Garrick Wallstrom

Arizona State University, Phoenix, Arizona, United States

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Publications (18)91.11 Total impact

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    ABSTRACT: Basal-like breast cancer (BLBC) is a rare aggressive subtype that is less likely to be detected through mammographic screening. Identification of circulating markers associated with BLBC could have promise in detecting and managing this deadly disease. Using samples from the Polish Breast Cancer study, a high-quality population-based case-control study of breast cancer, we screened 10,000 antigens on protein arrays using 45 BLBC patients and 45 controls, and identified 748 promising plasma autoantibodies (AAbs) associated with BLBC. ELISA assays of promising markers were performed on a total of 145 BLBC cases and 145 age-matched controls. Sensitivities at 98% specificity were calculated and a BLBC classifier was constructed. We identified a 13-AAbs (CTAG1B, CTAG2, TP53, RNF216, PPHLN1, PIP4K2C, ZBTB16, TAS2R8, WBP2NL, DOK2, PSRC1, MN1, TRIM21) that distinguished BLBC from controls with 33% sensitivity and 98% specificity. We also discovered a strong association of TP53 AAb with its protein expression (p=0.009) in BLBC patients. In addition, MN1 and TP53 AAbs were associated with worse survival (MN1 AAb marker HR=2.25 95%CI= 1.03-4.91 p=0.04; TP53, HR=2.02, 95%CI 1.06-3.85, p=0.03). We found limited evidence that AAb levels differed by demographic characteristics. These AAbs warrant further investigation in clinical studies to determine their value for further understanding the biology of BLBC and possible detection. Our study identifies 13 AAb markers associated specifically with BLBC and may improve detection or management of this deadly disease. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 06/2015; DOI:10.1158/1055-9965.EPI-15-0047 · 4.32 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P2-15-03-P2-15-03. DOI:10.1158/1538-7445.SABCS14-P2-15-03 · 9.28 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P4-02-09-P4-02-09. DOI:10.1158/1538-7445.SABCS14-P4-02-09 · 9.28 Impact Factor
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    Garrick Wallstrom, Karen S Anderson, Joshua Labaer
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    ABSTRACT: Sera from patients with ovarian cancer contain autoantibodies (AAb) to tumor-derived proteins that are potential biomarkers for early detection. To detect AAb, we probed high-density programmable protein microarrays (NAPPA) expressing 5,177 candidate tumor antigens with sera from patients with serous ovarian cancer (n=34 cases/30 controls) and measured bound IgG. Of these, 741 antigens were selected and probed with an independent set of ovarian cancer sera (n=58 cases/60 controls). Twelve potential autoantigens were identified with sensitivities ranging from 13-22% at >93% specificity. These were retested using a Luminex bead arrays using 60 cases and 60 controls, with sensitivities ranging from 0-31.7% at 95% specificity. Three AAb (p53, PTPRA, and PTGFR) had area under the curve (AUC) levels>60% (p<0.01), with the partial AUC (SPAUC) over 5 times greater than for a non-discriminating test (p<0.01). Using a panel of the top three AAb (p53, PTPRA, and PTGFR), if at least two AAb were positive, the sensitivity was 23.3% at 98.3% specificity. AAb to at least one of these top three antigens were also detected in 7/20 sera (35%) of patients with low CA125 levels and 0/15 controls. AAb to p53, PTPRA, and PTGFR are potential biomarkers for the early detection of ovarian cancer.
    Journal of Proteome Research 11/2014; 14(1). DOI:10.1021/pr500908n · 5.00 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):881-881. DOI:10.1158/1538-7445.AM2014-881 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):874-874. DOI:10.1158/1538-7445.AM2014-874 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):887-887. DOI:10.1158/1538-7445.AM2014-887 · 9.28 Impact Factor
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    ABSTRACT: Pathogenic and nonpathogenic species of bacteria and fungi release membrane vesicles (MV), containing proteins, polysaccharides, and lipids, into the extracellular milieu. Previously, we demonstrated that several mycobacterial species, including bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis, release MV containing lipids and proteins that subvert host immune response in a Toll-like receptor 2 (TLR2)-dependent manner (R. Prados-Rosales et al., J. Clin. Invest. 121:1471-1483, 2011, doi:10.1172/JCI44261). In this work, we analyzed the vaccine potential of MV in a mouse model and compared the effects of immunization with MV to those of standard BCG vaccination. Immunization with MV from BCG or M. tuberculosis elicited a mixed humoral and cellular response directed to both membrane and cell wall components, such as lipoproteins. However, only vaccination with M. tuberculosis MV was able to protect as well as live BCG immunization. M. tuberculosis MV boosted BCG vaccine efficacy. In summary, MV are highly immunogenic without adjuvants and elicit immune responses comparable to those achieved with BCG in protection against M. tuberculosis.
