Publications by authors named "Edward J Bedrick"

58 Publications

The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension.

Chest 2021 Oct 9. Epub 2021 Oct 9.

Department of Medicine, University of Arizona, Tucson, AZ; Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Arizona, Tucson, AZ. Electronic address:

Background: Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect as most patients remain in intermediate or high risk after initial treatment with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy.

Research Question: Does RV adaptation predict therapeutic response over time?

Study Design And Methods: We evaluated 52 incident treatment naïve patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3 mo.) and follow-up 2 (∼18 mo.). All patients were placed on goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I-II was not achieved. Therapeutic response was evaluated at follow-up 1 as non-responders (died) or responders and again at follow-up 2 as super-responders (low risk) or partial-responders (high/intermediate risk). Multiparametric risk was based on a simplified ERS/ESC guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean±SD or odds ratio [95%CI].

Results: Nine patients (17%) were non-responders. PAH-directed therapy improved ERS low risk from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was non-significantly higher in responders (0.9±0.4) versus non-responders (0.6±0.4, p=0.09) but was unable to predict super-responder status at follow-up 2 (odds ratio 1.40 [0.28-7.0], p=0.84). Baseline RVEF and change in Eed successfully predicted super-responder status at follow-up 2 (odds ratio 1.15 [1.0-1.27], p=0.009 and 0.29 [0.86-0.96], p=0.04, respectively).

Interpretation: In patients with advanced PAH, RV-PA coupling could not discriminate irreversible RV failure (non-responders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RVEF were the best predictors of therapeutic response.
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http://dx.doi.org/10.1016/j.chest.2021.09.040DOI Listing
October 2021

A Target for Increased Mortality Risk in Critically Ill Patients: The Concept of Perpetuity.

J Clin Med 2021 Sep 2;10(17). Epub 2021 Sep 2.

College of Medicine, Drexel University, 2900 W Queen Lane, Philadelphia, PA 19129, USA.

Background: Emergency medicine is acuity-based and focuses on time-sensitive treatments for life-threatening diseases. Prolonged time in the emergency department, however, is associated with higher mortality in critically ill patients. Thus, we explored management after an acuity-based intervention, which we call perpetuity, as a potential mechanism for increased risk. To explore this concept, we evaluated the impact of each hour above a lung-protective tidal volume on risk of mortality.

Methods: This cohort analysis includes all critically ill, non-trauma, adult patients admitted to two academic EDs between 1 November 2013 and 30 April 2017. Cox models with time-varying covariates were developed with time in perpetuity as a time-varying covariate, defined as hours above 8 mL/kg ideal body weight, adjusted for covariates. The primary outcome was the time to in-hospital death.

Results: Our analysis included 2025 patients, 321 (16%) of whom had at least 1 h of perpetuity time. A partial likelihood-ratio test comparing models with and without hours in perpetuity was statistically significant (χ(3) = 13.83, = 0.0031). There was an interaction between age and perpetuity (Relative risk (RR) 0.9995; 95% Confidence interval (CI): 0.9991-0.9998). For example, for each hour above 8 mL/kg ideal body weight, a 20-year-old with 90% oxygen saturation has a relative risk of death of 1.02, but a 40-year-old with 90% oxygen saturation has a relative risk of 1.01.

Conclusions: Perpetuity, illustrated through the lens of mechanical ventilation, may represent a target for improving outcomes in critically ill patients, starting in the emergency department. Research is needed to evaluate the types of patients and interventions in which perpetuity plays a role.
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http://dx.doi.org/10.3390/jcm10173971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432225PMC
September 2021

Test-Retest Reliability of a Semi-Structured Interview to Aid in Pediatric Traumatic Brain Injury Diagnosis.

J Int Neuropsychol Soc 2021 Aug 11:1-13. Epub 2021 Aug 11.

The Mind Research Network/Lovelace Biomedical Research Institute, Albuquerque, NM, USA.

Objective: Retrospective self-report is typically used for diagnosing previous pediatric traumatic brain injury (TBI). A new semi-structured interview instrument (New Mexico Assessment of Pediatric TBI; NewMAP TBI) investigated test-retest reliability for TBI characteristics in both the TBI that qualified for study inclusion and for lifetime history of TBI.

Method: One-hundred and eight-four mTBI (aged 8-18), 156 matched healthy controls (HC), and their parents completed the NewMAP TBI within 11 days (subacute; SA) and 4 months (early chronic; EC) of injury, with a subset returning at 1 year (late chronic; LC).

Results: The test-retest reliability of common TBI characteristics [loss of consciousness (LOC), post-traumatic amnesia (PTA), retrograde amnesia, confusion/disorientation] and post-concussion symptoms (PCS) were examined across study visits. Aside from PTA, binary reporting (present/absent) for all TBI characteristics exhibited acceptable (≥0.60) test-retest reliability for both Qualifying and Remote TBIs across all three visits. In contrast, reliability for continuous data (exact duration) was generally unacceptable, with LOC and PCS meeting acceptable criteria at only half of the assessments. Transforming continuous self-report ratings into discrete categories based on injury severity resulted in acceptable reliability. Reliability was not strongly affected by the parent completing the NewMAP TBI.

Conclusions: Categorical reporting of TBI characteristics in children and adolescents can aid clinicians in retrospectively obtaining reliable estimates of TBI severity up to a year post-injury. However, test-retest reliability is strongly impacted by the initial data distribution, selected statistical methods, and potentially by patient difficulty in distinguishing among conceptually similar medical concepts (i.e., PTA vs. confusion).
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http://dx.doi.org/10.1017/S1355617721000928DOI Listing
August 2021

Antiretroviral Laboratory Monitoring and Implications for HIV Clinical Care in the Era of COVID-19 and Beyond.

AIDS Res Hum Retroviruses 2021 04 17;37(4):297-303. Epub 2021 Mar 17.

Department of Medicine, University of Arizona, College of Medicine, Tucson, Arizona, USA.

