Publications by authors named "Matthew Zapala"

30 Publications

  • Page 1 of 1

Evaluating a Web-based Point-of-care Ultrasound Curriculum for the Diagnosis of Intussusception.

AEM Educ Train 2021 Jul 23;5(3):e10526. Epub 2020 Sep 23.

Department of Emergency Medicine and Pediatrics University of California San Francisco CA USA.

Objectives: Intussusception is a pediatric medical emergency that can be difficult to diagnose. Radiology-performed ultrasound is the diagnostic study of choice but may lead to delays due to lack of availability. Point-of-care ultrasound for intussusception (POCUS-I) studies have shown excellent accuracy and reduced lengths of stay, but there are limited POCUS-I training materials for pediatric emergency medicine (PEM) providers.

Methods: We performed a prospective cohort study assessing PEM physicians undergoing a primarily Web-based POCUS-I curriculum. We developed the POCUS-I curriculum using Kern's six-step model. The curriculum included a Web-based module and a brief, hands-on practice that was developed with a board-certified pediatric radiologist. POCUS-I technical skill, knowledge, and confidence were determined by a direct observation checklist, multiple-choice test, and a self-reported Likert-scale survey, respectively. We assessed participants immediately pre- and postcourse as well as 3 months later to assess for retention of skill, knowledge, and confidence.

Results: A total of 17 of 17 eligible PEM physicians at a single institution participated in the study. For the direct observation skills test, participants scored well after the course with a median (interquartile range [IQR]) score of 20 of 22 (20-21) and maintained high scores even after 3 months (20 [20-21]). On the written knowledge test, there was significant improvement from 57.4% (95% CI = 49.8 to 65.2) to 75.3% (95% CI = 68.1 to 81.6; p < 0.001) and this improvement was maintained at 3 months at 81.2% (95% CI = 74.5 to 86.8). Physicians also demonstrated improved confidence with POCUS-I after exposure to the curriculum, with 5.9% reporting somewhat or very confident prior to the course to 76.5% both after the course and after 3 months (p < 0.001).

Conclusion: After a primarily Web-based curriculum for POCUS-I, PEM physicians performed well in technical skill in POCUS-I and showed improvement in knowledge and confidence, all of which were maintained over 3 months.
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http://dx.doi.org/10.1002/aet2.10526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138103PMC
July 2021

Association of image-defined risk factors with clinical features, histopathology, and outcomes in neuroblastoma.

Cancer Med 2021 04 13;10(7):2232-2241. Epub 2020 Dec 13.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

Background: Clinical, molecular, and histopathologic features guide treatment for neuroblastoma, but obtaining tumor tissue may cause complications and is subject to sampling error due to tumor heterogeneity. We hypothesized that image-defined risk factors (IDRFs) would reflect molecular features, histopathology, and clinical outcomes in neuroblastoma.

Methods: We performed a retrospective cohort study of 76 patients with neuroblastoma or ganglioneuroblastoma. Diagnostic CT scans were reviewed for 20 IDRFs, which were consolidated into five IDRF groups (involvement of multiple body compartments, vascular encasement, tumor infiltration of adjacent organs/structures, airway compression, or intraspinal extension). IDRF groups were analyzed for association with clinical, molecular, and histopathologic features of neuroblastoma.

Results: Patients with more IDRF groups had a higher risk of surgical complications (OR = 3.1, p = 0.001). Tumor vascular encasement was associated with increased risk of surgical complications (OR = 5.40, p = 0.009) and increased risk of undifferentiated/poorly differentiated histologic grade (OR = 11.11, p = 0.013). Tumor infiltration of adjacent organs and structures was associated with decreased survival (HR = 8.90, p = 0.007), MYCN amplification (OR = 9.91, p = 0.001), high MKI (OR = 6.20, p = 0.003), and increased risk of International Neuroblastoma Staging System stage 4 disease (OR = 8.96, p < 0.001).

Conclusions: The presence of IDRFs at diagnosis was associated with high-risk clinical, molecular, and histopathologic features of neuroblastoma. The IDRF group tumor infiltration into adjacent organs and structures was associated with decreased survival. Collectively, these findings may assist surgical planning and medical management for neuroblastoma patients.
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http://dx.doi.org/10.1002/cam4.3663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982630PMC
April 2021

The role of computed tomography and magnetic resonance imaging for preoperative pediatric cochlear implantation work-up in academic institutions.

Cochlear Implants Int 2021 Mar 11;22(2):96-102. Epub 2020 Oct 11.

Department of Pediatric Otolaryngology, Rady Children's Hospital San Diego, San Diego, CA, USA.

Objective: The goal of the study is to investigate the association of pertinent preoperative temporal bone computed tomography (CT) and brain magnetic resonance imaging (MRI) results and intraoperative surgical findings and complications of pediatric cochlear implantation reported in academic settings.

Methods: This is a retrospective review of cochlear implant patients who received a pre-operative temporal bone CT and MRI of the brain between 2005 and 2012 at academic pediatric otolaryngology practices within children's hospitals in the United States and France. Scans were reviewed in a double-blind fashion and compared to intraoperative findings.

Results: 91 children were analyzed (mean age 5.54 +/- 0.58 years). A small facial recess identified on CT was associated with difficult insertion of electrodes (= 0.0003). A prominent sigmoid sinus noted on CT was associated of difficult insertion of electrodes (= 0.01), iatrogenic tegmen dehiscence (= 0.005), as well as difficult round window access (= 0.025). No specific CT finding was found to be associated with external auditory canal injury, perilymphatic gusher, or iatrogenic facial nerve injury. MRI brain and internal auditory canal findings were not predictive of surgical outcomes.