    mBio 08/2014; 5(5). DOI:10.1128/mBio.01921-14 · 6.88 Impact Factor
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    ABSTRACT: The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.
    PLoS ONE 01/2014; 9(1):e85448. DOI:10.1371/journal.pone.0085448 · 3.53 Impact Factor
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    ABSTRACT: Zoonotic viruses represent emerging or re-emerging pathogens that pose significant public health threats throughout the world. It is therefore crucial to advance current surveillance mechanisms for these viruses through outlets such as phylogeography. Despite the abundance of zoonotic viral sequence data in publicly available databases such as GenBank, phylogeographic analysis of these viruses is often limited by the lack of adequate geographic metadata. However, many GenBank records include references to articles with more detailed information and automated systems may help extract this information efficiently and effectively. In this paper, we describe our efforts to determine the proportion of GenBank records with "insufficient" geographic metadata for seven well-studied viruses. We also evaluate the performance of four different Named Entity Recognition (NER) systems for automatically extracting related entities using a manually created gold-standard.
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    ABSTRACT: The need for biomarkers that illuminate the pathophysiology of Type 1 diabetes (T1D), enhance early diagnosis and provide additional avenues for therapeutic intervention is well recognized in the scientific community. We conducted a proteome-scale, two-stage serological AAb screening followed by an independent validation study. In the first stage, the immunoreactivity was compared between T1D cases and healthy controls against ~6000 human proteins using the Nucleic Acid Programmable Protein Array (NAPPA). Genes identified with higher signal intensities in patients were challenged with a larger sample set during the second stage. Statistical analysis revealed 26 novel autoantigens and a known T1D associated autoantigen. During validation, we verified the presence of AAbs to dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) using the Luciferase ImmunoPrecipitation System (LIPS) assay (36% Sensitivity, 98% specificity). The AUC for a combination of DYRK2A and the classical T1D AAb IA-2A was 0.90 compared to 0.72 for DYRK2A and 0.64 for IA-2A alone. This is the first systematic screening for seroreactivity against large number of human proteins in T1D patients. We demonstrated the application of protein microarrays to identify novel autoantigens in T1D, expanded the current T1D "autoantigenome" and help fulfill the goal of searching for novel biomarker candidates for T1D. Protein microarrays provide a high-throughput platform that enables the profiling of serum antibodies to a large number of protein antigens. The value of AAb biomarkers in diagnosis, prognosis and treatment is well recognized in autoimmune diseases including T1D. We performed a systematic screening for new T1D-associated autoantigens by adapting the innovative protein array platform NAPPA. We believe the discovery in this study will add information on the candidate autoantigens that could potentially improve the diagnosis and help uncover the pathophysiology of T1D. The successful use of NAPPA in T1D AAb profiling will open the window for larger studies including more human antigen genes and other autoimmune diseases.
    Journal of proteomics 10/2013; 94. DOI:10.1016/j.jprot.2013.10.018 · 3.93 Impact Factor
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    ABSTRACT: High proportions of autistic children suffer from gastrointestinal (GI) disorders, implying a link between autism and abnormalities in gut microbial functions. Increasing evidence from recent high-throughput sequencing analyses indicates that disturbances in composition and diversity of gut microbiome are associated with various disease conditions. However, microbiome-level studies on autism are limited and mostly focused on pathogenic bacteria. Therefore, here we aimed to define systemic changes in gut microbiome associated with autism and autism-related GI problems. We recruited 20 neurotypical and 20 autistic children accompanied by a survey