In the era of COVID-19, providers are delaying laboratory testing in people with HIV (PWH). The purpose of this study was to examine the clinical significance of renal, liver, and lipid testing. We reviewed the charts of 261 PWH who initiated care at an academic HIV clinic between January 1, 2016 and December 21, 2018. Analysis included one-sided binomial exact tests and multiple linear, Poisson, and Beta regression models. The most common abnormality was a glomerular filtration rate (GFR) <60 mL/min (10%). Age <40 years [estimated relative rate (rr) 0.017, 95% confidence interval (CI) 0.207 to 0.494], cobicistat (rr 0.284, 95% CI 0.128 to 0.63), and tenofovir alafenamide (rr 0.295 95% CI 0.151 to 0.573) were associated with a decreased risk of GFR <60 mL/min. An increased AST and ALT ≥2 × upper limit of normal (ULN) was found in 5% and 3%, respectively. Hepatitis C and use of darunavir and lopinavir were associated with increased AST or ALT. When a GFR was <60 mL/min or an AST or ALT was ≥2 × ULN, no action was taken in 53% of cases. In 18% of cases the only intervention was repeat testing. The most common interventions after lipid results were calculation of a 10-year cardiovascular risk score (31%) and addition of a statin (18%). Taking action after lipid results was strongly associated with age ≥40 (rr 7.37, 95% CI 3.0 to 18.3). Young PWH without hepatitis C rarely have renal, liver, or lipid test results that alter clinical care. Decreased testing should be considered.
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http://dx.doi.org/10.1089/AID.2020.0263DOI Listing
April 2021

Race and Gender-Based Perceptions of Older Adults: Will the Youth Lead the Way?

J Racial Ethn Health Disparities 2020 Nov 3. Epub 2020 Nov 3.

Division of Cardiology, Department of Medicine, Sarver Heart Center, University of Arizona, 1501 North Campbell Avenue, PO Box 245046, Tucson, AZ, 85724, USA.

Background: Older individuals encounter the greatest racial/gender biases. It is unknown whether younger generations, who often lead culture shifts, have racial and gender biases against older populations.

Methods: Using Amazon's Mechanical Turk's crowdsourcing, we identified how an individual's race and gender are associated with perceptions of individuals aged mid-60s. Participants were asked to rate photograph appearances on Likert Scale (1-10). Interactions between participant and photograph race and gender were assessed with mixed effects models. Delta represents rating differences (positive value higher rating for Whites or women, negative value higher rating for African-Americans or men).

Results: Among 1563 participants (mean 35 years ± 12), both non-Hispanic White (WP) and all Other race/ethnicity (OP) participants perceived African-American photos as more trustworthy [Delta WP -0.60(95%CI-0.83, - 0.37); Delta OP - 0.51(- 0.74,-0.28), interaction p = 0.06], more attractive [Delta non-Hispanic White participants - 0.63(- 0.97, - 0.29); Delta Other race/ethnicity participants - 0.40 (- 0.74, - 0.28), interaction p < 0.001], healthier [Delta WP -0.31(- 0.53, - 0.08); Delta OP -0.24(- 0.45, -0.03), interaction p = 1.00], and less threatening than White photos [Delta WP 0.79(0.36,1.22); Delta OP 0.60(0.17,1.03), interaction p < 0.001]. Compared with OP, WP perceived African-American photos more favorably for intelligence (interaction p < 0.001). Both genders perceived photos of women as more trustworthy [Delta Women Participants (WmP) 0.50(0.27,0.73); Delta Men Participants(MnP) 0.31(0.08,0.54); interaction p < 0.001] and men as more threatening [Delta WmP -0.84(-1.27, -0.41), Delta MnP - 0.77(- 1.20, - 0.34), interaction p = 0.93]. Compared with MnP, WmP perceived photos of women as happier and more attractive than men (interaction p < 0.001). Compared with WmP, MnP perceived men as healthier than women (interaction p < 0.001).

Conclusions: Among a young generation, older African-Americans were perceived more favorably than Whites. Gender perceptions followed gender norms. This suggests a decline in implicit bias against older minorities, but gender biases persist. Future work should investigate whether similar patterns are observed in healthcare.
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http://dx.doi.org/10.1007/s40615-020-00903-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089121PMC
November 2020

Comparison of a Novel Rapid Lateral Flow Assay to Enzyme Immunoassay Results for Early Diagnosis of Coccidioidomycosis.

Clin Infect Dis 2020 Aug 20. Epub 2020 Aug 20.

The Valley Fever Center for Excellence, University of Arizona College of Medicine-Tucson, Tucson, Arizona.

Background: Coccidioidomycosis (CM) is a common cause of community acquired pneumonia (CAP) where CM is endemic. Manifestations include self-limited pulmonary infection, chronic fibrocavitary pulmonary disease, and disseminated coccidioidomycosis (DCM). Most infections are identified by serological assays including enzyme-linked immunoassay (EIA), complement fixation (CF) and immunodiffusion (IMDF). These are time-consuming and take days to result, impeding early diagnosis. A new lateral flow assay (LFA, Sōna, IMMY, Norman OK) improves time-to-result to one hour.

Methods: We prospectively enrolled 392 suspected CM patients, compared the LFA to standard EIA and included procalcitonin evaluation.

Results: Compared to standard EIA, LFA demonstrates 31% sensitivity (95% CI of 20%-44%) and 92% specificity (95% CI of 88%-95%). Acute pulmonary disease (74%) was the most common clinical syndrome. Hospitalized patients constituted 75% of subjects, and compared to outpatients, they more frequently had ≥ 3 previous healthcare facility visits (p = 0.05), received antibacterials (p & 0.01) and had > 3 antibacterial courses (p & 0.01). Procalcitonin (PCT) was &0.25 ng/ml in 52 (83%) EIA+ patients, suggesting infection was not bacterial.

Conclusions: When CM is a possible diagnosis, LFA identified nearly a third of EIA+ infections. Combined with PCT &0.25 ng/ml, LFA could reduce unnecessary antibacterial use by 77%.
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http://dx.doi.org/10.1093/cid/ciaa1205DOI Listing
August 2020

Neurosensory Screening and Symptom Provocation in Pediatric Mild Traumatic Brain Injury.