Conclusions: Preoperative CT and MRI remain an important planning tool for pediatric cochlear implantation, particularly in academic institutions. The findings of our study demonstrate that a detailed assessment of both preoperative CT and MRI are valuable for teaching and surgical planning.
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http://dx.doi.org/10.1080/14670100.2020.1830239DOI Listing
March 2021

Monitoring Arteriovenous Malformation Response to Genotype-Targeted Therapy.

Pediatrics 2020 09;146(3)

Pediatrics, University of California San Francisco, San Francisco, California.

Arteriovenous malformations (AVMs) have recently been reported to have a high incidence of somatic KRAS mutations suggesting potential for treatment with mitogen-activated protein kinase inhibitors. In this case report, we describe genotype-targeted treatment of a KRAS mutant metameric AVM in a patient with Cobb syndrome using the mitogen-activated protein kinase inhibitor trametinib. Therapeutic response was monitored with phase-contrast magnetic resonance angiography to quantify AVM arterial inflow as an imaging biomarker. Treatment with trametinib resulted in a substantial decrease in blood flow to the AVM, with a >75% reduction in arterial inflow after 6 months of trametinib therapy.
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http://dx.doi.org/10.1542/peds.2019-3206DOI Listing
September 2020

Evaluating the Performance of Augmented Reality in Displaying Magnetic Resonance Imaging-Derived Three-Dimensional Holographic Models.

J Med Imaging Radiat Sci 2020 03 18;51(1):95-102. Epub 2019 Dec 18.

UCSF Department of Radiology and Biomedical Imaging, San Francisco, California, USA. Electronic address:

Introduction/background: Establishing accuracy and precision of magnetic resonance (MR)-derived augmented reality (AR) models is critical before clinical utilization, particularly in preoperative planning. We investigate the performance of an AR application in representing and displaying MR-derived three-dimensional holographic models.

Methods: Thirty gold standard (GS) measurements were obtained on a magnetic resonance imaging (MRI) phantom (six interfiducial distances and five configurations). Four MRI pulse sequences were obtained for each of the five configurations, and distances measured in Picture Archiving and Communication System (PACS). Digital imaging and communications in medicine files were translated into three-dimensional models and then loaded onto a novel AR platform. Measurements were also obtained with the software's AR caliper tool. Significant differences among the three groups (GS, PACS, and AR) were assessed with the Kruskal-Wallis test and nonsample median test. Accuracy analysis of GS vs. AR was performed. Precision (percent deviation) of the AR-based caliper tool was also assessed.

Results: No statistically significant difference existed between AR and GS measurements (P = .6208). PACS demonstrated mean squared error (MSE) of 0.29%. AR digital caliper demonstrated an MSE of 0.3%. Three-dimensional T2 CUBE AR measurements using the platform's AR caliper tool demonstrated an MSE of 8.6%. Percent deviation of AR software caliper tool ranged between 1.9% and 3.9%.

Discussion: AR demonstrated a high degree of accuracy in comparison to GS, comparable to PACS-based measurements. AR caliper tool demonstrated overall lower accuracy than with physical calipers, although with MSE <10% and greatest measured difference from GS measuring <5 mm. AR-based caliper demonstrated a high degree of precision.

Conclusion: There was no statistically significant difference between GS measurements and three-dimensional AR measurements in MRI phantom models.
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http://dx.doi.org/10.1016/j.jmir.2019.10.006DOI Listing
March 2020

Improved diagnostic confidence and accuracy of pediatric elbow fractures with digital tomosynthesis.

Pediatr Radiol 2020 03 19;50(3):363-370. Epub 2019 Nov 19.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, Benioff Children's Hospital, 1975 Fourth St., San Francisco, CA, 94158, USA.

Background: Pediatric elbow fractures are common but remain challenging to accurately diagnose. Digital tomosynthesis is a technique that has shown promise in difficult adult fracture patterns but has not been formally studied in the pediatric population.

Objective: To assess the added value of digital tomosynthesis on the detection and diagnostic confidence of pediatric elbow fractures.

Materials And Methods: A retrospective study was performed between January 2016 and December 2017 in pediatric patients (≤18 years) to assess the ability of conventional elbow radiographs and digital tomosynthesis to detect elbow fractures. One hundred twenty-one pediatric patients with concern for pediatric elbow trauma (64 males, 57 females; mean age: 8.1 years, range: 1 year to 17 years) were imaged with both conventional elbow radiographs and digital tomosynthesis. Two blinded pediatric radiologists identified fractures and indicated their diagnostic confidence. Observer agreement was assessed with Cohen's Kappa coefficient and a nonparametric Wilcoxon rank sum test was used to compare the degree of diagnostic confidence between standard radiographs alone and standard radiographs with digital tomosynthesis. McNemar's test was used to assess the difference in the rate of fracture detection between the two methods and sensitivity, specificity, precision, accuracy and diagnostic odds ratios were calculated.

Results: Compared with standard radiographs alone, standard radiographs with digital tomosynthesis improved inter-rater agreement, sensitivity, specificity, accuracy, precision and the diagnostic odds ratio for fracture detection and increased diagnostic confidence (Rater 1: P=0.01, Rater 2: P=0.003).

Conclusion: The addition of digital tomosynthesis with conventional elbow radiographs improves diagnostic confidence and performance for the detection of pediatric elbow fractures.
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http://dx.doi.org/10.1007/s00247-019-04548-5DOI Listing
March 2020

Digital tomosynthesis of the pediatric elbow.

Pediatr Radiol 2019 11 4;49(12):1643-1651. Epub 2019 Nov 4.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, Benioff Children's Hospital, 1975 Fourth St., San Francisco, CA, 94158, USA.