of both autistic severity and GI symptoms. By pyrosequencing the V2/V3 regions in bacterial 16S rDNA from fecal DNA samples, we compared gut microbiomes of GI symptom-free neurotypical children with those of autistic children mostly presenting GI symptoms. Unexpectedly, the presence of autistic symptoms, rather than the severity of GI symptoms, was associated with less diverse gut microbiomes. Further, rigorous statistical tests with multiple testing corrections showed significantly lower abundances of the genera Prevotella, Coprococcus, and unclassified Veillonellaceae in autistic samples. These are intriguingly versatile carbohydrate-degrading and/or fermenting bacteria, suggesting a potential influence of unusual diet patterns observed in autistic children. However, multivariate analyses showed that autism-related changes in both overall diversity and individual genus abundances were correlated with the presence of autistic symptoms but not with their diet patterns. Taken together, autism and accompanying GI symptoms were characterized by distinct and less diverse gut microbial compositions with lower levels of Prevotella, Coprococcus, and unclassified Veillonellaceae.
    PLoS ONE 07/2013; 8(7):e68322. DOI:10.1371/journal.pone.0068322 · 3.53 Impact Factor
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    ABSTRACT: PURPOSE: We aim to develop a protein microarray platform capable of presenting both natural and denatured forms of proteins for antibody biomarker discovery. We will further optimize plasma screening protocols to improve detection. EXPERIMENTAL DESIGN: We developed a new covalent capture protein microarray chemistry using HaloTag fusion proteins and ligand. To enhance protein yield, we used HeLa cell lysate as an in vitro transcription translation system (IVTT). Escherichia coli (E. coli) lysates were added to the plasma blocking buffer to reduce non-specific background. These protein microarrays were probed with plasma samples and autoantibody responses were quantified and compared with or without denaturing buffer treatment. RESULTS: We demonstrated that protein microarrays using the covalent attachment chemistry endured denaturing conditions. Blocking with E. coli lysates greatly reduced the background signals and expression with IVTT based on HeLa cell lysates significantly improved the antibody signals on protein microarrays probed with plasma samples. Plasma samples probed on denatured protein arrays produced autoantibody profiles distinct from those probed on natively displayed proteins. CONCLUSIONS AND CLINICAL RELEVANCE: This versatile protein microarray platform allows the display of both natural and denatured proteins, offers a new dimension to search for disease-specific antibodies, broadens the repertoire of potential biomarkers, and will potentially yield clinical diagnostics with greater performance.
    PROTEOMICS - CLINICAL APPLICATIONS 06/2013; 7(5-6). DOI:10.1002/prca.201200062 · 2.68 Impact Factor
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    ABSTRACT: We present a microarray nonlinear calibration (MiNC) method for quantifying antibody binding to the surface of protein microarrays that significantly increases the linear dynamic range and reduces assay variation compared with traditional approaches. A serological analysis of guinea pig Mycobacterium tuberculosis models showed that a larger number of putative antigen targets were identified with MiNC, which is consistent with the improved assay performance of protein microarrays. MiNC has the potential to be employed in biomedical research using multiplex antibody assays that need quantitation, including the discovery of antibody biomarkers, clinical diagnostics with multi-antibody signatures, and construction of immune mathematical models.
    BioTechniques 05/2013; 54(5):257-64. DOI:10.2144/000114028 · 2.75 Impact Factor
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    Garrick Wallstrom, Karen S Anderson, Joshua Labaer
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    ABSTRACT: BACKGROUND: Modern genomic and proteomic studies reveal that many diseases are heterogeneous, comprising multiple different subtypes. The common notion that one biomarker can be predictive for all patients may need to be replaced by an understanding that each subtype has its own set of unique biomarkers, affecting how discovery studies are designed and analyzed. METHODS: We used Monte Carlo simulation to measure and compare the performance of eight selection methods with homogeneous and heterogeneous diseases using both single-stage and two-stage designs. We also applied the selection methods in an actual proteomic biomarker screening study of heterogeneous breast cancer cases. RESULTS: Different selection