J Head Trauma Rehabil 2020 Jul/Aug;35(4):270-278

The Mind Research Network/Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico (Drs Mayer, Stephenson, Hanlon, and Phillips, Messrs Wertz, Dodd, and Shaff, and Mss Robertson-Benta and Pabbathi Reddy); Departments of Psychiatry and Behavioral Sciences (Dr Mayer), Psychology (Drs Mayer and Campbell), Neurology (Drs Mayer and Phillips), and Emergency Medicine (Mr Oglesbee and Dr Park), University of New Mexico, Albuquerque; Department of Epidemiology and Biostatistics, University of Arizona, Tucson (Dr Bedrick); Center for Injury Research and Prevention, Department of Pediatrics (Drs Master, Grady, and Arbogast), and Division of Orthopedic Surgery (Drs Master and Grady), The Children's Hospital of Philadelphia, Philadelphia; Department of Pediatrics and Emergency Medicine, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada (Dr Zemek); Department of Psychology (Dr Yeates), Alberta Children's Hospital Research Institute (Dr Yeates), and Hotchkiss Brain Institute (Dr Yeates), University of Calgary, Calgary, Alberta, Canada; Department of Neurosurgery, Medical College of Wisconsin, Milwaukee (Dr Meier); Departments of Cell Biology, Neurobiology and Anatomy (Dr Meier) and Biomedical Engineering (Dr Meier), Medical College of Wisconsin, Milwaukee; Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts (Dr Mannix); and UBMD Department of Orthopaedics and Sports Medicine, Jacobs School of Medicine, University at Buffalo, Buffalo, New York (Dr Leddy).

Objective: To evaluate diagnostic/prognostic implications of neurosensory testing during the subacute stage in patients with pediatric mild traumatic brain injury (pmTBI).

Setting: Recruitment from pediatric emergency department and urgent care clinics, assessment in a controlled environment.

Participants: In total, 146 pmTBI patients evaluated 7.4 ± 2.3 days and approximately 4 months postinjury; 104 age/sex-matched healthy controls (HCs) at equivalent time points.

Design: Prospective cohort study.

Main Measures: Neurosensory examination based on sequence of 10 established tests of vestibular-ocular, oculomotor, vestibulospinal, and visual functioning.

Results: The amount of symptom provocation (positive change from pretest symptomatology) was significantly increased in pmTBI relative to HCs on every subtest 1 week postinjury, as were deficits in monocular accommodative amplitude and King-Devick Test errors. However, symptom provocation did not meaningfully alter diagnostic sensitivity/specificity relative to more easily obtained pretest symptom ratings. Evidence of clinically significant symptom provocation 1 week postinjury improved sensitivity (Δ = +12.9%) of identifying patients with persistent postconcussive symptoms 4 months postinjury on an independent symptom measure.

Conclusions: The diagnostic sensitivity/specificity of neurosensory testing in acutely concussed youth may be limited at 1 week postinjury as a function of natural recovery occurring in most emergency department cohorts. Neurosensory screening may have greater utility for identifying patients who experience delayed recovery.
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http://dx.doi.org/10.1097/HTR.0000000000000560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335318PMC
September 2021

Comparison of Methods for Classifying Persistent Post-Concussive Symptoms in Children.

J Neurotrauma 2020 07 12;37(13):1504-1511. Epub 2020 Mar 12.

Department of Psychiatry and Behavioral Sciences, University of New Mexico, Albuquerque, New Mexico, USA.

Pediatric mild traumatic brain injury (pmTBI) has received increased public scrutiny over the past decade, especially regarding children who experience persistent post-concussive symptoms (PPCS). However, several methods for defining PPCS exist in clinical and scientific literature, and even healthy children frequently exhibit non-specific, concussive-like symptoms. Inter-method agreement (six PPCS methods), observed misclassification rates, and other psychometric properties were examined in large cohorts of consecutively recruited adolescent patients with pmTBI ( = 162) 1 week and 4 months post-injury and in age/sex-matched healthy controls (HC;  = 117) at equivalent time intervals. Six published PPCS methods were stratified into Simple Change (e.g., , 10th revision [ICD-10]) and Standardized Change (e.g., reliable change indices) algorithms. Among HC, test-retest reliability was fair to good across the 4-month assessment window, with evidence of bias (i.e., higher symptom ratings) during retrospective relative to other assessments. Misclassification rates among HC were higher (>30%) for Simple Change algorithms, with poor inter-rater reliability of symptom burden across HC and their parents. A 49% spread existed in terms of the proportion of pmTBI patients "diagnosed" with PPCS at 4 months, with superior inter-method agreement among standardized change algorithms. In conclusion, the self-reporting of symptom burden is only modestly reliable in typically developing adolescents over a 4-month period, with additional evidence for systematic bias in both adolescent and parental ratings. Significant variation existed for identifying pmTBI patients who had "recovered" (i.e., those who did not meet individual criteria for PPCS) from concussion across the six definitions, representing a considerable challenge for estimating the true incidence rate of PPCS in published literature. Although relatively straightforward to obtain, current findings question the utility of the most commonly used Simple Change scores for diagnosis of PPCS in clinical settings.
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http://dx.doi.org/10.1089/neu.2019.6805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307699PMC
July 2020

PrEP Knowledge and Attitudes Among Adults Attending Public Health Clinics in Southern Arizona.

J Community Health 2020 04;45(2):400-406

University of Arizona Health Sciences Center, 1501 N Campbell Ave, P.O. Box 245039, Tucson, AZ, 85724, USA.

HIV pre-exposure prophylaxis (PrEP) is underutilized among Hispanics, women, and low-income individuals. To better understand PrEP barriers in this population, questionnaires were administered to 500 patients attending public health clinics in southern Arizona which provide family planning and sexually transmitted infections care. Sixty-three percent believed that they had no risk of HIV infection. When asked "Before today, did you know that there was a pill that can prevent HIV infection?" 80% of persons answered no. Among women, 88% answered no to this question. As expected, individuals with a higher perceived HIV risk (OR 1.76) or one HIV risk factor (OR 5.85) had a higher probability of knowledge. Among survey participants 87% would take a daily pill, 91% would visit a health-care provider every 3 months, and 92% would have laboratory testing every 3 months. Fifty-four percent would not be afraid or embarrassed if friends or family knew they were taking PrEP. Seventy-two percent would take PrEP despite temporary nausea. Sixty-two percent would pay ≥ $40 every 3 months for PrEP. Lack of knowledge, rather than patient attitudes, is the more important barrier to wider utilization of PrEP among individuals, especially women, attending public health clinics in Southern Arizona. Future efforts need to focus on education and access to PrEP in underserved populations including women and Hispanics.
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http://dx.doi.org/10.1007/s10900-019-00758-yDOI Listing
April 2020

Data reduction prior to inference: Are there consequences of comparing groups using a t-test based on principal component scores?

