Publications by authors named "Chris Allan"

28 Publications

  • Page 1 of 1

Comparison of machine learning models to classify Auditory Brainstem Responses recorded from children with Auditory Processing Disorder.

Comput Methods Programs Biomed 2021 Mar 17;200:105942. Epub 2021 Jan 17.

Department of Electrical & Computer Engineering, Western University, London, Ontario, Canada; National Centre for Audiology, Western University, London, Ontario, Canada; School of Biomedical Engineering, Western University, London, Ontario, Canada; Department of Medical Biophysics, Western University, London, Ontario, Canada; Department of Otolaryngology - Head and Neck Surgery, Western University, London, Ontario, Canada.

Introduction: Auditory brainstem responses (ABRs) offer a unique opportunity to assess the neural integrity of the peripheral auditory nervous system in individuals presenting with listening difficulties. ABRs are typically recorded and analyzed by an audiologist who manually measures the timing and quality of the waveforms. The interpretation of ABRs requires considerable experience and training, and inappropriate interpretation can lead to incorrect judgments about the integrity of the system. Machine learning (ML) techniques may be a suitable approach to automate ABR interpretation and reduce human error.

Objectives: The main objective of this paper was to identify a suitable ML technique to automate the analysis of ABR responses recorded as a part of the electrophysiological testing in the Auditory Processing Disorder clinical test battery.

Methods: ABR responses recorded during routine clinical assessment from 136 children being evaluated for auditory processing difficulties were analyzed using several common ML algorithms: Support Vector Machines (SVM), Random Forests (RF), Decision Trees (DT), Gradient Boosting (GB), Extreme Gradient Boosting (Xgboost), and Neural Networks (NN). A variety of signal feature extraction techniques were used to extract features from the ABR waveforms as inputs to the ML algorithms. Statistical significance testing and confusion matrices were used to identify the most robust model capable of accurately identifying neurological abnormalities present in ABRs.

Results: Clinically significant features in the time-frequency representation of the signal were identified. The ML model trained using the Xgboost algorithm was identified as the most robust model with an accuracy of 92% compared to other models.

Conclusion: The findings of the present study demonstrate that it is possible to develop accurate ML models to automate the process of analyzing ABR waveforms recorded at suprathreshold levels. There is currently no ML-based application to screen children with listening difficulties. Therefore, it is expected that this work will be translated into an evaluation tool that can be used by audiologists in the clinic. Furthermore, this work may aid future researchers in exploring ML paradigms to improve clinical test batteries used by audiologists in achieving accurate diagnoses.
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http://dx.doi.org/10.1016/j.cmpb.2021.105942DOI Listing
March 2021

Safety Standards in Pharmaceutical Compounding, Part 2: A Closer Look at Agency Information, Oversight, and Assistance.

Int J Pharm Compd 2020 Sep-Oct;24(5):371-379

Occupational and Environmental Safety Office, Fire and Life Safety Division, Duke University and Health System, Durham, North Carolina.

In the U.S., compounding pharmacies are regulated primarily by state boards of pharmacy, which often collaborate with federal agencies such as the Drug Enforcement Administration or the Department of Health and Human Services. Other organizations, such as the U.S. Food and Drug Administration, the Occupat ional Safety and Health Administration, the Environmental Protection Agency, and state departments of agriculture or labor may also have jurisdiction over compounding pharmacies and their employees. In addition, compounding pharmacies are subject to the requirements of Section 503A of the Federal Food, Drug, and Cosmetic Act. Complying with requirements for training and competency and documenting adherence to various agency regulations may seem daunting, but guidance in doing so is available from independent organizations such as the United States Pharmacopeial Convention, Inc., and the Pharmacy Compounding Accreditation Board. In this second article in a series on safety standards in pharmaceutical compounding, we discuss the roles of several of those influential federal organizations and the benefits that guidance from independent agencies provides for compounding pharmacists. Questions of interest to pharmacists who seek to comply with established agency safety standards are also answered.
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October 2020

Safety Standards in Pharmaceutical Compounding, Part 1: The Occupational Safety and Health Administration.

Int J Pharm Compd 2020 Jul-Aug;24(4):270-276

Occupational and Environmental Safety Office, Fire and Life Safety Division, Duke University and Health System, Durham, North Carolina.

Ensuring a safe working environment for employees is of paramount importance to all responsible compounding pharmacists, and adhering to safety standards established by the U.S. Occupational Safety and Health Administration renders achieving that goal more likely. However, information about such compliance (especially with respect to pharmaceutical compounding) may not be readily available. In this first article in a 3-part series, an overview of Occupational Safety and Health Administration standards that address employee safety in the workplace is provided and pertinent questions of interest to compounders are answered. In series parts 2 and 3, ensuring compliance with those standards is discussed in more detail and issues pertaining specifically to fire prevention in compounding facilities are addressed.
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July 2020

Perceptual and Objective Assessment of Envelope Enhancement for Children With Auditory Processing Disorder.

IEEE Trans Neural Syst Rehabil Eng 2020 01 3;28(1):143-151. Epub 2019 Dec 3.