Imaging pediatric elbow trauma in the acute setting remains diagnostically challenging given difficult patient positioning, multiple ossification centers of the pediatric elbow, overlapping structures, and complex joint anatomy. Digital tomosynthesis is a technique where the X-ray source travels across a limited arc angle, obtaining a series of low-dose exposures that are in turn digitally reconstructed to produce high in-plane resolution at a relatively low overall radiation dose. Digital tomosynthesis is now more commonly integrated into standard radiographic machines and offers a new and exciting way to assess the pediatric elbow. In this review article we discuss the clinical applications of digital tomosynthesis in pediatric elbow trauma along with challenges related to technique, patient positioning and artifacts.
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http://dx.doi.org/10.1007/s00247-019-04444-yDOI Listing
November 2019

Assessment of quiet T2 weighted PROPELLER sequence in pediatric abdominal imaging.

Clin Imaging 2019 Jan - Feb;53:12-16. Epub 2018 Sep 26.

Radiology, UCSF Benioff Children's Hospital, San Francisco, CA, United States.

Introduction: Elevated acoustic noise during Magnetic Resonance Imaging (MRI) has been associated with patient anxiety and altered cochlear function. Acoustic Reduction Technique (ART) T2 weighted (T2w) periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) has been studied in brain MR but not abdominopelvic imaging. The purpose of our study was to evaluate the image quality and acoustic noise level of ART T2w PROPELLER sequence in comparison with the conventional T2w PROPELLER sequence in pediatric abdomino-pelvic imaging.

Methods: Eleven consecutive pediatric patients undergoing abdomino-pelvic MRI were scanned on a 3 Tesla magnet using standard and ART T2w PROPELLER sequences. After scanning completion, objective sound level measurements were performed with a sound level meter and microphone. Mann-Whitney U test was used for a non-parametric two-tailed statistical analysis of acoustics, image rating and scan time with significance level set to 0.05. Overall inter-rater agreement was calculated using Cohen's kappa coefficient.

Results: Eleven pediatric patients (4 females and 7 males) between 26 days and 18 years of age (mean = 10.0, SD = 5.8) were included. ART T2w produced lower levels of acoustic noise than standard technique in a comparison of mean decibel readings from eleven trials of standard and ART T2w (p value = 0.00008). Streak artifacts were rated greater in ART T2w by both raters (p-value = 0.00278 and 0.00252). There was no significant difference in bile duct blurring, respiratory ghosting, pulsation, fat suppression or hepatic parenchymal depiction.

Conclusion: Presence of additional streaking artifacts should be considered along with the benefit of reduced acoustic noise from ART T2w.
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http://dx.doi.org/10.1016/j.clinimag.2018.09.014DOI Listing
March 2019

Intussusception: past, present and future.

Pediatr Radiol 2017 Aug 4;47(9):1101-1108. Epub 2017 Aug 4.

Department of Radiology and Biomedical Imaging, Benioff Children's Hospital, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA, 94143, USA.

Intussusception is a common etiology of acute abdominal pain in children. Over the last 70 years, there have been significant changes in how we diagnose and treat intussusception, with a more recent focus on the role of ultrasound. In this article we discuss historical and current approaches to intussusception, with an emphasis on ultrasound as a diagnostic and therapeutic modality.
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http://dx.doi.org/10.1007/s00247-017-3878-xDOI Listing
August 2017

Assessing 3D T2 FSE sequence for identification of the normal appendix: working toward a single-sequence MR appendicitis protocol.

Emerg Radiol 2017 Dec 19;24(6):653-660. Epub 2017 Jul 19.

Department of Radiology and Biomedical Imaging, UCSF Benioff Children's Hospital, 1975 4th St C1758L, San Francisco, CA, 94158, USA.

Purposes: To assess the ability of a single isotropic 3D T2 FSE sequence to identify the normal appendix in children with potential implication as alternative second-line modality in pediatric appendicitis.

Materials And Methods: Retrospective review of MR abdomino-pelvis or pelvis in children from Oct 2014-Dec 2016 was done. Only exams with 3D T2 FSE sequence performed on a single scanner type were selected. Patients with history of post appendectomy, studies in which field of view did not include ileocecal valve, with technical and protocol errors, or with fat-saturated acquisition were excluded. All images were blindly reviewed by three radiologists. The following questions were asked: (1) Is the appendix visualized?, (2) What is the most clearly demonstrable plane?, (3) Where is the appendix located?, (4) Are there any findings indicating appendicitis? Average pairwise percentage and Fleiss Kappa were used to assess the inter-rater agreement on the visualization and location of the appendix.

Results: A total of 22 MRI studies were reviewed (F = 13:M = 9, Mean age = 11.45 yrs. [SD = 4.3]). Total MRI scan time was estimated at 6 mins. Readers saw appendix in 72.7-81.8%, and saw with high confidence in 12 cases (54.5%), low confidence in 4-6 case (18.2-27.3%), and did not see in 4-6 cases(18.2-27.3%). The average pairwise percentage agreement was 71.2%. Fleiss Kappa of overall rating of visualization was 0.52 (p < 0.001). Fleiss Kappa of high confidence of visualization was 0.76 (p < 0.001). Reader 1 and reader 2 saw the appendix best on the axial plane. Reader 3 saw the appendix best on the coronal plane. For location, deep pelvis was the most common identified location. The average pairwise percentage agreement was 68.2% and Fleiss Kappa was 0.76 (p < 0.001). There is no findings indicating appendicitis.

Conclusion: A single 3D T2 FSE sequence had good ability to detect normal appendices and also allowed multiplanar reconstructions, which may use as a single-sequence protocol in cases of suspected appendicitis in children when ultrasound is inconclusive.
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http://dx.doi.org/10.1007/s10140-017-1538-yDOI Listing
December 2017

Musculoskeletal Traumatic Injuries in Children: Characteristic Imaging Findings and Mimickers.

Radiol Clin North Am 2017 Jul 27;55(4):785-802. Epub 2017 Mar 27.

Division of Thoracic Imaging, Department of Radiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Musculoskeletal traumatic injuries in children demonstrate characteristic imaging findings. The physis is the most susceptible structure to traumatic injury. The periosteum in children plays a key role in rapid bone healing and stability. The main complications of fractures in children are premature physeal closure, potential limb length discrepancy, and angular deformities. Understanding the normal bone growth, healing, and complications of pediatric fractures is crucial for appropriate imaging diagnosis. This article discusses currently available imaging modalities with up-to-date techniques, underlying mechanisms, and characteristic imaging findings of musculoskeletal traumatic injuries and mimickers encountered in daily clinical practice.
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http://dx.doi.org/10.1016/j.rcl.2017.02.011DOI Listing
July 2017

Thoracic Neoplasms in Children: Contemporary Perspectives and Imaging Assessment.

Radiol Clin North Am 2017 Jul 19;55(4):657-676. Epub 2017 Apr 19.

Department of Radiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

This article focuses on commonly encountered primary lung, airway, mediastinal, and chest wall neoplasms that occur in the pediatric population. Although primary pediatric thoracic neoplasms are rare, imaging is critical in their diagnostic work-up. An overview of the latest imaging techniques specific to evaluate these pediatric thoracic neoplasms is presented across the spectrum of modalities from radiography to PET/MR imaging. In addition, the characteristic imaging appearances of these pediatric primary thoracic neoplasms are discussed with an emphasis on what the radiologist needs to know in routine clinical practice.
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http://dx.doi.org/10.1016/j.rcl.2017.02.008DOI Listing
July 2017

Incidental Findings on Pediatric Abdominal Magnetic Resonance Angiography.

Acad Radiol 2017 09 9;24(9):1107-1113. Epub 2017 Mar 9.

Department of Radiology and Biomedical Imaging, UCSF Benioff Children's Hospital, 1975 4th St C1768L, San Francisco, California, 94158, United States.

Rationale And Objectives: Abdominal magnetic resonance angiography (MRA) has gained favor in pediatric patients owing to its lack of ionizing radiation and noninvasive nature. Reports exist regarding incidental findings on body MRA in adult patients. However, the incidental findings in pediatric abdominal MRA have not been previously reported. Our study aims to determine the frequencies, characteristics, and categories of incidental findings in pediatric patients undergoing abdominal MRA.

Materials And Methods: Retrospective study was performed in 78 consecutive contrast-enhanced abdominal MRA of patients between ages 0 and 20 years over a 7-year time period. The presence of incidental vascular and extravascular findings was noted. Reports were categorized in consensus by two radiologists as no incidental finding (group A), normal or normal variants or nonsignificant incidental common findings (group B), or abnormal incidental findings (group C). Group C was reviewed to determine whether additional management was performed.

Results: A total of 40 boys and 38 girls (51%:49%) were reported, with a mean age of 12.3 years (standard deviation ±5.6 years, range 7 days to 20 years). Three most common indications for MRA were renal artery stenosis (24.4%), vasculitis (21.8%), and suspected intra-abdominal venous thrombosis (14.1%). We identified a total of 92 incidental findings in 50 of 78 patients; 60 findings in 29 patients in group B, and 32 findings in 21 patients in group C. Atelectasis at the lung bases was the most common incidental finding in group B (14 of 78 patients). The most common findings in group C were ascites, scoliosis, and splenomegaly. There were three abnormal incidental findings that led to causative workup and/or further management (moderate ascites, pericardial and pleural effusion, and venous malformation). The remaining cases with abnormal findings received treatment of their primary conditions only.

Conclusions: Pediatric abdominal MRA revealed a large number of incidental findings. The large majority were findings without clinical significance. Basal lung atelectasis was the most common overall incidental and nonsignificant finding, whereas ascites was the most common abnormal incidental finding. Although not all abnormal incidental findings affected management, appropriate identification and communication of relevant findings would improve patient care.
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http://dx.doi.org/10.1016/j.acra.2017.01.019DOI Listing
September 2017

Comparison of Mechanical Versus Hand Administration of IV Contrast Agents for Pediatric Pulmonary CT Angiography.

AJR Am J Roentgenol 2017 Mar 11;208(3):632-636. Epub 2017 Jan 11.

1 Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA.

Objective: The purpose of this study was to assess the difference between mechanical versus hand administration of IV contrast agents on the diagnostic quality of pediatric pulmonary CT angiography (CTA).

Materials And Methods: A retrospective review of the medical records was performed to detect pediatric patients (≤ 18 years) with pulmonary CTA performed between September 2012 and March 2015. Patients were placed into two cohorts on the basis of the method of contrast administration (mechanical vs hand). Additional information obtained included IV size or gauge, IV site, amount and type of contrast agent administered, and rate of administration (mL/s). The quality of the CT images was independently evaluated by two pediatric radiologists using a qualitative 4-point visual assessment scale and quantitatively with attenuation (HU). An ANOVA controlling for age compared the contrast enhancement in the central pulmonary arteries between the cohorts.

Results: One hundred forty-eight consecutive pediatric patients (71 boys and 77 girls; mean age, 11.1 years; age range, 8 days-17.9 years) were identified between September 2012 and March 2015. Mechanical administration of contrast material was performed in 117 patients (79.1%; mean age [± SD], 13.7 ± 3.7 years), and hand administration of contrast material was performed in 31 patients (20.9%; mean age, 1.6 ± 1.8 years). After adjusting for age, the degree of enhancement within the pulmonary arteries was not statistically different between the two IV contrast administration methods at the main pulmonary artery (mechanical vs hand administration: mean attenuation, 310 ± 128 vs 338 ± 142 HU, respectively, p = 0.505), right pulmonary artery (305 ± 124 vs 329 ± 146 HU, p = 0.556), and left pulmonary artery (303 ± 125 vs 340 ± 151 HU, p = 0.349).