Authors:
Edward J Bedrick

Biometrics 2020 06 14;76(2):508-517. Epub 2019 Nov 14.

Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, Center for Biomedical Informatics and Biostatistics, University of Arizona, Tucson, Arizona.

Researchers often use a two-step process to analyze multivariate data. First, dimensionality is reduced using a technique such as principal component analysis, followed by a group comparison using a -test or analysis of variance. Although this practice is often discouraged, the statistical properties of this procedure are not well understood, starting with the hypothesis being tested. We suggest that this approach might be considering two distinct hypotheses, one of which is a global test of no differences in the mean vectors, and the other being a focused test of a specific linear combination where the coefficients have been estimated from the data. We study the asymptotic properties of the two-sample -statistic for these two scenarios, assuming a nonsparse setting. We show that the size of the global test agrees with the presumed level but that the test has poor power. In contrast, the size of the focused test can be arbitrarily distorted with certain mean and covariance structures. A simple method is provided to correct the size of the focused test. Data analyses and simulations are used to illustrate the results. Recommendations on the use of this two-step method and the related use of principal components for prediction are provided.
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http://dx.doi.org/10.1111/biom.13159DOI Listing
June 2020

Delays in Coccidioidomycosis Diagnosis and Associated Healthcare Utilization, Tucson, Arizona, USA.

Emerg Infect Dis 2019 09;25(9):1745-1747

Tucson, Arizona, USA, is a highly coccidioidomycosis-endemic area. We conducted a retrospective review of 815 patients in Tucson over 2.7 years. Of 276 patients with coccidioidomycosis, 246 had a delay in diagnosis; median delay was 23 days. Diagnosis delay was associated with coccidioidomycosis-related costs totaling $589,053 and included extensive antibacterial drug use.
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http://dx.doi.org/10.3201/eid2509.190023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711243PMC
September 2019

Novel disease syndromes unveiled by integrative multiscale network analysis of diseases sharing molecular effectors and comorbidities.

BMC Med Genomics 2018 Dec 31;11(Suppl 6):112. Epub 2018 Dec 31.

Center for Biomedical Informatics and Biostatistics, The University of Arizona, Tucson, AZ, 85721, USA.

Background: Forty-two percent of patients experience disease comorbidity, contributing substantially to mortality rates and increased healthcare costs. Yet, the possibility of underlying shared mechanisms for diseases remains not well established, and few studies have confirmed their molecular predictions with clinical datasets.

Methods: In this work, we integrated genome-wide association study (GWAS) associating diseases and single nucleotide polymorphisms (SNPs) with transcript regulatory activity from expression quantitative trait loci (eQTL). This allowed novel mechanistic insights for noncoding and intergenic regions. We then analyzed pairs of SNPs across diseases to identify shared molecular effectors robust to multiple test correction (False Discovery Rate FDR < 0.05). We hypothesized that disease pairs found to be molecularly convergent would also be significantly overrepresented among comorbidities in clinical datasets. To assess our hypothesis, we used clinical claims datasets from the Healthcare Cost and Utilization Project (HCUP) and calculated significant disease comorbidities (FDR < 0.05). We finally verified if disease pairs resulting molecularly convergent were also statistically comorbid more than by chance using the Fisher's Exact Test.

Results: Our approach integrates: (i) 6175 SNPs associated with 238 diseases from ~ 1000 GWAS, (ii) eQTL associations from 19 tissues, and (iii) claims data for 35 million patients from HCUP. Logistic regression (controlled for age, gender, and race) identified comorbidities in HCUP, while enrichment analyses identified cis- and trans-eQTL downstream effectors of GWAS-identified variants. Among ~ 16,000 combinations of diseases, 398 disease-pairs were prioritized by both convergent eQTL-genetics (RNA overlap enrichment, FDR < 0.05) and clinical comorbidities (OR > 1.5, FDR < 0.05). Case studies of comorbidities illustrate specific convergent noncoding regulatory elements. An intergenic architecture of disease comorbidity was unveiled due to GWAS and eQTL-derived convergent mechanisms between distinct diseases being overrepresented among observed comorbidities in clinical datasets (OR = 8.6, p-value = 6.4 × 10 FET).

Conclusions: These comorbid diseases with convergent eQTL genetic mechanisms suggest clinical syndromes. While it took over a decade to confirm the genetic underpinning of the metabolic syndrome, this study is likely highlighting hundreds of new ones. Further, this knowledge may improve the clinical management of comorbidities with precision and shed light on novel approaches of drug repositioning or SNP-guided precision molecular therapy inclusive of intergenic risks.
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http://dx.doi.org/10.1186/s12920-018-0428-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311938PMC
December 2018

Exposure to Diabetes in Utero Is Associated with Earlier Pubertal Timing and Faster Pubertal Growth in the Offspring: The EPOCH Study.

J Pediatr 2019 03 6;206:105-112. Epub 2018 Dec 6.

Department of Epidemiology, Colorado School of Public Health, Aurora, CO.

Objective: To examine the associations of in utero exposure to maternal diabetes with surrogate measures of offspring pubertal timing (age at peak height velocity [APHV]) and speed of pubertal growth (peak height velocity [PHV]).

Study Design: Data from 77 exposed and 340 unexposed youth followed from age 2 to 19 years (51% non-Hispanic white, 50% female) were analyzed using the Exploring Perinatal Outcomes among Children study, a historical prospective cohort. Maternal diabetes status was collected from obstetric records, and child heights from 2 years to current age from pediatric records. Other covariates were collected during research visits. The superimposition by translation and rotation method, using height measurements (4-52 per participant), modeled APHV and PHV. Accelerated failure time analyses were used to test whether exposure to maternal diabetes was associated with younger APHV and faster PHV.