This paper evaluated the performance of an envelope enhancement (EE) algorithm subjectively by children with auditory processing disorder (APD), and objectively through computational models. Speech intelligibility data was collected from children with APD, for unprocessed and envelope-enhanced speech in the presence of stationary and non-stationary background noise at different signal to noise ratios (SNRs), both with and without noise reduction (NR) algorithms as a front-end to the EE algorithm. Furthermore, intrusive and non-intrusive objective speech intelligibility metrics were derived to predict the perceptual impact of this EE algorithm. Subjective data for stationary noise conditions revealed that the combination of NR and EE algorithms significantly improved the speech intelligibility scores at poor SNRs. In contrast, the same combination was ineffective in improving speech intelligibility in non-stationary noise conditions. Taken together, subjective results suggest that exaggerating the envelope cues improves speech identification scores for children with APD. However, the benefit obtained varies depending upon the type and level of the background noise. Both intrusive and non-intrusive objective speech intelligibility estimators exhibited good correlation with the subjective data, with the intrusive metric demonstrating better generalization capabilities. Implications of these results for hearing aid applications for children with APD is discussed.
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http://dx.doi.org/10.1109/TNSRE.2019.2957230DOI Listing
January 2020

Bringing Open Data to Whole Slide Imaging.

Digit Pathol (2019) 2019 Apr 3;2019:3-10. Epub 2019 Jul 3.

Dept of Computational Biology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.

Faced with the need to support a growing number of whole slide imaging (WSI) file formats, our team has extended a long-standing community file format (OME-TIFF) for use in digital pathology. The format makes use of the core TIFF specification to store multi-resolution (or "pyramidal") representations of a single slide in a flexible, performant manner. Here we describe the structure of this format, its performance characteristics, as well as an open-source library support for reading and writing pyramidal OME-TIFFs.
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http://dx.doi.org/10.1007/978-3-030-23937-4_1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774793PMC
April 2019

The Medial Olivocochlear Reflex Is Unlikely to Play a Role in Listening Difficulties in Children.

Trends Hear 2019 Jan-Dec;23:2331216519870942

School of Communication Sciences and Disorders, Western University, London, ON, Canada.

The medial olivocochlear reflex (MOCR) has been implicated in several auditory processes. The putative role of the MOCR in improving speech perception in noise is particularly relevant for children who complain of listening difficulties (LiD). The hypothesis that the MOCR may be impaired in individuals with LiD or auditory processing disorder has led to several investigations but without consensus. In two related studies, we compared the MOCR functioning of children with LiD and typically developing (TD) children in the same age range (7-17 years). In Study 1, we investigated ipsilateral, contralateral, and bilateral MOCR using forward-masked click-evoked otoacoustic emissions (CEOAEs;  = 17 TD, 17 LiD). In Study 2, we employed three OAE types: CEOAEs ( = 16 TD, 21 LiD), stimulus frequency OAEs ( = 21 TD, 30 LiD), and distortion product OAEs ( = 17 TD, 22 LiD) in a contralateral noise paradigm. Results from both studies suggest that the MOCR functioning is not significantly different between the two groups. Some likely reasons for differences in findings among published studies could stem from the lack of strict data quality measures (e.g., high signal-to-noise ratio, control for the middle ear muscle reflex) that were enforced in the present study. The inherent variability of the MOCR, the subpar reliability of current MOCR methods, and the heterogeneity in auditory processing deficits that underlie auditory processing disorder make detecting clinically relevant differences in MOCR function impractical using current methods.
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http://dx.doi.org/10.1177/2331216519870942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767729PMC
March 2020

Auditory Brainstem Responses in Children with Auditory Processing Disorder.

J Am Acad Audiol 2019 Nov/Dec;30(10):904-917. Epub 2019 Jun 24.

National Centre for Audiology, Western University, London, Canada.

Background: The ASHA recommends including electrophysiological measures in an auditory processing disorder (APD) assessment battery, but few audiologists do so, potentially because of limited published evidence for its utility.

Purpose: This study compared the auditory brainstem responses (ABRs) of children with APD with age-matched children and adults.

Study Sample: This study retrospectively examined the records of 108 children suspected of APD (sAPD) who had click-evoked ABRs recorded as part of their clinical assessment. Twenty adults and 22 typically developing (TD) children were recruited as controls.

Data Collection And Analysis: Click-evoked ABRs were recorded at slow (13.3 clicks/sec) and faster (57.7 clicks/sec) stimulation rates. ABRs were analyzed using typical clinical measures (latencies and interpeak intervals for waves I, III, and V) and using a model proposed by Ponton et al that offered a more detailed analysis of axonal conduction time and synaptic transmission delay.

Results: Both clinical measures and the Ponton model analysis showed no significant differences between TD children and adults. Children sAPD showed absolute latencies that were significantly prolonged when compared with adults but not when compared with TD children. But individual children sAPD showed clinically significant delays (>2 standard deviations of TD children's data). Examination of responses delineating axonal versus synaptic transmission showed significant delays in synaptic transmission in the group of children sAPD in comparison to TD children and adults. These results suggest that a significant portion of children with listening difficulties showed evidence of reduced or atypical brainstem functioning. Examining the responses for axonal and synaptic delays revealed evidence of a synaptic pattern of abnormalities in a significant portion (37.03%) of children sAPD. Such observations could provide objective evidence of factors potentially contributing to listening difficulties that are frequently reported in children identified with APD.

Conclusions: Children sAPD often showed abnormalities in the ABR, suggesting a neurophysiologic origin of their reported difficulties, frequently originating at or before the first synapse. This study provides supportive evidence for the value of click-evoked ABRs in comprehensive auditory processing assessment batteries.
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http://dx.doi.org/10.3766/jaaa.18046DOI Listing
October 2020

Spectral ripple discrimination in children with auditory processing disorder.

Int J Audiol 2019 11 14;58(11):733-737. Epub 2019 Jun 14.

National Centre for Audiology, Western University , London , Canada.

The purpose of this study was to examine developmental trends in spectral ripple discrimination (SRD) and to compare the performance of typically developing children to children with auditory processing disorder (APD). Cross-sectional study. Fifteen children with APD, as well as 17 typically developing children and 14 adults reporting no listening or academic difficulties participated. Typically developing children showed poor SRD thresholds compared to adults, indicating prolonged maturation of spectral shape recognition. Both typically developing children and APD children showed a maturational trend in SRD, but a General Linear Model fit to their thresholds showed that children with APD displayed SRD thresholds that were significantly poorer than those of typically developing children when controlling for age. This suggests that in APD children, SRD maturation lags behind typically developing children. Poor spectral ripple discrimination may explain some of the listening difficulties experienced by children with APD.
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http://dx.doi.org/10.1080/14992027.2019.1627007DOI Listing
November 2019

Auditory Localization and Spatial Release From Masking in Children With Suspected Auditory Processing Disorder.

Ear Hear 2019 Sep/Oct;40(5):1187-1196

School of Communication Sciences and Disorders, and the National Centre for Audiology, Western University, London, Ontario, Canada.

Objectives: We sought to investigate whether children referred to our audiology clinic with a complaint of listening difficulty, that is, suspected of auditory processing disorder (APD), have difficulties localizing sounds in noise and whether they have reduced benefit from spatial release from masking.

Design: Forty-seven typically hearing children in the age range of 7 to 17 years took part in the study. Twenty-one typically developing (TD) children served as controls, and the other 26 children, referred to our audiology clinic with listening problems, were the study group: suspected APD (sAPD). The ability to localize a speech target (the word "baseball") was measured in quiet, broadband noise, and speech-babble in a hemi-anechoic chamber. Participants stood at the center of a loudspeaker array that delivered the target in a diffused noise-field created by presenting independent noise from four loudspeakers spaced 90° apart starting at 45°. In the noise conditions, the signal-to-noise ratio was varied between -12 and 0 dB in 6-dB steps by keeping the noise level constant at 66 dB SPL and varying the target level. Localization ability was indexed by two metrics, one assessing variability in lateral plane [lateral scatter (Lscat)] and the other accuracy in the front/back dimension [front/back percent correct (FBpc)]. Spatial release from masking (SRM) was measured using a modified version of the Hearing in Noise Test (HINT). In this HINT paradigm, speech targets were always presented from the loudspeaker at 0°, and a single noise source was presented either at 0°, 90°, or 270° at 65 dB A. The SRM was calculated as the difference between the 50% correct HINT speech reception threshold obtained when both speech and noise were collocated at 0° and when the noise was presented at either 90° or 270°.

Results: As expected, in both groups, localization in noise improved as a function of signal-to-noise ratio. Broadband noise caused significantly larger disruption in FBpc than in Lscat when compared with speech babble. There were, however, no group effects or group interactions, suggesting that the children in the sAPD group did not differ significantly from TD children in either localization metric (Lscat and FBpc). While a significant SRM was observed in both groups, there were no group effects or group interactions. Collectively, the data suggest that children in the sAPD group did not differ significantly from the TD group for either binaural measure investigated in the study.

Conclusions: As is evident from a few poor performers, some children with listening difficulties may have difficulty in localizing sounds and may not benefit from spatial separation of speech and noise. However, the heterogeneity in APD and the variability in our data do not support the notion that localization is a global APD problem. Future studies that employ a case study design might provide more insights.
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http://dx.doi.org/10.1097/AUD.0000000000000703DOI Listing
March 2020

Europe's new device regulations fail to protect the public.

BMJ 2018 Oct 10;363:k4205. Epub 2018 Oct 10.

Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1136/bmj.k4205DOI Listing
October 2018

Online examiner calibration across specialties.

Clin Teach 2018 10 26;15(5):377-381. Epub 2017 Sep 26.