Conclusion: It is possible to perform diagnostic-quality pulmonary CTA for the assessment of the central pulmonary arteries with hand administration of IV contrast material in pediatric patients with small-gauge IV catheters.
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http://dx.doi.org/10.2214/AJR.16.16768DOI Listing
March 2017

Magnetic resonance imaging of Müllerian duct anomalies in children.

Pediatr Radiol 2016 May 26;46(6):796-805. Epub 2016 May 26.

Department of Radiology and Biomedical Imaging, University of California San Francisco, 505 Parnassus Ave., M-391, San Francisco, CA, USA.

Müllerian duct anomalies encompass a wide variety of disorders resulting from abnormalities in the embryological development of the Müllerian ducts. In the prepubertal pediatric population, Müllerian duct anomalies are often incidental findings on studies obtained for other reasons. The onset of menses can prompt more clinical symptoms. Proper characterization of Müllerian duct anomalies is important because these anomalies can affect the development of gynecological disorders as well as fertility. Müllerian duct anomalies also carry a high association with other congenital anomalies, particularly renal abnormalities. MRI is widely considered the best modality for assessing Müllerian duct anomalies; it provides multiplanar capability, clear anatomical detail and tissue characterization without ionizing radiation. MRI allows for careful description of Müllerian duct anomalies, often leading to classification into the most widely accepted classification system for Müllerian duct anomalies. This system, developed by the American Society of Reproductive Medicine, includes seven subtypes: uterine agenesis/hypoplasia, unicornuate, didelphys, bicornuate, septate, arcuate, and diethylstilbestrol (DES) drug-related uterus. In cases of complex anomalies that defy classification, MRI allows detailed depiction of all components of the anatomical abnormality, allowing for proper management and surgical planning.
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http://dx.doi.org/10.1007/s00247-016-3583-1DOI Listing
May 2016

Growth recovery lines are more common in infants at high vs. low risk for abuse.

Pediatr Radiol 2016 Aug 5;46(9):1275-81. Epub 2016 May 5.

Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Growth recovery lines, also known as growth arrest lines, are transverse radiodense metaphyseal bands that develop due to a temporary arrest of endochondral ossification caused by local or systemic insults.

Objective: To determine if growth recovery lines are more common in infants at high risk versus low risk for abuse.

Materials And Methods: Reports of American College of Radiology compliant skeletal surveys (1999-2013) were reviewed with clinical records. Infants at low risk for abuse had a skull fracture without significant intracranial injury, history of a fall and clinical determination of low risk (child protection team/social work assessment). Infants at high risk had significant intracranial injury, retinal hemorrhages, other skeletal injuries and clinical determination of high risk. There were 52 low-risk infants (mean: 4.7 months, range: 0.4-12 months) and 21 high-risk infants (mean: 4.2 months, range: 0.8-9.1 months). Two blinded radiologists independently evaluated the skeletal survey radiographs of the knees/lower legs for the presence of at least one growth recovery line.

Results: When growth recovery lines are scored as probably present or definitely present, their prevalence in the low-risk group was 38% (standard deviation [SD] = 8%; reader 1 = 17/52, reader 2 = 23/52) vs. 71% (SD = 7%; reader 1 = 16/21, reader 2 = 14/21) in the high-risk group (P < 0.001; odds ratio 4.0, 95% CI: 1.7-9.5).

Conclusion: Growth recovery lines are encountered at a significantly higher rate in infants at high risk vs. low risk for abuse. This suggests that abused infants are prone to a temporary disturbance in endochondral ossification as a result of episodic physiological stresses.
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http://dx.doi.org/10.1007/s00247-016-3621-zDOI Listing
August 2016

The radiogenomic risk score stratifies outcomes in a renal cell cancer phase 2 clinical trial.

Eur Radiol 2016 Aug 11;26(8):2798-807. Epub 2015 Nov 11.

Department of Radiological Sciences, University of California-Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.

Objectives: To characterize a radiogenomic risk score (RRS), a previously defined biomarker, and to evaluate its potential for stratifying radiological progression-free survival (rPFS) in patients with metastatic renal cell carcinoma (mRCC) undergoing pre-surgical treatment with bevacizumab.

Methodology: In this IRB-approved study, prospective imaging analysis of the RRS was performed on phase II clinical trial data of mRCC patients (n = 41) evaluating whether patient stratification according to the RRS resulted in groups more or less likely to have a rPFS to pre-surgical bevacizumab prior to cytoreductive nephrectomy. Survival times of RRS subgroups were analyzed using Kaplan-Meier survival analysis.

Results: The RRS is enriched in diverse molecular processes including drug response, stress response, protein kinase regulation, and signal transduction pathways (P < 0.05). The RRS successfully stratified rPFS to bevacizumab based on pre-treatment computed tomography imaging with a median progression-free survival of 6 versus >25 months (P = 0.005) and overall survival of 25 versus >37 months in the high and low RRS groups (P = 0.03), respectively. Conventional prognostic predictors including the Motzer and Heng criteria were not predictive in this cohort (P > 0.05).

Conclusions: The RRS stratifies rPFS to bevacizumab in patients from a phase II clinical trial with mRCC undergoing cytoreductive nephrectomy and pre-surgical bevacizumab.

Key Points: • The RRS SOMA stratifies patient outcomes in a phase II clinical trial. • RRS stratifies subjects into prognostic groups in a discrete or continuous fashion. • RRS is biologically enriched in diverse processes including drug response programs.
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http://dx.doi.org/10.1007/s00330-015-4082-8DOI Listing
August 2016

The Radiogenomic Risk Score: Construction of a Prognostic Quantitative, Noninvasive Image-based Molecular Assay for Renal Cell Carcinoma.

Radiology 2015 Oct 19;277(1):114-23. Epub 2015 Aug 19.