Results: Adjusting for child's sex, race/ethnicity, and socioeconomic status, median APHV was reached ~3 months earlier in youth exposed to maternal diabetes compared with unexposed youth (P < .03). Youth exposed to maternal diabetes had a faster PHV than unexposed youth: exposed girls had 10.5% greater median PHV compared with unexposed girls and exposed boys had a 4.0% greater median PHV compared with unexposed boys (P < .001 for exposure by sex interaction).

Conclusions: Our findings provide evidence that exposure to maternal diabetes in utero is associated with earlier pubertal timing and faster pubertal growth. Whether earlier puberty or faster speed of pubertal growth mediates the association between maternal diabetes exposure and later chronic disease risk remains to be studied.
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http://dx.doi.org/10.1016/j.jpeds.2018.10.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389400PMC
March 2019

Regularized continuous-time Markov Model via elastic net.

Biometrics 2018 09 13;74(3):1045-1054. Epub 2018 Mar 13.

Department of Epidemiology and Biostatistics, University of Arizona, Tucson, Arizona, U.S.A.

Continuous-time Markov models are commonly used to analyze longitudinal transitions between multiple disease states in panel data, where participants' disease states are only observed at multiple time points, and the exact state paths between observations are unknown. However, when covariate effects are incorporated and allowed to vary for different transitions, the number of potential parameters to estimate can become large even when the number of covariates is moderate, and traditional maximum likelihood estimation and subset model selection procedures can easily become unstable due to overfitting. We propose a novel regularized continuous-time Markov model with the elastic net penalty, which is capable of simultaneous variable selection and estimation for large number of parameters. We derive an efficient coordinate descent algorithm to solve the penalized optimization problem, which is fully automatic and data driven. We further consider an extension where one of the states is death, and time of death is exactly known but the state path leading to death is unknown. The proposed method is extensively evaluated in a simulation study, and demonstrated in an application to real-world data on airflow limitation state transitions.
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http://dx.doi.org/10.1111/biom.12868DOI Listing
September 2018

Spatial distribution bias in subject-specific abnormalities analyses.

Brain Imaging Behav 2018 Dec;12(6):1828-1834

The Mind Research Network/Lovelace Biomedical and Environmental Research Institute, Pete & Nancy Domenici Hall, 1101 Yale Blvd. NE, Albuquerque, NM, 87106, USA.

The neuroimaging community has seen a renewed interest in algorithms that provide a location-independent summary of subject-specific abnormalities (SSA) to assess individual lesion load. More recently, these methods have been extended to assess whether multiple individuals within the same cohort exhibit extrema in the same spatial location (e.g., voxel or region of interest). However, the statistical validity of this approach has not been rigorously established. The current study evaluated the potential for a spatial bias in the distribution of SSA using several common z-transformation algorithms (leave-one-out [LOO]; independent sample [IDS]; Enhanced Z-Score Microstructural Assessment of Pathology [EZ-MAP]; distribution-corrected z-scores [DisCo-Z]) using both simulated data and DTI data from 50 healthy controls. Results indicated that methods which z-transformed data based on statistical moments from a reference group (LOO, DisCo-Z) led to bias in the spatial location of extrema for the comparison group. In contrast, methods that z-transformed data using an independent third group (EZ-MAP, IDS) resulted in no spatial bias. Importantly, none of the methods exhibited bias when results were summed across all individual elements. The spatial bias is primarily driven by sampling error, in which differences in the mean and standard deviation of the untransformed data have a higher probability of producing extrema in the same spatial location for the comparison but not reference group. In conclusion, evaluating SSA overlap within cohorts should be either be avoided in deference to established group-wise comparisons or performed only when data is available from an independent third group.
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http://dx.doi.org/10.1007/s11682-018-9836-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089678PMC
December 2018

Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension.

Am J Med 2018 06 5;131(6):702.e7-702.e13. Epub 2018 Feb 5.

The University of Arizona Health Sciences, The University of Arizona, Tucson. Electronic address:

Background: Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction.

Methods: Using an adjusted model for age, sex, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension.

Results: A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P = .012), along with reduced log(pulmonary artery capacitance) (P = .006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes.

Conclusion: Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension.
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http://dx.doi.org/10.1016/j.amjmed.2017.12.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963998PMC
June 2018

An evaluation of Z-transform algorithms for identifying subject-specific abnormalities in neuroimaging data.

Brain Imaging Behav 2018 Apr;12(2):437-448

Radiology Department, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.

The need for algorithms that capture subject-specific abnormalities (SSA) in neuroimaging data is increasingly recognized across many neuropsychiatric disorders. However, the effects of initial distributional properties (e.g., normal versus non-normally distributed data), sample size, and typical preprocessing steps (spatial normalization, blurring kernel and minimal cluster requirements) on SSA remain poorly understood. The current study evaluated the performance of several commonly used z-transform algorithms [leave-one-out (LOO); independent sample (IDS); Enhanced Z-score Microstructural Assessment of Pathology (EZ-MAP); distribution-corrected z-scores (DisCo-Z); and robust z-scores (ROB-Z)] for identifying SSA using simulated and diffusion tensor imaging data from healthy controls (N = 50). Results indicated that all methods (LOO, IDS, EZ-MAP and DisCo-Z) with the exception of the ROB-Z eliminated spurious differences that are present across artificially created groups following a standard z-transform. However, LOO and IDS consistently overestimated the true number of extrema (i.e., SSA) across all sample sizes and distributions. The EZ-MAP and DisCo-Z algorithms more accurately estimated extrema across most distributions and sample sizes, with the exception of skewed distributions. DTI results indicated that registration algorithm (linear versus non-linear) and blurring kernel size differentially affected the number of extrema in positive versus negative tails. Increasing the blurring kernel size increased the number of extrema, although this effect was much more prominent when a minimum cluster volume was applied to the data. In summary, current results highlight the need to statistically compare the frequency of SSA in control samples or to develop appropriate confidence intervals for patient data.
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http://dx.doi.org/10.1007/s11682-017-9702-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607089PMC
April 2018

Childhood hematologic cancer and residential proximity to oil and gas development.