Discipline of Surgery, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

Background: Integrating undergraduate medical curricula horizontally across clinical medical specialties may be a more patient-centred and learner-centred approach than rotating students through specialty-specific teaching and assessment, but requires some interspecialty calibration of examiner judgements. Our aim was to evaluate the acceptability and feasibility of an online pilot of interdisciplinary examiner calibration. Fair clinical assessment is important to both medical students and clinical teachers METHODS: Clinical teachers were invited to rate video-recorded student objective structured clinical examination (OSCE) performances and join subsequent online discussions using the university's learning management system. Post-project survey free-text and Likert-scale participant responses were analysed to evaluate the acceptability of the pilot and to identify recommendations for improvement.

Results: Although 68 clinicians were recruited to participate, and there were 1599 hits on recordings and discussion threads, only 25 clinical teachers rated at least one student performance, and 18 posted at least one comment. Participants, including rural doctors, appeared to value the opportunity for interdisciplinary rating calibration and discussion. Although the asynchronous online format had advantages, especially for rural doctors, participants reported considerable IT challenges.

Discussion: Our findings suggest that fair clinical assessment is important to both medical students and clinical teachers. Interspecialty discussions about assessment may have the potential to enrich intraspecialty perspectives, enhance interspecialty engagement and collaboration, and improve the quality of clinical teacher assessment. Better alignment of university and hospital systems, a face to face component and other modifications may have enhanced clinician engagement with this project. Findings suggest that specialty assessment cultures and content expertise may not be barriers to pursuing more integrated approaches to assessment.
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http://dx.doi.org/10.1111/tct.12701DOI Listing
October 2018

Acoustic Reflexes in Normal-Hearing Adults, Typically Developing Children, and Children with Suspected Auditory Processing Disorder: Thresholds, Real-Ear Corrections, and the Role of Static Compliance on Estimates.

J Am Acad Audiol 2017 Jun;28(6):480-490

National Centre for Audiology, Western University, London, ON, Canada.

Background: Previous studies have suggested elevated reflex thresholds in children with auditory processing disorders (APDs). However, some aspects of the child's ear such as ear canal volume and static compliance of the middle ear could possibly affect the measurements of reflex thresholds and thus impact its interpretation. Sound levels used to elicit reflexes in a child's ear may be higher than predicted by calibration in a standard 2-cc coupler, and lower static compliance could make visualization of very small changes in impedance at threshold difficult. For this purpose, it is important to evaluate threshold data with consideration of differences between children and adults.

Purpose: A set of studies were conducted. The first compared reflex thresholds obtained using standard clinical procedures in children with suspected APD to that of typically developing children and adults to test the replicability of previous studies. The second study examined the impact of ear canal volume on estimates of reflex thresholds by applying real-ear corrections. Lastly, the relationship between static compliance and reflex threshold estimates was explored.

Research Design: The research is a set of case-control studies with a repeated measures design.

Study Sample: The first study included data from 20 normal-hearing adults, 28 typically developing children, and 66 children suspected of having an APD. The second study included 28 normal-hearing adults and 30 typically developing children.

Data Collection And Analysis: In the first study, crossed and uncrossed reflex thresholds were measured in 5-dB step size. Reflex thresholds were analyzed using repeated measures analysis of variance (RM-ANOVA). In the second study, uncrossed reflex thresholds, real-ear correction, ear canal volume, and static compliance were measured. Reflex thresholds were measured using a 1-dB step size. The effect of real-ear correction and static compliance on reflex threshold was examined using RM-ANOVA and Pearson correlation coefficient, respectively.

Results: Study 1 replicated previous studies showing elevated reflex thresholds in many children with suspected APD when compared to data from adults using standard clinical procedures, especially in the crossed condition. The thresholds measured in children with suspected APD tended to be higher than those measured in the typically developing children. There were no significant differences between the typically developing children and adults. However, when real-ear calibrated stimulus levels were used, it was found that children's thresholds were elicited at higher levels than in the adults. A significant relationship between reflex thresholds and static compliance was found in the adult data, showing a trend for higher thresholds in ears with lower static compliance, but no such relationship was found in the data from the children.

Conclusions: This study suggests that reflex measures in children should be adjusted for real-ear-to-coupler differences before interpretation. The data in children with suspected APD support previous studies suggesting abnormalities in reflex thresholds. The lack of correlation between threshold and static compliance estimates in children as was observed in the adults may suggest a nonmechanical explanation for age and clinically related effects.
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http://dx.doi.org/10.3766/jaaa.15136DOI Listing
June 2017

Localization-in-noise and binaural medial olivocochlear functioning in children and young adults.

J Acoust Soc Am 2016 Jan;139(1):247-62

National Centre for Audiology, Western University, London, Ontario N6G 1H1, Canada.

