All posts by Erik Erhardt

Erik Barry Erhardt, PhD, is an Associate Professor of Statistics at the University of New Mexico Department of Mathematics and Statistics, where he has served as Director of the Statistics Consulting Clinic, and is currently Director of the Biostatistics and NeuroInformatics (BNI) Core for the second phase of the Center for Biomedical Research Excellence (COBRE) in Brain Function and Mental Illness at the Mind Research Network. His research interests include Bayesian and Frequentist statistical methods for stable isotope sourcing and brain imaging. Erik is a Howard Hughes Medical Institute Interfaces Scholar collaborating in interdisciplinary research and offering consulting services in statistics.

Paper published: Nasal vaccination of young rainbow trout (Oncorhynchus mykiss) against infectious hematopoietic necrosis and enteric red mouth disease

Nasal vaccination of young rainbow trout (Oncorhynchus mykiss) against infectious hematopoietic necrosis and enteric red mouth disease Salinas, I, EB Erhardt, and S LaPatra. Developmental & Comparative Immunology, 53(1), pdf, pp. 105–111 Online: June 23, 2015 http://www.sciencedirect.com/science/article/pii/S0145305X1500124X DOI: 10.1016/j.dci.2015.05.015 Abstract Determining the earliest age at which farmed fish can be successfully vaccinated is a very important question for fish farmers. Nasal vaccines are novel mucosal vaccines that prevent aquatic infectious diseases of finfish. The present study investigates the ontogeny of the olfactory organ of rainbow trout by histology and aims to establish the earliest age for vaccination against infectious hematopoietic necrosis (IHN) and enteric red mouth (ERM) disease using the nasal route. Rainbow trout (Oncorhynchus mykiss) were vaccinated intranasally (I.N) at three different ages: 1050° days (DD) (group A); 450 DD (group B); and 360 DD (group C), or 70, 30 and 24 days post-hatch (dph), respectively. The mean weights of groups A, B and C were 4.69 g, 2.9 g and 2.37 g, respectively. Fish received either a live attenuated IHN virus vaccine, ERM formalin killed bacterin or saline (mock vaccinated). Fish were challenged to the corresponding live pathogen 28 days post-vaccination. IHN vaccine delivery at 360 DD resulted in 40% mortality likely due to residual virulence of the vaccine. No mortality was observed in the ERM nasal delivery groups. Following challenge, very high protection rates against IHN virus were recorded in all three age groups with survivals of 95%, 100% and 97.5% in groups A, B and C, respectively. Survival against ERM was 82.5%, 87.5% and 77.5% in groups A, B and C, respectively. Survival rates did not differ among ages for either vaccine. Our results indicate the feasibility and effectiveness of nasal vaccination as early as 360 DD and vaccination-related mortalities when a live attenuated viral vaccine was used in the youngest fish.
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Paper published: Multidimensional frequency domain analysis of full-volume fMRI reveals significant effects of age, gender and mental illness on the spatiotemporal organization of resting-state brain activity

Multidimensional frequency domain analysis of full-volume fMRI reveals significant effects of age, gender and mental illness on the spatiotemporal organization of resting-state brain activity Miller, RL, EB Erhardt, EA Allen, AM Michael, JA Turner, J Bustillo, JM Ford, DH Mathalon, TGM van Erp, S Potkin, A Preda, G Pearlson, and VD Calhoun (2015). Frontiers in Neuroscience. 9(203) pdf, 1–19. Online: June 16, 2015 http://journal.frontiersin.org/article/10.3389/fnins.2015.00203/abstract doi: 10.3389/fnins.2015.00203 Abstract Clinical research employing functional magnetic resonance imaging (fMRI) is often conducted within the connectionist paradigm, focusing on patterns of connectivity between voxels, regions of interest (ROIs) or spatially distributed functional networks. Connectivity-based analyses are concerned with pairwise correlations of the temporal activation associated with restrictions of the whole-brain hemodynamic signal to locations of a priori interest. There is a more abstract question however that such spatially granular correlation-based approaches do not elucidate: Are the broad spatiotemporal organizing principles of brains in certain populations distinguishable from those of others? Global patterns (in space and time) of hemodynamic activation are rarely scrutinized for features that might characterize complex psychiatric conditions, aging effects or gender—among other variables of potential interest to researchers. We introduce a canonical, transparent technique for characterizing the role in overall brain activation of spatially scaled periodic patterns with given temporal recurrence rates. A core feature of our technique is the spatiotemporal spectral profile (STSP), a readily interpretable 2D reduction of the native four-dimensional brain × time frequency domain that is still “big enough” to capture important group differences in globally patterned brain activation. Its power to distinguish populations of interest is demonstrated on a large balanced multi-site resting fMRI dataset with nearly equal numbers of schizophrenia patients and healthy controls. Our analysis reveals striking differences in the spatiotemporal organization of brain activity that correlate with the presence of diagnosed schizophrenia, as well as with gender and age. To the best of our knowledge, this is the first demonstration that a 4D frequency domain analysis of full volume fMRI data exposes clinically or demographically relevant differences in resting-state brain function.
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Paper published: Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children’s Oncology Group study

Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children’s Oncology Group study Linabery, AM, EB Erhardt, MM Richardson, RF Ambinder, DL Friedman, SL Glaser, A Monnereau, LG Spector, JA Ross, and S Grufferman International Journal of Cancer 137(9), pdf, pp. 2163–2174 Online: May 19, 2015 http://onlinelibrary.wiley.com.libproxy.unm.edu/doi/10.1002/ijc.29589/full DOI: 10.1002/ijc.29589 Abstract Family history of lymphoid neoplasm (LN) is a strong and consistently observed Hodgkin lymphoma (HL) risk factor, although it has been only marginally examined in pediatric/adolescent patients. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL cases diagnosed at 0–14 years at Children’s Oncology Group institutions in 1989–2003. Detailed histories were captured by structured telephone interviews with parents of 517 cases and 783 controls. Epstein–Barr virus (EBV) RNA detection was performed for 355 available case tumors. Two analytic strategies were applied to estimate associations between family cancer history and pediatric/adolescent HL. In a standard case–control approach, multivariate conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). In a reconstructed cohort approach, each relative was included as a separate observation, and multivariate proportional hazards regression was used to produce hazard ratios (HRs) and 95% CIs. Using the latter, pediatric/adolescent HL was associated with a positive family history (HR = 1.20, 95% CI: 1.06–1.36), particularly early-onset cancers (HR = 1.30, 95% CI: 1.06–1.59) and those in the paternal lineage (HR = 1.38, 95% CI: 1.16–1.65), with a suggested association for LN in first-degree relatives (HR = 3.61, 95% CI: 0.87–15.01). There were no discernable patterns for EBV+ versus EBV– HL. The clustering of LN within pedigrees may signal shared genetic susceptibility or common environmental exposures. Heritable genetic risk variants have only recently begun to be discovered, however. These results are consistent with other studies and provide a compelling rationale for family-based studies to garner information about genetic susceptibility to HL.
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Paper published: Family history of cancer and childhood rhabdomyosarcoma: a report from the Children’s Oncology Group and the Utah Population Database

Family history of cancer and childhood rhabdomyosarcoma: a report from the Children’s Oncology Group and the Utah Population Database Lupo, PJ, HE Danysh, SE Plon, K Curtin, D Malkin, S Hettmer, DS Hawkins, SX Skapek, LG Spector, K Papworth, B Melin, EB Erhardt, S Grufferman, and JD Schiffman Cancer Medicine 2015, 4(5), pdf, 781–790 Online: March 23, 2015 http://onlinelibrary.wiley.com/doi/10.1002/cam4.448/full DOI: 10.1002/cam4.448 Abstract Relatively little is known about the epidemiology and factors underlying susceptibility to childhood rhabdomyosarcoma (RMS). To better characterize genetic susceptibility to childhood RMS, we evaluated the role of family history of cancer using data from the largest case–control study of RMS and the Utah Population Database (UPDB). RMS cases (n = 322) were obtained from the Children’s Oncology Group (COG). Population-based controls (n = 322) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate the association between family history of cancer and childhood RMS. The results were validated using the UPDB, from which 130 RMS cases were identified and matched to controls (n = 1300) on sex and year of birth. The results were combined to generate summary odds ratios (ORs) and 95% confidence intervals (CI). Having a first-degree relative with a cancer history was more common in RMS cases than controls (ORs = 1.39, 95% CI: 0.97–1.98). Notably, this association was stronger among those with embryonal RMS (ORs = 2.44, 95% CI: 1.54–3.86). Moreover, having a first-degree relative who was younger at diagnosis of cancer (<30 years) was associated with a greater risk of RMS (ORs = 2.37, 95% CI: 1.34–4.18). In the largest analysis of its kind, we found that most children diagnosed with RMS did not have a family history of cancer. However, our results indicate an increased risk of RMS (particularly embryonal RMS) in children who have a first-degree relative with cancer, and among those whose relatives were diagnosed with cancer at <30 years of age.
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Paper published: Assessing dynamic brain graphs of time-varying connectivity in fMRI data: application to healthy controls and patients with schizophrenia