From the Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Box 951721, CHS 17-135, 10833 LeConte Ave, Los Angeles, CA 90095-1721 (N.J., M.Z., S.B., M.D.K.); Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Tex (E.J.); Department of Radiology, Hospital of Veterans Affairs, University of California-San Diego, San Diego, Calif (M.Z., L.A.); Scottsdale Medical Imaging, Scottsdale, Ariz (R.K.); Department of Urology, Stanford University School of Medicine, Stanford, Calif (H.Z., J.D.B.); Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea Hospital, Umea, Sweden (R.T.S., B.L.); and Department of Statistics, Stanford University, Stanford, Calif (R.J.T.).

Purpose: To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image.

Materials And Methods: In this institutional review board approved study, gene expression profile data and contrast material-enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression-based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis.

Results: Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57, P < .001, classification accuracy 70.1%, P < .001) and predicted disease-specific survival (log rank P < .001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P < .001, classification accuracy 68.6%, P < .001) and disease-specific survival (log-rank P < .001) and that it was independent of stage, grade, and performance status (multivariate Cox model P < .05, log-rank P < .001).

Conclusion: A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible.
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http://dx.doi.org/10.1148/radiol.2015150800DOI Listing
October 2015

Statistical properties of multivariate distance matrix regression for high-dimensional data analysis.

Front Genet 2012 27;3:190. Epub 2012 Sep 27.

Department of Radiology, University of California at San Diego La Jolla, CA, USA.

Multivariate distance matrix regression (MDMR) analysis is a statistical technique that allows researchers to relate P variables to an additional M factors collected on N individuals, where P ≫ N. The technique can be applied to a number of research settings involving high-dimensional data types such as DNA sequence data, gene expression microarray data, and imaging data. MDMR analysis involves computing the distance between all pairs of individuals with respect to P variables of interest and constructing an N × N matrix whose elements reflect these distances. Permutation tests can be used to test linear hypotheses that consider whether or not the M additional factors collected on the individuals can explain variation in the observed distances between and among the N individuals as reflected in the matrix. Despite its appeal and utility, properties of the statistics used in MDMR analysis have not been explored in detail. In this paper we consider the level accuracy and power of MDMR analysis assuming different distance measures and analysis settings. We also describe the utility of MDMR analysis in assessing hypotheses about the appropriate number of clusters arising from a cluster analysis.
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http://dx.doi.org/10.3389/fgene.2012.00190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461701PMC
October 2012

Identification of polymorphisms associated with hypertriglyceridemia and prolonged survival induced by bexarotene in treating non-small cell lung cancer.

Anticancer Res 2011 Jun;31(6):2303-11

Ligand Pharmaceuticals, 5003 Ruette De Mer, San Diego, CA 92130, USA.

Background: Bexarotene was evaluated in treating advanced non small cell lung cancer (NSCLC) in two phase III trials. Although a significant survival benefit was not observed for the overall bexarotene-treated population (617 patients), a third of bexarotene-treated patients who developed high-grade hypertriglyceridemia exhibited significantly longer survival.

Patients And Methods: In order to identify genomic polymorphisms that could serve as potential predictive biomarkers for response and improved survival in NSCLC patients, DNA samples extracted from plasma archived from 403 patients were genotyped using Affymetrix 500K whole genome SNP arrays and/or Sequenom iPLEX™ assays.

Results: Fourteen SNPs were identified on nine loci that showed significant associations with high-grade hypertriglyceridemia induced by bexarotene. Four such single nucleotide polymorphisms (SNPs) reside on the region upstream of solute carrier family 10, member 2 (SLC10A2), and one SNP is located close to lymphocyte cytosolic protein 1 (LCP1), whose expression correlated with the activity of bexarotene in tumor cells.

Conclusion: We identified novel polymorphisms exhibiting significant association with bexarotene induced hypertriglyceridemia, implicating their potential in predicting bexarotene-improved survival response.
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June 2011

In silico QTL mapping of basal liver iron levels in inbred mouse strains.

Physiol Genomics 2011 Feb 9;43(3):136-47. Epub 2010 Nov 9.

Department of Nutritional Science and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA.

Both iron deficiency and iron excess are detrimental in many organisms, and previous studies in both mice and humans suggest that genetic variation may influence iron status in mammals. However, these genetic factors are not well defined. To address this issue, we measured basal liver iron levels in 18 inbred strains of mice of both sexes on a defined iron diet and found ∼4-fold variation in liver iron in males (lowest 153 μg/g, highest 661 μg/g) and ∼3-fold variation in females (lowest 222 μg/g, highest 658 μg/g). We carried out a genome-wide association mapping to identify haplotypes underlying differences in liver iron and three other related traits (copper and zinc liver levels, and plasma diferric transferrin levels) in a subset of 14 inbred strains for which genotype information was available. We identified two putative quantitative trait loci (QTL) that contain genes with a known role in iron metabolism: Eif2ak1 and Igf2r. We also identified four putative QTL that reside in previously identified iron-related QTL and 22 novel putative QTL. The most promising putative QTL include a 0.22 Mb region on Chromosome 7 and a 0.32 Mb region on Chromosome 11 that both contain only one candidate gene, Adam12 and Gria1, respectively. Identified putative QTL are good candidates for further refinement and subsequent functional studies.
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http://dx.doi.org/10.1152/physiolgenomics.00025.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055709PMC
February 2011

The effects of globin on microarray-based gene expression analysis of mouse blood.

Mamm Genome 2010 Jun 16;21(5-6):268-75. Epub 2010 May 16.

Graduate Program in Biomedical Sciences, Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.