PLoS One 2017 15;12(2):e0170423. Epub 2017 Feb 15.

Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Anschutz Campus, Aurora, Colorado, United States of America.

Background: Oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas. We explored whether residential proximity to oil and gas development was associated with risk for hematologic cancers using a registry-based case-control study design.

Methods: Participants were 0-24 years old, living in rural Colorado, and diagnosed with cancer between 2001-2013. For each child in our study, we calculated inverse distance weighted (IDW) oil and gas well counts within a 16.1-kilometer radius of residence at cancer diagnosis for each year in a 10 year latency period to estimate density of oil and gas development. Logistic regression, adjusted for age, race, gender, income, and elevation was used to estimate associations across IDW well count tertiles for 87 acute lymphocytic leukemia (ALL) cases and 50 non-Hodgkin lymphoma (NHL) cases, compared to 528 controls with non-hematologic cancers.

Findings: Overall, ALL cases 0-24 years old were more likely to live in the highest IDW well count tertiles compared to controls, but findings differed substantially by age. For ages 5-24, ALL cases were 4.3 times as likely to live in the highest tertile, compared to controls (95% CI: 1.1 to 16), with a monotonic increase in risk across tertiles (trend p-value = 0.035). Further adjustment for year of diagnosis increased the association. No association was found between ALL for children aged 0-4 years or NHL and IDW well counts. While our study benefited from the ability to select cases and controls from the same population, use of cancer-controls, the limited number of ALL and NHL cases, and aggregation of ages into five year ranges, may have biased our associations toward the null. In addition, absence of information on O&G well activities, meteorology, and topography likely reduced temporal and spatial specificity in IDW well counts.

Conclusion: Because oil and gas development has potential to expose a large population to known hematologic carcinogens, further study is clearly needed to substantiate both our positive and negative findings. Future studies should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest (e.g. benzene) near homes, schools, and day care centers; provide age-specific residential histories; compare cases to controls without cancer; and address other potential confounders, and environmental stressors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310851PMC
August 2017

Food Source Prediction of Shiga Toxin-Producing Escherichia coli Outbreaks Using Demographic and Outbreak Characteristics, United States, 1998-2014.

Foodborne Pathog Dis 2016 10 15;13(10):527-534. Epub 2016 Aug 15.

1 Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver , Aurora, Colorado.

Background: Foodborne illness is a continuing public health problem in the United States. Although outbreak-associated illnesses represent a fraction of all foodborne illnesses, foodborne outbreak investigations provide critical information on the pathogens, foods, and food-pathogen pairs causing illness. Therefore, identification of a food source in an outbreak investigation is key to impacting food safety.

Objective: The objective of this study was to systematically identify outbreak-associated case demographic and outbreak characteristics that are predictive of food sources using Shiga toxin-producing Escherichia coli (STEC) outbreaks reported to Centers for Disease Control and Prevention (CDC) from 1998 to 2014 with a single ingredient identified.

Materials And Methods: Differences between STEC food sources by all candidate predictors were assessed univariately. Multinomial logistic regression was used to build a prediction model, which was internally validated using a split-sample approach.

Results: There were 206 single-ingredient STEC outbreaks reported to CDC, including 125 (61%) beef outbreaks, 30 (14%) dairy outbreaks, and 51 (25%) vegetable outbreaks. The model differentiated food sources, with an overall sensitivity of 80% in the derivation set and 61% in the validation set.

Conclusions: This study demonstrates the feasibility for a tool for public health professionals to rule out food sources during hypothesis generation in foodborne outbreak investigation and to improve efficiency while complementing existing methods.
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http://dx.doi.org/10.1089/fpd.2016.2140DOI Listing
October 2016

An approach for quantifying small effects in regression models.

Stat Methods Med Res 2018 04 14;27(4):1088-1098. Epub 2016 Jun 14.

2 Sandia National Laboratories, Albuquerque, NM, USA.

We develop a novel approach for quantifying small effects in regression models. Our method is based on variation in the mean function, in contrast to methods that focus on regression coefficients. Our idea applies in diverse settings such as testing for a negligible trend and quantifying differences in regression functions across strata. Straightforward Bayesian methods are proposed for inference. Four examples are used to illustrate the ideas.
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http://dx.doi.org/10.1177/0962280216653152DOI Listing
April 2018

Choosing a Cluster Sampling Design for Lot Quality Assurance Sampling Surveys.

PLoS One 2015 30;10(6):e0129564. Epub 2015 Jun 30.

Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.

Lot quality assurance sampling (LQAS) surveys are commonly used for monitoring and evaluation in resource-limited settings. Recently several methods have been proposed to combine LQAS with cluster sampling for more timely and cost-effective data collection. For some of these methods, the standard binomial model can be used for constructing decision rules as the clustering can be ignored. For other designs, considered here, clustering is accommodated in the design phase. In this paper, we compare these latter cluster LQAS methodologies and provide recommendations for choosing a cluster LQAS design. We compare technical differences in the three methods and determine situations in which the choice of method results in a substantively different design. We consider two different aspects of the methods: the distributional assumptions and the clustering parameterization. Further, we provide software tools for implementing each method and clarify misconceptions about these designs in the literature. We illustrate the differences in these methods using vaccination and nutrition cluster LQAS surveys as example designs. The cluster methods are not sensitive to the distributional assumptions but can result in substantially different designs (sample sizes) depending on the clustering parameterization. However, none of the clustering parameterizations used in the existing methods appears to be consistent with the observed data, and, consequently, choice between the cluster LQAS methods is not straightforward. Further research should attempt to characterize clustering patterns in specific applications and provide suggestions for best-practice cluster LQAS designs on a setting-specific basis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129564PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488393PMC
April 2016

Refractory trigeminal neuralgia treatment outcomes following CyberKnife radiosurgery.

Radiat Oncol 2014 Dec 14;9:257. Epub 2014 Dec 14.

Department of Radiation Oncology, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.

Introduction: A handful of studies have reported outcomes with CyberKnife radiosurgery (CKRS) for the treatment of trigeminal neuralgia. However, the follow-up has been short with no minimum follow-up required and have included patients with short duration of symptoms. Here we report our institutional experience on patients with a minimum follow-up of 1 year and a median follow-up of 28 months (mean 38.84 months).