Assessing dynamic brain graphs of time-varying connectivity in fMRI data: application to healthy controls and patients with schizophrenia Yu, Q, EB Erhardt, J Sui, Y Du, H He, D Hjelm, M Cetin, S Rachakonda, R Miller, G Pearlson, and VD Calhoun NeuroImage 107, pdf supp, pp. 345–355. Online: 15 February 2015 http://www.sciencedirect.com/science/article/pii/S105381191401012X DOI: 10.1016/j.neuroimage.2014.12.020 Abstract Graph theory-based analysis has been widely employed in brain imaging studies, and altered topological properties of brain connectivity have emerged as important features of mental diseases such as schizophrenia. However, most previous studies have focused on graph metrics of stationary brain graphs, ignoring that brain connectivity exhibits fluctuations over time. Here we develop a new framework for accessing dynamic graph properties of time-varying functional brain connectivity in resting-state fMRI data and apply it to healthy controls (HCs) and patients with schizophrenia (SZs). Specifically, nodes of brain graphs are defined by intrinsic connectivity networks (ICNs) identified by group independent component analysis (ICA). Dynamic graph metrics of the time-varying brain connectivity estimated by the correlation of sliding time-windowed ICA time courses of ICNs are calculated. First- and second-level connectivity states are detected based on the correlation of nodal connectivity strength between time-varying brain graphs. Our results indicate that SZs show decreased variance in the dynamic graph metrics. Consistent with prior stationary functional brain connectivity works, graph measures of identified first-level connectivity states show lower values in SZs. In addition, more first-level connectivity states are disassociated with the second-level connectivity state which resembles the stationary connectivity pattern computed by the entire scan. Collectively, the findings provide new evidence about altered dynamic brain graphs in schizophrenia, which may underscore the abnormal brain performance in this mental illness.
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Paper published: Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials

Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials Rosenberg, GA, J Prestopnik, J Adair, BN Huisa, J Knoefel, A Caprihan, C Gasparovic, J Thompson, EB Erhardt, and R Schrader Journal of Neurology, Neurosurgery, and Psychiatry, pdf Online: January 24, 2015 http://jnnp.bmj.com/content/early/2015/01/23/jnnp-2014-309421.abstract doi: 10.1136/jnnp-2014-309421 Abstract Objectives Vascular cognitive impairment (VCI) is a heterogeneous group of cerebrovascular diseases secondary to large and small vessel disease. We hypothesised that biomarkers obtained early in the disease could identify a homogeneous subpopulation with small vessel disease. Methods We obtained disease markers in 62 patients with VCI that included neurological findings, neuropsychological tests, multimodal MR and cerebrospinal fluid measurements of albumin ratio, matrix metalloproteinases (MMPs), amyloid-β1–42 and phosphorylated-τ181. Proton MR spectroscopic imaging showed ischaemic white matter and permeability of the blood-brain barrier (BBB) was measured with dynamic contrast-enhanced MRI. We constructed a 10-point Binswanger disease score (BDS) with subjective and objective disease markers. In addition, an objective set of biomarkers was used for an exploratory factor analysis (EFA) to select patients with BD. Patients were followed for an average of 2 years to obtain clinical consensus diagnoses. Results An initial BDS of 6 or greater was significantly correlated with a final diagnosis of BD (p<0.05; area under the curve (AUC)=0.79). EFA reduced nine objective biomarkers to four factors. The most predictive of BD was the factor containing the inflammatory biomarkers of increased BBB permeability, elevated albumin index and reduced MMP-2 index (factor 2; AUC=0.78). Both measures independently predicted a diagnosis of BD, and combining them improved the diagnostic accuracy. Conclusions Biomarkers predicted the diagnosis of the BD type of subcortical ischaemic vascular disease. Using pathophysiological biomarkers to select homogeneous groups of patients needs to be tested in targeted treatment trials.
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Paper published: Evaluation of dual nasal delivery of infectious hematopoietic necrosis virus and enteric red mouth vaccines in rainbow trout (Oncorhynchus mykiss)