The use of mouse blood as a model for human blood is often considered in the development of clinically relevant, gene expression-based disease biomarkers. However, the ability to derive biologically meaningful insights from microarray-based gene expression patterns in mouse whole blood, as in human whole blood, is hindered by high levels of globin mRNA. In order to characterize the effects of globin reduction on gene expression of peripheral mouse blood, we performed gene set enrichment analysis on genes identified as expressed in blood via microarray-based genome-wide transcriptome analysis. Depletion of globin mRNA enhanced the quality of microarray data as shown by improved gene expression detection and increased sensitivity. Compared to genes expressed in whole blood, genes detected as expressed in blood following globin reduction were enriched for low abundance transcripts implicated in many biological pathways, including development, g-protein signaling, and immune response. Broadly, globin reduction resulted in improved detection of expressed genes that serve as molecular binding proteins and enzymes in cellular metabolism, intracellular transport/localization, transcription, and translation, as well as genes that potentially could act as biomarkers for diseases such as schizophrenia. These significantly enriched pathways overlap considerably with those identified in globin-reduced human blood suggesting that globin-reduced mouse blood gene expression studies may be useful for identifying genes relevant to human disease. Overall, the results of this investigation provide a better understanding of the impact of reducing globin transcripts in mouse blood and highlight the potential of microarray-based, globin-reduced, mouse blood gene expression studies in biomarker development.
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http://dx.doi.org/10.1007/s00335-010-9261-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890980PMC
June 2010

Gene expression in mouse brain following chronic hypoxia: role of sarcospan in glial cell death.

Physiol Genomics 2008 Feb 4;32(3):370-9. Epub 2007 Dec 4.

Department of Pediatrics (Section of Respiratory Medicine) and Neuroscience, University of California San Diego, La Jolla, CA 92093-0735, USA.

Hypoxia is a hallmark of respiratory, neurological, or hematological diseases as well as life at high altitude. For example, chronic constant hypoxia (CCH) occurs in chronic lung diseases or at high altitude, whereas chronic intermittent hypoxia (CIH) occurs in diseases such as sleep apnea or sickle cell disease. Despite the fact that such conditions are frequent, the cellular and molecular mechanisms underlying the effect of hypoxia, whether constant or intermittent, are not well understood. In this study, we first determined the effect of CCH and CIH on global gene expression in different regions of mouse brain using microarrays and then investigated the biological role of genes of interest. We found that: 1) in the cortical region, the expression level of 80 genes was significantly altered by CIH (16 up- and 64 downregulated), and this number increased to 137 genes following CCH (34 up- and 103 downregulated); 2) a similar number of gene alterations was identified in the hippocampal area, and the majority of the changes in this region were upregulations; 3) two genes (Sspn and Ttc27) were downregulated in both brain regions and following both treatments; and 4) RNA interference-mediated knockdown of Sspn increased cell death in hypoxia in a cell culture system. We conclude that CIH or CCH induced significant and distinguishable alterations in gene expression in cortex and hippocampus and that Sspn seems to play a critical role in inducing cell death under hypoxic conditions.
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http://dx.doi.org/10.1152/physiolgenomics.00147.2007DOI Listing
February 2008

Detecting genetic variation in microarray expression data.

Genome Res 2007 Aug 3;17(8):1228-35. Epub 2007 Jul 3.

The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

The use of high-density oligonucleotide arrays to measure the expression levels of thousands of genes in parallel has become commonplace. To take further advantage of the growing body of data, we developed a method, termed "GeSNP," to mine the detailed hybridization patterns in oligonucleotide array expression data for evidence of genetic variation. To demonstrate the performance of the algorithm, the hybridization patterns in data obtained previously from SAMP8/Ta, SAMP10/Ta, and SAMR1/Ta inbred mice and from humans and chimpanzees were analyzed. Genes with consistent strain-specific and species-specific hybridization pattern differences were identified, and approximately 90% of the candidate genes were independently confirmed to harbor sequence differences. Importantly, the quality of gene expression data was also improved by masking the probes of regions with putative sequence differences between species and strains. To illustrate the application to human disease groups, data from an inflammatory bowel disease study were analyzed. GeSNP identified sequence differences in candidate genes previously discovered in independent association and linkage studies and uncovered many promising new candidates. This approach enables the opportunistic extraction of genetic variation information from new or pre-existing gene expression data obtained with high-density oligonucleotide arrays.
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http://dx.doi.org/10.1101/gr.6307307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933513PMC
August 2007

Accommodating pathway information in expression quantitative trait locus analysis.

Genomics 2007 Jul 9;90(1):132-42. Epub 2007 May 9.

Polymorphism Research Laboratory, Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USA.

The availability of high-throughput genotyping technologies and microarray assays has allowed researchers to consider pursuing investigations whose ultimate goal is the identification of genetic variations that influence levels of gene expression, e.g., "expression quantitative trait locus" or "eQTL" mapping studies. However, the large number of genes whose expression levels can be tested for association with genetic variations in such studies can create both statistical and biological interpretive problems. We consider the integrated analysis of eQTL mapping data that incorporates pathway, function, and disease process information. The goal of this analysis is to determine if compelling patterns emerge from the data that are consistent with the notion that perturbations in the molecular physiologic environment induced by genetic variations implicate the expression patterns of multiple genes via genetic network relationships or feedback mechanisms. We apply available genetic network and pathway analysis software, as well as a novel regression analysis technique, to carry out the proposed studies. We also consider extensions of the proposed strategies and areas of future research.
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http://dx.doi.org/10.1016/j.ygeno.2007.03.003DOI Listing
July 2007

DNA variation and brain region-specific expression profiles exhibit different relationships between inbred mouse strains: implications for eQTL mapping studies.

Genome Biol 2007 ;8(2):R25

The Salk Institute for Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Background: Expression quantitative trait locus (eQTL) mapping is used to find loci that are responsible for the transcriptional activity of a particular gene. In recent eQTL studies, expression profiles were derived from either homogenized whole brain or collections of large brain regions. However, the brain is a very heterogeneous organ, and expression profiles of different brain regions vary significantly. Because of the importance and potential power of eQTL studies in identifying regulatory networks, we analyzed gene expression patterns in different brain regions from multiple inbred mouse strains and investigated the implications for the design and analysis of eQTL studies.