Methods: Twenty-five patients with medically and surgically intractable TN received CKRS with a mean marginal radiation dose of 64 Gy applied to an average isodose line of 86% of the affected trigeminal nerve. Follow-up data were obtained by clinical examination and telephone questionnaire. Outcome results were categorized based on the Barrow Neurological Institute (BNI) pain scale with BNI I-III considered to be good outcomes and BNI IV-V considered as treatment failure. BNI facial numbness score was used to assess treatment complications.

Results: A large proportion of patients (42.9%) reported pain relief within 1 month following CKRS treatment. The mean time to recurrence of severe pain was 27.8 months (range 1-129 months). At median follow-up of 28 months (mean 38.84 months), actuarial rate of freedom from severe pain (BNI ≥ III) was 72%. At last follow-up 2 (8%) patients had freedom from any pain and no medications (BNI I) and the majority (48%) had some pain that was adequately controlled with medications. Seven patients (28%) had no response to treatment and continued to suffer from severe pain (BNI IV or V). Patient's diabetic status and overall post-treatment BNI facial numbness scores were statistically significant predictors of treatment outcomes.

Conclusion: CKRS represents an acceptable salvage option for with medically and/or surgically refractory patients. Even patients with severely debilitating symptoms may experience significant and sustained pain relief after CKRS. Particularly, CKRS remains an attractive option in patients who are not good surgical candidates or possibly even failed surgical therapy. This data should help in setting realistic expectations for weighing the various available treatment options.
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http://dx.doi.org/10.1186/s13014-014-0257-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273323PMC
December 2014

Stigma and barriers to accessing mental health services perceived by Air Force nursing personnel.

Mil Med 2014 Nov;179(11):1354-60

University of New Mexico, College of Nursing, MSC09 5350, 1 University of New Mexico, Albuquerque, NM 87131.

We investigated perceptions of stigma and barriers associated with accessing mental health services among active component U.S. Air Force officer and enlisted nursing personnel (N = 211). The Britt and Hoge et al Stigma scale and Hoge et al Barriers to Care scale were administered via an anonymous, online survey. Stigma items pertained to concerns that might affect decisions to seek mental health treatment. Most of the sample agreed with the items "Members of my unit might have less confidence in me" and "My unit leadership might treat me differently." Approximately 20% to 46% agreed with the other four stigma items. Officer nursing personnel were significantly more likely than enlisted to agree that accessing mental health services would be embarrassing, harm their career, or cause leaders to blame them for the problem (p ≤ 0.03 for each comparison). Getting time off from work for treatment and scheduling appointments were perceived as barriers by 41% and 21% of respondents, respectively. We conclude that proportions of Air Force nursing personnel reporting concerns about potential stigmatizing consequences of seeking mental health care are substantial and similar to ranges previously reported by military service members screening positive for mental health problems after deployment.
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http://dx.doi.org/10.7205/MILMED-D-14-00114DOI Listing
November 2014

Methods for identifying subject-specific abnormalities in neuroimaging data.

Hum Brain Mapp 2014 Nov 13;35(11):5457-70. Epub 2014 Jun 13.

The Mind Research Network/Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico; Neurology Department, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Psychology, University of New Mexico, Albuquerque, New Mexico.

Algorithms that are capable of capturing subject-specific abnormalities (SSA) in neuroimaging data have long been an area of focus for diverse neuropsychiatric conditions such as multiple sclerosis, schizophrenia, and traumatic brain injury. Several algorithms have been proposed that define SSA in patients (i.e., comparison group) relative to image intensity levels derived from healthy controls (HC) (i.e., reference group) based on extreme values. However, the assumptions underlying these approaches have not always been fully validated, and may be dependent on the statistical distributions of the transformed data. The current study evaluated variations of two commonly used techniques ("pothole" method and standardization with an independent reference group) for identifying SSA using simulated data (derived from normal, t and chi-square distributions) and fractional anisotropy maps derived from 50 HC. Results indicated substantial group-wise bias in the estimation of extreme data points using the pothole method, with the degree of bias being inversely related to sample size. Statistical theory was utilized to develop a distribution-corrected z-score (DisCo-Z) threshold, with additional simulations demonstrating elimination of the bias and a more consistent estimation of extremes based on expected distributional properties. Data from previously published studies examining SSA in mild traumatic brain injury were then re-analyzed using the DisCo-Z method, with results confirming the evidence of group-wise bias. We conclude that the benefits of identifying SSA in neuropsychiatric research are substantial, but that proposed SSA approaches require careful implementation under the different distributional properties that characterize neuroimaging data.
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http://dx.doi.org/10.1002/hbm.22563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6869579PMC
November 2014

Does a large infant head or a short perineal body increase the risk of obstetrical perineal trauma?

Birth 2014 Jun 3;41(2):147-52. Epub 2014 Apr 3.

Southcentral Foundation, Anchorage, AK, USA.

Background: Perineal trauma after vaginal delivery can have significant long-term consequences. It is unknown if a larger infant head circumference or smaller maternal perineal anatomy are risk factors for perineal trauma after vaginal delivery.

Methods: We conducted a prospective cohort study of low-risk nulliparous women. Data collected included maternal characteristics, antepartum Pelvic Organ Prolapse Quantification measurements of the perineal body and genital hiatus, labor characteristics, perineal trauma, and infant head circumference. Perineal trauma was defined as trauma that extended into the muscles of the perineum (second-degree or deeper). Univariate and multivariate logistic models were created to calculate odds ratios (OR) and 95 percent confidence intervals (CI).

Results: We observed 448 vaginal births. Multivariate analysis demonstrated a significant association between infant head circumference at birth and perineal trauma: OR 1.22 for each increase of 1 cm in head circumference (95% CI 1.05-1.43). There was no association between perineal body or genital hiatus length and perineal trauma.

Conclusions: In nulliparous low-risk women a larger infant head circumference at birth increases the likelihood of perineal trauma, although the effect is modest. Antenatal perineal body and genital hiatus measurements do not predict perineal trauma. These results do not support alteration in mode of delivery or other obstetric practices.
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http://dx.doi.org/10.1111/birt.12101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032593PMC
June 2014

Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study.