Children as young as 5 yr old localize sounds as accurately as adults in quiet in the frontal hemifield. However, children's ability to localize in noise and in the front/back (F/B) dimension are scantily studied. To address this, the first part of this study investigated localization-in-noise ability of children vs young adults in two maskers: broadband noise (BBN) and speech-babble (SB) at three signal-to-noise ratios: -12, -6, and 0 dB. In the second part, relationship between binaural medial olivocochlear system (MOC) function and localization-in-noise was investigated. In both studies, 21 children and 21 young adults participated. Results indicate, while children are able to differentiate sounds arriving in the F/B dimension on par with adults in quiet and in BBN, larger differences were found for SB. Accuracy of children's localization in noise (for both maskers) in the lateral plane was also poorer than adults'. Significant differences in binaural MOC interaction (mBIC; the difference between the sum of two monaural- and binaural-MOC strength) between adults and children were also found. For reasons which are not clear, adult F/B localization in BBN correlates better with mBIC while children's F/B localization in SB correlated better with binaural MOC strength.
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http://dx.doi.org/10.1121/1.4939708DOI Listing
January 2016

Metadata management for high content screening in OMERO.

Methods 2016 Mar 22;96:27-32. Epub 2015 Oct 22.

Centre for Gene Regulation & Expression, University of Dundee, Dundee, Scotland, UK; Glencoe Software, Inc., Seattle, WA, USA. Electronic address:

High content screening (HCS) experiments create a classic data management challenge-multiple, large sets of heterogeneous structured and unstructured data, that must be integrated and linked to produce a set of "final" results. These different data include images, reagents, protocols, analytic output, and phenotypes, all of which must be stored, linked and made accessible for users, scientists, collaborators and where appropriate the wider community. The OME Consortium has built several open source tools for managing, linking and sharing these different types of data. The OME Data Model is a metadata specification that supports the image data and metadata recorded in HCS experiments. Bio-Formats is a Java library that reads recorded image data and metadata and includes support for several HCS screening systems. OMERO is an enterprise data management application that integrates image data, experimental and analytic metadata and makes them accessible for visualization, mining, sharing and downstream analysis. We discuss how Bio-Formats and OMERO handle these different data types, and how they can be used to integrate, link and share HCS experiments in facilities and public data repositories. OME specifications and software are open source and are available at https://www.openmicroscopy.org.
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http://dx.doi.org/10.1016/j.ymeth.2015.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773399PMC
March 2016

Cochlear Delay and Medial Olivocochlear Functioning in Children with Suspected Auditory Processing Disorder.

PLoS One 2015 28;10(8):e0136906. Epub 2015 Aug 28.

National Center for Audiology, Western University, London, ON, Canada; School of Communication Sciences and Disorders, Western University, London, ON, Canada.

Behavioral manifestations of processing deficits associated with auditory processing disorder (APD) have been well documented. However, little is known about their anatomical underpinnings, especially cochlear processing. Cochlear delays, a proxy for cochlear tuning, measured using stimulus frequency otoacoustic emission (SFOAE) group delay, and the influence of the medial olivocochlear (MOC) system activation at the auditory periphery was studied in 23 children suspected with APD (sAPD) and 22 typically developing (TD) children. Results suggest that children suspected with APD have longer SFOAE group delays (possibly due to sharper cochlear tuning) and reduced MOC function compared to TD children. Other differences between the groups include correlation between MOC function and SFOAE delay in quiet in the TD group, and lack thereof in the sAPD group. MOC-mediated changes in SFOAE delay were in opposite directions between groups: increase in delay in TD vs. reduction in delay in the sAPD group. Longer SFOAE group delays in the sAPD group may lead to longer cochlear filter ringing, and potential increase in forward masking. These results indicate differences in cochlear and MOC function between sAPD and TD groups. Further studies are warranted to explore the possibility of cochlea as a potential site for processing deficits in APD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136906PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552631PMC
May 2016

Publishing and sharing multi-dimensional image data with OMERO.

Mamm Genome 2015 Oct 30;26(9-10):441-7. Epub 2015 Jul 30.

Centre for Gene Regulation & Expression, University of Dundee, Dundee, Scotland, UK.

Imaging data are used in the life and biomedical sciences to measure the molecular and structural composition and dynamics of cells, tissues, and organisms. Datasets range in size from megabytes to terabytes and usually contain a combination of binary pixel data and metadata that describe the acquisition process and any derived results. The OMERO image data management platform allows users to securely share image datasets according to specific permissions levels: data can be held privately, shared with a set of colleagues, or made available via a public URL. Users control access by assigning data to specific Groups with defined membership and access rights. OMERO's Permission system supports simple data sharing in a lab, collaborative data analysis, and even teaching environments. OMERO software is open source and released by the OME Consortium at www.openmicroscopy.org.
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http://dx.doi.org/10.1007/s00335-015-9587-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602067PMC
October 2015

Crossed and uncrossed acoustic reflex growth functions in normal-hearing adults, typically developing children, and children with suspected auditory processing disorder.

Int J Audiol 2015 24;54(9):620-6. Epub 2015 Jun 24.

National Centre for Audiology, Western University , London, Ontario , Canada.

Objective: Previous data suggested that children with suspected auditory processing disorders (APD) often show elevated or absent acoustic reflex thresholds, especially in crossed conditions (e.g. Allen & Allan, 2014 ). This study further explored these effects by measuring acoustic reflex growth functions (ARGF).