Results: Gene expression profiles of five brain regions in six inbred mouse strains were studied. Few genes exhibited a significant strain-specific expression pattern, whereas a large number of genes exhibited brain region-specific patterns. We constructed phylogenetic trees based on the expression relationships between the strains and compared them with a DNA-level relationship tree. The trees based on the expression of strain-specific genes were constant across brain regions and mirrored DNA-level variation. However, the trees based on region-specific genes exhibited a different set of strain relationships, depending on the brain region. An eQTL analysis showed enrichment of cis-acting regulators among strain-specific genes, whereas brain region-specific genes appear to be mainly regulated by trans-acting elements.

Conclusion: Our results suggest that many regulatory networks are highly brain region specific and indicate the importance of conducting eQTL mapping studies using data from brain regions or tissues that are physiologically and phenotypically relevant to the trait of interest.
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http://dx.doi.org/10.1186/gb-2007-8-2-r25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852412PMC
July 2007

Multivariate regression analysis of distance matrices for testing associations between gene expression patterns and related variables.

Proc Natl Acad Sci U S A 2006 Dec 4;103(51):19430-5. Epub 2006 Dec 4.

Biomedical Sciences Graduate Program and the Polymorphism Research Laboratory, Department of Psychiatry, Moores UCSD Cancer Center, Center for Human Genetics and Genomics, University of California at San Diego, La Jolla, CA 92093, USA.

A fundamental step in the analysis of gene expression and other high-dimensional genomic data is the calculation of the similarity or distance between pairs of individual samples in a study. If one has collected N total samples and assayed the expression level of G genes on those samples, then an N x N similarity matrix can be formed that reflects the correlation or similarity of the samples with respect to the expression values over the G genes. This matrix can then be examined for patterns via standard data reduction and cluster analysis techniques. We consider an alternative to conventional data reduction and cluster analyses of similarity matrices that is rooted in traditional linear models. This analysis method allows predictor variables collected on the samples to be related to variation in the pairwise similarity/distance values reflected in the matrix. The proposed multivariate method avoids the need for reducing the dimensions of a similarity matrix, can be used to assess relationships between the genes used to construct the matrix and additional information collected on the samples under study, and can be used to analyze individual genes or groups of genes identified in different ways. The technique can be used with any high-dimensional assay or data type and is ideally suited for testing subsets of genes defined by their participation in a biochemical pathway or other a priori grouping. We showcase the methodology using three published gene expression data sets.
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http://dx.doi.org/10.1073/pnas.0609333103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1748243PMC
December 2006

Adult mouse brain gene expression patterns bear an embryologic imprint.

Proc Natl Acad Sci U S A 2005 Jul 7;102(29):10357-62. Epub 2005 Jul 7.

Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

The current model to explain the organization of the mammalian nervous system is based on studies of anatomy, embryology, and evolution. To further investigate the molecular organization of the adult mammalian brain, we have built a gene expression-based brain map. We measured gene expression patterns for 24 neural tissues covering the mouse central nervous system and found, surprisingly, that the adult brain bears a transcriptional "imprint" consistent with both embryological origins and classic evolutionary relationships. Embryonic cellular position along the anterior-posterior axis of the neural tube was shown to be closely associated with, and possibly a determinant of, the gene expression patterns in adult structures. We also observed a significant number of embryonic patterning and homeobox genes with region-specific expression in the adult nervous system. The relationships between global expression patterns for different anatomical regions and the nature of the observed region-specific genes suggest that the adult brain retains a degree of overall gene expression established during embryogenesis that is important for regional specificity and the functional relationships between regions in the adult. The complete collection of extensively annotated gene expression data along with data mining and visualization tools have been made available on a publicly accessible web site (www.barlow-lockhart-brainmapnimhgrant.org).
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http://dx.doi.org/10.1073/pnas.0503357102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1173363PMC
July 2005

Elevated gene expression levels distinguish human from non-human primate brains.

Proc Natl Acad Sci U S A 2003 Oct 13;100(22):13030-5. Epub 2003 Oct 13.

Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Little is known about how the human brain differs from that of our closest relatives. To investigate the genetic basis of human specializations in brain organization and cognition, we compared gene expression profiles for the cerebral cortex of humans, chimpanzees, and rhesus macaques by using several independent techniques. We identified 169 genes that exhibited expression differences between human and chimpanzee cortex, and 91 were ascribed to the human lineage by using macaques as an outgroup. Surprisingly, most differences between the brains of humans and non-human primates involved up-regulation, with approximately 90% of the genes being more highly expressed in humans. By contrast, in the comparison of human and chimpanzee heart and liver, the numbers of up- and down-regulated genes were nearly identical. Our results indicate that the human brain displays a distinctive pattern of gene expression relative to non-human primates, with higher expression levels for many genes belonging to a wide variety of functional classes. The increased expression of these genes could provide the basis for extensive modifications of cerebral physiology and function in humans and suggests that the human brain is characterized by elevated levels of neuronal activity.
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http://dx.doi.org/10.1073/pnas.2135499100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC240739PMC
October 2003

Software and methods for oligonucleotide and cDNA array data analysis.

Genome Biol 2002 23;3(6):SOFTWARE0001. Epub 2002 May 23.

The Salk Institute for Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Two HTML-based programs were developed to analyze and filter gene-expression data: 'Bullfrog' for Affymetrix oligonucleotide arrays and 'Spot' for custom cDNA arrays. The programs provide intuitive data-filtering tools through an easy-to-use interface. A background subtraction and normalization program for cDNA arrays was also built that provides an informative summary report with data-quality assessments. These programs are freeware to aid in the analysis of gene-expression results and facilitate the search for genes responsible for interesting biological processes and phenotypes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC139376PMC
http://dx.doi.org/10.1186/gb-2002-3-6-software0001DOI Listing
August 2002