methods were optimal and more than 2-fold larger sample sizes were needed for heterogeneous diseases compared with homogeneous diseases. We also found that for larger studies, two-stage designs can achieve nearly the same statistical power as single-stage designs at significantly reduced cost. CONCLUSIONS: We found that disease heterogeneity profoundly affected biomarker performance. We report sample size requirements and provide guidance on the design and analysis of biomarker discovery studies for both homogeneous and heterogeneous diseases. Impact: We have shown that studies to identify biomarkers for the early detection of heterogeneous disease require different statistical selection methods and larger sample sizes than if the disease were homogeneous. These findings provide a methodological platform for biomarker discovery of heterogeneous diseases.
    Cancer Epidemiology Biomarkers & Prevention 03/2013; 22(5). DOI:10.1158/1055-9965.EPI-12-1236 · 4.32 Impact Factor
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    ABSTRACT: Abstract Peptide and protein identification via tandem mass spectrometry (MS/MS) lies at the heart of proteomic characterization of biological samples. Several algorithms are able to search, score, and assign peptides to large MS/MS datasets. Most popular methods, however, underutilize the intensity information available in the tandem mass spectrum due to the complex nature of the peptide fragmentation process, thus contributing to loss of potential identifications. We present a novel probabilistic scoring algorithm called Context-Sensitive Peptide Identification (CSPI) based on highly flexible Input-Output Hidden Markov Models (IO-HMM) that capture the influence of peptide physicochemical properties on their observed MS/MS spectra. We use several local and global properties of peptides and their fragment ions from literature. Comparison with two popular algorithms, Crux (re-implementation of SEQUEST) and X!Tandem, on multiple datasets of varying complexity, shows that peptide identification scores from our models are able to achieve greater discrimination between true and false peptides, identifying up to ∼25% more peptides at a False Discovery Rate (FDR) of 1%. We evaluated two alternative normalization schemes for fragment ion-intensities, a global rank-based and a local window-based. Our results indicate the importance of appropriate normalization methods for learning superior models. Further, combining our scores with Crux using a state-of-the-art procedure, Percolator, we demonstrate the utility of using scoring features from intensity-based models, identifying ∼4-8 % additional identifications over Percolator at 1% FDR. IO-HMMs offer a scalable and flexible framework with several modeling choices to learn complex patterns embedded in MS/MS data.
    Omics: a journal of integrative biology 01/2013; 17(2). DOI:10.1089/omi.2012.0073 · 2.73 Impact Factor
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    ABSTRACT: Cancer patients spontaneously generate autoantibodies (AAb) to tumor-derived proteins. To detect AAb, we have probed novel high-density custom protein microarrays (NAPPA) expressing 4988 candidate tumor antigens with sera from patients with early stage breast cancer (IBC), and bound IgG was measured. We used a three-phase serial screening approach. First, a prescreen was performed to eliminate uninformative antigens. Sera from stage I-III IBC (n = 53) and healthy women (n = 53) were screened for AAb to all 4988 protein antigens. Antigens were selected if the 95th percentile of signal of cases and controls were significantly different (p < 0.05) and if the number of cases with signals above the 95th percentile of controls was significant (p < 0.05). These 761 antigens were screened using an independent set of IBC sera (n = 51) and sera from women with benign breast disease (BBD) (n = 39). From these, 119 antigens had a partial area under the ROC curve (p < 0.05), with sensitivities ranging from 9-40% at >91% specificity. Twenty-eight of these antigens were confirmed using an independent serum cohort (n = 51 cases/38 controls, p < 0.05). Using all 28 AAb, a classifier was identified with a sensitivity of 80.8% and a specificity of 61.6% (AUC = 0.756). These are potential biomarkers for the early detection of breast cancer.
    Journal of Proteome Research 10/2010; 10(1):85-96. DOI:10.1021/pr100686b · 5.00 Impact Factor

Publication Stats

158 Citations
91.11 Total Impact Points

Institutions

  • 2010–2015
    • Arizona State University
      • Center for Personalized Diagnostics
      Phoenix, Arizona, United States
  • 2013
    • University of Toronto
      • Terrence Donelly Centre for Cellular and Biomolecular Research
      Toronto, Ontario, Canada