Design: Crossed and uncrossed ARGF slopes were obtained by linear fits between reflex amplitudes and increases in activator level from threshold to 15 dB above it.

Study Sample: Normal-hearing adults, typically developing children and children with reported listening difficulties and suspected of having an APD, participated.

Results: The ARGF slopes were shallower in crossed than in uncrossed conditions for all groups but the magnitude of the effect was significantly greater in the children with suspected APD. There were no differences between the typically developing children and the adults.

Conclusions: The results suggest shallower ARGFs in children with suspected APD. Given the role of the acoustic reflex in facilitating hearing speech in noise these findings may begin to shed light on physiologic explanations for some of the difficulties that are reported by children with suspected APD.
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http://dx.doi.org/10.3109/14992027.2015.1043147DOI Listing
May 2016

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

Authors:
Jenny C Taylor Hilary C Martin Stefano Lise John Broxholme Jean-Baptiste Cazier Andy Rimmer Alexander Kanapin Gerton Lunter Simon Fiddy Chris Allan A Radu Aricescu Moustafa Attar Christian Babbs Jennifer Becq David Beeson Celeste Bento Patricia Bignell Edward Blair Veronica J Buckle Katherine Bull Ondrej Cais Holger Cario Helen Chapel Richard R Copley Richard Cornall Jude Craft Karin Dahan Emma E Davenport Calliope Dendrou Olivier Devuyst Aimée L Fenwick Jonathan Flint Lars Fugger Rodney D Gilbert Anne Goriely Angie Green Ingo H Greger Russell Grocock Anja V Gruszczyk Robert Hastings Edouard Hatton Doug Higgs Adrian Hill Chris Holmes Malcolm Howard Linda Hughes Peter Humburg David Johnson Fredrik Karpe Zoya Kingsbury Usha Kini Julian C Knight Jonathan Krohn Sarah Lamble Craig Langman Lorne Lonie Joshua Luck Davis McCarthy Simon J McGowan Mary Frances McMullin Kerry A Miller Lisa Murray Andrea H Németh M Andrew Nesbit David Nutt Elizabeth Ormondroyd Annette Bang Oturai Alistair Pagnamenta Smita Y Patel Melanie Percy Nayia Petousi Paolo Piazza Sian E Piret Guadalupe Polanco-Echeverry Niko Popitsch Fiona Powrie Chris Pugh Lynn Quek Peter A Robbins Kathryn Robson Alexandra Russo Natasha Sahgal Pauline A van Schouwenburg Anna Schuh Earl Silverman Alison Simmons Per Soelberg Sørensen Elizabeth Sweeney John Taylor Rajesh V Thakker Ian Tomlinson Amy Trebes Stephen Rf Twigg Holm H Uhlig Paresh Vyas Tim Vyse Steven A Wall Hugh Watkins Michael P Whyte Lorna Witty Ben Wright Chris Yau David Buck Sean Humphray Peter J Ratcliffe John I Bell Andrew Om Wilkie David Bentley Peter Donnelly Gilean McVean

Nat Genet 2015 Jul 18;47(7):717-726. Epub 2015 May 18.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.
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http://dx.doi.org/10.1038/ng.3304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601524PMC
July 2015

Patterns of Recurrence in Patients with Stage IIIB/C Cutaneous Melanoma of the Head and Neck Following Surgery With and Without Adjuvant Radiation Therapy: Is Isolated Regional Recurrence Salvageable?

Ann Surg Oncol 2015 Nov 13;22(12):4052-9. Epub 2015 Jan 13.

Queensland Melanoma Project, Discipline of Surgery, Princess Alexandra Hospital, The University of Queensland, Woolloongabba, QLD, Australia.

Background: Understanding recurrence patterns is vital for guiding treatment. This study describes recurrence patterns for patients with stage IIIB/C head and neck melanoma (HNM) after therapeutic lymph node dissection (TLND) ± adjuvant radiation therapy (RT). We also report outcomes for salvage therapy for patients with isolated regional relapse.

Methods And Materials: A single-institution prospective database of 173 patients with American Joint Committee on Cancer (AJCC) stage IIIB/C HNM undergoing TLND between 1997 and 2012 was retrospectively reviewed. Timing and patterns of recurrence were reviewed. Univariable and multivariable analyses were undertaken using the Kaplan-Meier and Cox regression methods to determine factors predictive of recurrence. Median follow-up was 32 months.

Results: Adjuvant RT was administered to 66/173 (38 %) patients. Patients selected for RT had a higher AJCC stage and had more extracapsular invasion. The 5-year distant, cervical nodal and in-transit recurrence rates were 38, 10, and 13 %, respectively, following surgery alone compared with 60, 17, and 31 %, respectively, for the adjuvant RT group. The head and neck regional 5-year recurrence rate (combining in-basin nodal and in-transit) was 23 % for the entire cohort. Isolated cervical recurrence occurred in 19 patients: 17/19 underwent salvage surgery (10/17 patients received RT after salvage surgery) and 2/19 had RT alone. However, distant recurrence occurred in 12/19 salvage patients, with most occurring within 12 months, while 4/19 were disease free.