Evaluation of dual nasal delivery of infectious hematopoietic necrosis virus and enteric red mouth vaccines in rainbow trout (Oncorhynchus mykiss) Scott LaPatra, Samantha Kao, Erik B. Erhardt, Irene Salinas Vaccine 33(6), pdf, pp. 771–776 Online: January 3, 2015 http://www.sciencedirect.com/science/article/pii/S0264410X14017101 DOI: 10.1016/j.vaccine.2014.12.055 Abstract Farmed fish are susceptible to different infectious disease agents including viruses and bacteria. Thus, multivalent vaccines or vaccination programs against two or more pathogens are valuable tools in aquaculture. Recently, nasal vaccines have been shown to be very effective in rainbow trout. The current study investigates, for the first time, the use of the nasal route in dual vaccination trials against two important aquatic diseases, infectious hematopoietic necrosis virus (IHN) and enteric red mouth (ERM) disease. Rainbow trout received live attenuated IHN virus (IHNV) vaccine and the ERM bacterin using four different vaccine delivery methods and were challenged with virulent IHNV or Yersinia ruckeri 7 (100 deg day) and 28 (400 deg day) days post-vaccination. The highest survival rates against IHNV at day 7 were obtained by nasal vaccination either when IHNV and ERM were delivered separately into each nare or when they were premixed and delivered to both nasal rosettes (group D). Protection at 28 days against IHNV was similar in all four vaccinated groups. Early protection against ERM was highest in fish that received each vaccine in separate nares (group B), whereas protection at 28 days was highest in the i.p. vaccinated group (group E), followed by the nasally vaccinated group (group B). Survival results were supported by histological observations of the left and right olfactory organ which showed strong immune responses one day (14 deg days) after vaccination in group B vaccinated fish. These data indicate that dual vaccination against two different pathogens via the nasal route is a very effective vaccination strategy for use in aquaculture, particularly when each nare is used separately during delivery. Further long-term studies should evaluate the contribution of adaptive immunity to the protection levels observed.
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Paper published: Nasal immunity is an ancient arm of the mucosal immune system of vertebrates

Nasal immunity is an ancient arm of the mucosal immune system of vertebrates Luca Tacchi, Rami Musharrafieh, Erin T. Larragoite, Kyle Crossey, Erik B. Erhardt, Samuel A. M. Martin, Scott E. LaPatra, & Irene Salinas Nature Communications 5 (5205), pdf, doi: 10.1038/ncomms6205 Online 22 October 2014 http://www.nature.com/ncomms/2014/141022/ncomms6205/full/ncomms6205.html Abstract The mucosal surfaces of all vertebrates have been exposed to similar evolutionary pressures for millions of years. In terrestrial vertebrates such as birds and mammals, the nasopharynx-associated lymphoid tissue (NALT) represents a first line of immune defence. Here we propose that NALT is an ancient arm of the mucosal immune system not restricted to terrestrial vertebrates. We find that NALT is present in rainbow trout and that it resembles other teleost mucosa-associated lymphoid tissues. Trout NALT consists of diffuse lymphoid cells and lacks tonsils and adenoids. The predominant B-cell subset found in trout NALT are IgT + B cells, similar to skin and gut. The trout olfactory organ is colonized by abundant symbiotic bacteria, which are coated by trout secretory immunoglobulin. Trout NALT is capable of mounting strong anti-viral immune responses following nasal delivery of a live attenuated viral vaccine. Our results open up a new tool for the control of aquatic infectious diseases via nasal vaccination.
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