Blood 2012 Feb 30;119(8):1872-81. Epub 2011 Dec 30.

University of New Mexico Cancer Center and Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.

Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.
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http://dx.doi.org/10.1182/blood-2011-10-382861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293641PMC
February 2012

Brain biochemistry and personality: a magnetic resonance spectroscopy study.

PLoS One 2011 3;6(11):e26758. Epub 2011 Nov 3.

The Mind Research Network, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.

To investigate the biochemical correlates of normal personality we utilized proton magnetic resonance spectroscopy ((1)H-MRS). Our sample consisted of 60 subjects ranging in age from 18 to 32 (27 females). Personality was assessed with the NEO Five-Factor Inventory (NEO-FFI). We measured brain biochemistry within the precuneus, the cingulate cortex, and underlying white matter. We hypothesized that brain biochemistry within these regions would predict individual differences across major domains of personality functioning. Biochemical models were fit for all personality domains including Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. Our findings involved differing concentrations of Choline (Cho), Creatine (Cre), and N-acetylaspartate (NAA) in regions both within (i.e., posterior cingulate cortex) and white matter underlying (i.e., precuneus) the Default Mode Network (DMN). These results add to an emerging literature regarding personality neuroscience, and implicate biochemical integrity within the default mode network as constraining major personality domains within normal human subjects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026758PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207834PMC
March 2012

A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1.

Mol Biol Cell 2011 Sep 20;22(18):3289-305. Epub 2011 Jul 20.

Department of Pathology, Harvard Medical School, Boston, MA 02215, USA.

Primary cilia regulate epithelial differentiation and organ function. Failure of mutant polycystins to localize to cilia abolishes flow-stimulated calcium signaling and causes autosomal dominant polycystic kidney disease. We identify a conserved amino acid sequence, KVHPSST, in the C-terminus of polycystin-1 (PC1) that serves as a ciliary-targeting signal. PC1 binds a multimeric protein complex consisting of several GTPases (Arf4, Rab6, Rab11) and the GTPase-activating protein (GAP), ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) in the Golgi, which facilitates vesicle budding and Golgi exocytosis. A related N-terminal ciliary-targeting sequence in polycystin-2 similarly binds Arf4. Deletion of the extreme C-terminus of PC1 ablates Arf4 and ASAP1 binding and prevents ciliary localization of an integral membrane CD16.7-PC1 chimera. Interactions are confirmed for chimeric and endogenous proteins through quantitated in vitro and cell-based approaches. PC1 also complexes with Rab8; knockdown of trafficking regulators Arf4 or Rab8 functionally blocks CD16.7-PC1 trafficking to cilia. Mutations in rhodopsin disrupt a similar signal and cause retinitis pigmentosa, while Bardet-Biedl syndrome, primary open-angle glaucoma, and tumor cell invasiveness are linked to dysregulation of ASAP1 or Rab8 or its effectors. In this paper, we provide evidence for a conserved GTPase-dependent ciliary-trafficking mechanism that is shared between epithelia and neurons, and is essential in ciliary-trafficking and cell homeostasis.
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http://dx.doi.org/10.1091/mbc.E11-01-0082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172256PMC
September 2011

Relationship of protein and calorie intake to the severity of oral mucositis in patients with head and neck cancer receiving radiation therapy.

Head Neck 2012 May 20;34(5):655-62. Epub 2011 Jun 20.

Department of Internal Medicine, University of New Mexico Cancer Center, Albuquerque, New Mexico, USA.

Background: The purpose of this study was to evaluate the relationship of calorie and protein intake to the severity of oral mucositis in patients with head and neck cancer receiving radiation therapy.

Methods: Patients with head and neck cancer undergoing ≥60 Gy of radiation were eligible. Weekly data were collected for oral mucositis grade and protein and calorie intake. Proportional odds models examined the association of oral mucositis severity with nutritional predictors.

Results: During a 24-month period, 40 evaluable patients met criteria for inclusion. In a multivariate backward selection model, the sole significant nutritional predictor of reduced oral mucositis severity was meeting the protein goal for the current week (p = .01; adjusted odds ratio [OR], 2.30).

Conclusion: Patients who met protein-related goals during radiotherapy for head and neck cancer had less severe oral mucositis. Nutritional counseling during radiotherapy, with emphasis on protein goals, may reduce oral mucositis severity.
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http://dx.doi.org/10.1002/hed.21795DOI Listing
May 2012

Test-retest reliability and reproducibility of short-echo-time spectroscopic imaging of human brain at 3T.

Magn Reson Med 2011 Aug 28;66(2):324-32. Epub 2011 Feb 28.

The Mind Research Network, Albuquerque, New Mexico 87106, USA.

A 1H magnetic resonance spectroscopic imaging study at 3T and short echo time was conducted to evaluate both the reproducibility, as measured by the interscan coefficient of variation (CV), and test-retest reliability, as measured by the intraclass correlation coefficient (ICC), of measurements of glutamate (Glu), combined glutamate and glutamine (Glx), myo-inositol (mI), N-acetylaspartate, creatine, and choline in 21 healthy subjects. The effect of partial volume correction on these measures and the relationship of reproducibility and reliability to data quality were also examined. A 1H magnetic resonance spectroscopic imaging slice was prescribed above the lateral ventricles and single repeat scans were performed within 30 min to minimize physiologic variability. Interscan CVs based on all the voxels varied from 0.05 to 0.07 for N-acetylaspartate, creatine, and choline to 0.10-0.13 for mI, Glu, and Glx. Findings on the reproducibility of gray and white matter estimates of N-acetylaspartate, creatine, and choline are consistent with previous studies using longer echo times, with CVs in the range of 0.02-0.04 and ICC in the range of 0.65-0.90. CVs for Glu, Glx, and mI are much lower than reported in previous studies at 1.5 T, while white matter mI (CV=0.04, ICC=0.93) and gray matter Glx (CV=0.04, ICC=0.68) demonstrated both high reproducibility and test-retest reliability.
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http://dx.doi.org/10.1002/mrm.22858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130105PMC
August 2011
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