Conclusions: Using a selective approach for adjuvant RT, isolated cervical recurrence after TLND is uncommon. Isolated cervical recurrence can be salvaged effectively with further local therapy; however, distant disease frequently follows.
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http://dx.doi.org/10.1245/s10434-014-4356-4DOI Listing
November 2015

Auditory processing disorders: relationship to cognitive processes and underlying auditory neural integrity.

Int J Pediatr Otorhinolaryngol 2014 Feb 20;78(2):198-208. Epub 2013 Nov 20.

National Centre for Audiology, Western University, Canada. Electronic address:

Background: Auditory processing disorder (APD) in children has been reported and discussed in the clinical and research literature for many years yet there remains poor agreement on diagnostic criteria, the relationship between APD and cognitive skills, and the importance of assessing underlying neural integrity.

Purpose: The present study used a repeated measures design to examine the relationship between a clinical APD diagnosis achieved with behavioral tests used in many clinics, cognitive abilities measured with standardized tests of intelligence, academic achievement, language, phonology, memory and attention and measures of auditory neural integrity as measured with acoustic reflex thresholds and auditory brainstem responses.

Method: Participants were 63 children, 7-17 years of age, who reported listening difficulties in spite of normal hearing thresholds. Parents/guardians completed surveys about the child's auditory and attention behavior while children completed an audiologic examination that included 5 behavioral tests of auditory processing ability. Standardized tests that examined intelligence, academic achievement, language, phonology, memory and attention, and objective tests auditory function included crossed and uncrossed acoustic reflex thresholds and auditory brainstem responses (ABR) were also administered to each child.

Results: Forty of the children received an APD diagnosis based on the 5 behavioral tests and 23 did not. The groups of children performed similarly on intelligence measures but the children with an APD diagnosis tended to perform more poorly on other cognitive measures. Auditory brainstem responses and acoustic reflex thresholds were often abnormal in both groups of children.

Summary: Results of this study suggest that a purely behavioral test battery may be insufficient to accurately identify all children with auditory processing disorders. Physiologic test measures, including acoustic reflex and auditory brainstem response tests, are important indicators of auditory function and may be the only indication of a problem. The results also suggest that performance on behavioral APD tests may be strongly influenced by the child's language levels.
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http://dx.doi.org/10.1016/j.ijporl.2013.10.048DOI Listing
February 2014

Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.

PLoS Genet 2012 6;8(12):e1003074. Epub 2012 Dec 6.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.
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http://dx.doi.org/10.1371/journal.pgen.1003074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516553PMC
May 2013

OMERO: flexible, model-driven data management for experimental biology.

Nat Methods 2012 Feb 28;9(3):245-53. Epub 2012 Feb 28.

Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.

Data-intensive research depends on tools that manage multidimensional, heterogeneous datasets. We built OME Remote Objects (OMERO), a software platform that enables access to and use of a wide range of biological data. OMERO uses a server-based middleware application to provide a unified interface for images, matrices and tables. OMERO's design and flexibility have enabled its use for light-microscopy, high-content-screening, electron-microscopy and even non-image-genotype data. OMERO is open-source software, available at http://openmicroscopy.org/.
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http://dx.doi.org/10.1038/nmeth.1896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437820PMC
February 2012

Metadata matters: access to image data in the real world.

J Cell Biol 2010 May;189(5):777-82

Laboratory for Optical and Computational Instrumentation, Department of Molecular Biology, Graduate School, University of Wisconsin at Madison, Madison, WI 53711, USA.

Data sharing is important in the biological sciences to prevent duplication of effort, to promote scientific integrity, and to facilitate and disseminate scientific discovery. Sharing requires centralized repositories, and submission to and utility of these resources require common data formats. This is particularly challenging for multidimensional microscopy image data, which are acquired from a variety of platforms with a myriad of proprietary file formats (PFFs). In this paper, we describe an open standard format that we have developed for microscopy image data. We call on the community to use open image data standards and to insist that all imaging platforms support these file formats. This will build the foundation for an open image data repository.
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http://dx.doi.org/10.1083/jcb.201004104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878938PMC
May 2010

Open tools for storage and management of quantitative image data.

Methods Cell Biol 2008 ;85:555-70

Division of Gene Regulation and Expression, College of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Dundee, Scotland DD1 5EH, United Kingdom.

The explosion in quantitative imaging has driven the need to develop tools for storing, managing, analyzing, and viewing large sets of data. In this chapter, we discuss tools we have built for storing large data sets for the lifetime of a typical research project. As part of the Open Microscopy Environment (OME) Consortium, we have built a series of open-source tools that support the manipulation and visualization of large sets of complex image data. Images from a number of proprietary file formats can be imported and then accessed from a single server running in a laboratory or imaging facility. We discuss the capabilities of the OME Server, a Perl-based data management system that is designed for large-scale analysis of image data using a web browser-based user interface. In addition, we have recently released a lighter weight Java-based OME Remote Objects Server that supports remote applications for managing and viewing image data. Together these systems provide a suite of tools for large-scale quantitative imaging that is now commonly used throughout cell and developmental biology.
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http://dx.doi.org/10.1016/S0091-679X(08)85024-8DOI Listing
February 2008

Open microscopy environment and findspots: integrating image informatics with quantitative multidimensional image analysis.

Biotechniques 2006 Aug;41(2):199-208

University of Dundee, Dundee, Scotland, UK.

Biomedical research and drug development increasingly involve the extraction of quantitative data from digital microscope images, such as those obtained using fluorescence microscopy. Here, we describe a novel approach for both managing and analyzing such images. The Open Microscopy Environment (OME) is a sophisticated open-source scientific image management database that coordinates the organization, storage, and analysis of the large volumes of image data typically generated by modern imaging methods. We describe FindSpots, a powerful image-analysis package integrated in OME that will be of use to those who wish to identify and measure objects within microscope images or time-lapse movies. The algorithm used in FindSpots is in fact only one of many possible segmentation (object detection) algorithms, and the underlying data model used by OME to capture and store its results can also be used to store results from other segmentation algorithms. In this report, we illustrate how image segmentation can be achieved in OME using one such implementation of a segmentation algorithm, and how this output subsequently can be displayed graphically or processed numerically using a spreadsheet.
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http://dx.doi.org/10.2144/000112224DOI Listing
August 2006

A conceptual model for interprofessional education: the international classification of functioning, disability and health (ICF).

J Interprof Care 2006 Jun;20(3):235-45

Doctoral Program in Rehabilitation Sciences, The University of Western Ontario, London, Ontario, Canada.

A shared language and conceptual framework is essential to successful interprofessional collaboration. The World Health Organization's International Classification of Functioning, Disability and Health (ICF) provides a shared language and conceptual framework that transcends traditional disciplinary boundaries. This paper will familiarize readers with the ICF and describe the biopsychosocial perspective that is adopted in its conceptual framework and language. The presentation of a case study will illustrate how the ICF can enhance interprofessional learning by promoting a multidimensional perspective of an individual's health concerns. The case study will also highlight the value of the shared language and conceptual framework of the ICF for interprofessional collaboration. It is argued that a strong foundation in the principles exemplified by the ICF may serve to enhance interprofessional communication, and in so doing, encourage involvement in interprofessional collaboration and healthcare.
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http://dx.doi.org/10.1080/13561820600718139DOI Listing
June 2006

The Open Microscopy Environment (OME) Data Model and XML file: open tools for informatics and quantitative analysis in biological imaging.

Genome Biol 2005 3;6(5):R47. Epub 2005 May 3.

Laboratory of Genetics National Institute on Aging, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.

The Open Microscopy Environment (OME) defines a data model and a software implementation to serve as an informatics framework for imaging in biological microscopy experiments, including representation of acquisition parameters, annotations and image analysis results. OME is designed to support high-content cell-based screening as well as traditional image analysis applications. The OME Data Model, expressed in Extensible Markup Language (XML) and realized in a traditional database, is both extensible and self-describing, allowing it to meet emerging imaging and analysis needs.
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http://dx.doi.org/10.1186/gb-2005-6-5-r47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1175959PMC
May 2006

Delta12-prostaglandin D2 is a potent and selective CRTH2 receptor agonist and causes activation of human eosinophils and Th2 lymphocytes.

Prostaglandins Other Lipid Mediat 2005 Jan;75(1-4):153-67

Drug Discovery Department, Oxagen Limited, 91 Milton Park, Abingdon, Oxon OX14 4RY, UK.

Prostaglandin D2 (PGD2) is a lipid mediator produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients. There are two receptors for PGD2, namely the D prostanoid (DP) receptor and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). The proinflammatory effects of PGD2 leading to recruitment of eosinophils and Th2 lymphocytes into inflamed tissues is thought to be predominantly due to action on CRTH2. Several PGD2 metabolites have been described as potent and selective agonists for CRTH2. In this study we have characterized the activity of delta12-PGD2, a product of PGD2 isomerization by albumin. Delta12-PGD2 induced calcium mobilization in CHO cells expressing human CRTH2 receptor, with efficacy and potency similar to those of PGD2. These effects were blocked by the TP/CRTH2 antagonist ramatroban. delta12-PGD2 bound to CRTH2 receptor with a pKi of 7.63, and a 55-fold selectivity for CRTH2 compared to DP. In Th2 lymphocytes, delta12-PGD2 induced calcium mobilization with high potency and an efficacy similar to that of PGD2. delta12-PGD2 also caused activation of eosinophils as measured by shape change. Taken together, these results show that delta12-PGD2 is a potent and selective agonist for CRTH2 receptor and can cause activation of eosinophils and Th2 lymphocytes. These data also confirm the selective effect of other PGD2 metabolites on CRTH2 and illustrate how the metabolism of PGD2 may influence the pattern of leukocyte infiltration at sites of allergic inflammation.
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http://dx.doi.org/10.1016/j.prostaglandins.2004.11.003DOI Listing
January 2005