and tumors. Therefore, variation in the expression of these pathway-associated factors is at least partially caused by variation in gene dosage and CNAs among breast cancers. We have also found the expression of two latent factors without any chromosomal enrichment is highly associated with 12q CNA, likely an instance of "trans"-variations in which CNA leads to the variations in gene expression outside of the CNA region. In addition, we have found that factor 26 (1q CNA) is negatively correlated with HIF-1alpha protein and hypoxia pathways in breast tumors and cell lines. This agrees with, and for the first time links, known good prognosis associated with both a low hypoxia signature and the presence of CNA in this region. Taken together, these results suggest the possibility that tumor segmental aneuploidy makes significant contributions to variation in the lactic acidosis/hypoxia gene signatures in human cancers and demonstrate that latent factor analysis is a powerful means to uncover such a linkage.Item Open Access Multilocus sequence typing of serially collected isolates of Cryptococcus from HIV-infected patients in South Africa.(J Clin Microbiol, 2014-06) Van Wyk, Marelize; Govender, Nelesh P; Mitchell, Thomas G; Litvintseva, Anastasia P; GERMS-SAPatients with cryptococcal meningitis in sub-Saharan Africa frequently relapse following treatment. The natural history and etiology of these recurrent episodes warrant investigation. Here, we used multilocus sequence typing (MLST) to compare the molecular genotypes of strains of Cryptococcus neoformans and Cryptococcus gattii isolated from serial episodes of cryptococcal meningitis that were separated by at least 110 days. The most common MLST genotypes among the isolates were the dominant global clinical genotypes (M5 and M4) of molecular type VNI, as well as the VNI genotypes apparently restricted to southern Africa. In addition, there was considerable genetic diversity among these South African isolates, as 15% of the patients had unique genotypes. Eleven percent of the patients were reinfected with a genetically different strain following their initial diagnosis and treatment. However, the majority of serial episodes (89%) were caused by strains with the same genotype as the original strain. These results indicate that serial episodes of cryptococcosis in South Africa are frequently associated with persistence or relapse of the original infection. Using a reference broth microdilution method, we found that the serial isolates of 11% of the patients infected with strains of C. neoformans var. grubii with identical genotypes exhibited ≥4-fold increases in the MICs to fluconazole. Therefore, these recurrent episodes may have been precipitated by inadequate induction or consolidation of antifungal treatment and occasionally may have been due to increased resistance to fluconazole, which may have developed during the chronic infection.Item Open Access Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques.(Frontiers in immunology, 2023-01) Tuyishime, Marina; Spreng, Rachel L; Hueber, Brady; Nohara, Junsuke; Goodman, Derrick; Chan, Cliburn; Barfield, Richard; Beck, Whitney E; Jha, Shalini; Asdell, Stephanie; Wiehe, Kevin; He, Max M; Easterhoff, David; Conley, Haleigh E; Hoxie, Taylor; Gurley, Thaddeus; Jones, Caroline; Adhikary, Nihar Deb; Villinger, Francois; Thomas, Rasmi; Denny, Thomas N; Moody, Michael Anthony; Tomaras, Georgia D; Pollara, Justin; Reeves, R Keith; Ferrari, GuidoRhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials.