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1.  Controlled Support MEG imaging 
NeuroImage  2006;33(3):878-885.
In this paper, we present a novel approach to imaging sparse and focal neural current sources from MEG (magnetoencephalography) data. Using the framework of Tikhonov regularization theory, we introduce a new stabilizer that uses the concept of controlled support to incorporate a priori assumptions about the area occupied by focal sources. The paper discusses the underlying Tikhonov theory and its relationship to a Bayesian formulation which in turn allows us to interpret and better understand other related algorithms.
doi:10.1016/j.neuroimage.2006.07.023
PMCID: PMC4057891  PMID: 16978882
2.  White matter structure assessment from reduced HARDI data using low-rank polynomial approximations 
Assessing white matter fiber orientations directly from DWI measurements in single-shell HARDI has many advantages. One of these advantages is the ability to model multiple fibers using fewer parameters than are required to describe an ODF and, thus, reduce the number of DW samples needed for the reconstruction. However, fitting a model directly to the data using Gaussian mixture, for instance, is known as an initialization-dependent unstable process. This paper presents a novel direct fitting technique for single-shell HARDI that enjoys the advantages of direct fitting without sacrificing the accuracy and stability even when the number of gradient directions is relatively low. This technique is based on a spherical deconvolution technique and decomposition of a homogeneous polynomial into a sum of powers of linear forms, known as a symmetric tensor decomposition. The fiber-ODF (fODF), which is described by a homogeneous polynomial, is approximated here by a discrete sum of even-order linear-forms that are directly related to rank-1 tensors and represent single-fibers. This polynomial approximation is convolved to a single-fiber response function, and the result is optimized against the DWI measurements to assess the fiber orientations and the volume fractions directly. This formulation is accompanied by a robust iterative alternating numerical scheme which is based on the Levenberg-Marquardt technique. Using simulated data and in vivo, human brain data we show that the proposed algorithm is stable, accurate and can model complex fiber structures using only 12 gradient directions.
PMCID: PMC4013549  PMID: 24818174
3.  Delaying Treatment of Ocular Hypertension 
Archives of ophthalmology  2010;128(3):276-287.
Objective
To compare the safety and efficacy of earlier vs later treatment in preventing primary open-angle glaucoma (POAG) in individuals with ocular hypertension.
Methods
One thousand six hundred thirty-six individuals with intraocular pressure (IOP) from 24 to 32 mm Hg in 1 eye and 21 to 32 mm Hg in the fellow eye were randomized to observation or to topical ocular hypotensive medication. Median time of treatment in the medication group was 13.0 years. After a median of 7.5 years without treatment, the observation group received medication for a median of 5.5 years. To determine if there is a penalty for delaying treatment, we compared the cumulative proportions of participants who developed POAG at a median follow-up of 13 years in the original observation group and in the original medication group.
Main Outcome Measures
Cumulative proportion of participants who developed POAG.
Results
The cumulative proportion of participants in the original observation group who developed POAG at 13 years was 0.22 (95% confidence interval [CI], 0.19–0.25), vs 0.16 (95% CI, 0.13–0.19) in the original medication group (P=.009). Among participants at the highest third of baseline risk of developing POAG, the cumulative proportion who developed POAG was 0.40 (95% CI, 0.33–0.46) in the original observation group and 0.28 (95% CI, 0.22–0.34) in the original medication group. There was little evidence of increased adverse events associated with medication.
Application to Clinical Practice
Absolute reduction was greatest among participants at the highest baseline risk of developing POAG. Individuals at high risk of developing POAG may benefit from more frequent examinations and early preventive treatment.
Trial Registration
clinicaltrials.gov Identifier: NCT00000125
doi:10.1001/archophthalmol.2010.20
PMCID: PMC3966140  PMID: 20212196
4.  Refinement of Pointwise Linear Regression Criteria for Determining Glaucoma Progression 
Purpose.
A variety of pointwise linear regression (PLR) criteria have been proposed for determining glaucomatous visual field progression. However, alternative PLR criteria have only been assessed on a limited basis. The purpose of this study was to evaluate a range of PLR slope and significance criteria to define a clinically useful progression decision rule for longitudinal visual field examinations.
Methods.
Visual field data for each of 140 eyes (one per participant among 96 cases and 44 controls) were evaluated using the Humphrey Field Analyzer II program 24-2 Swedish interactive thresholding algorithm standard test strategy and Goldmann size III stimuli. The pointwise linear regression A2 (PLRA2) method was used to analyze the data, which included nine visual field examinations performed every 6 months for 4 years. Data from the Ocular Hypertension Treatment Study (OHTS) were used to validate the decision rule.
Results.
Several slope criteria produced specificities of 0.90 or higher, particularly slope criteria of less than −1.2 dB/y. The use of the slope criterion less than −1.2 dB/y at a significance level of P < 0.04 for classification resulted in a hit rate of 0.38, more than a 2-fold increase compared with a commonly used standard slope criterion of less than −1.0 dB/y at a significance level of P < 0.01. A similar increase in the hit rate was shown for a slope of less than −1.2 dB/y and P < 0.04 compared with the standard criterion in the independent OHTS validation data.
Conclusions.
When systematically evaluating criteria for detecting glaucoma progression, PLR criteria can be refined by requiring a stricter slope criterion such as less than −1.2 dB/y and relaxing the significance criterion to P < 0.04. Increasing the hit rate of PLR will be useful for early detection and treatment of glaucoma.
Systematic evaluation of pointwise linear regression (PLR) criteria indicates that trend analysis using PLR can be refined by considering more restrictive declines in slope and relaxing the significance criterion to increase the likelihood of detecting glaucoma progression with PLR.
doi:10.1167/iovs.13-11680
PMCID: PMC3778872  PMID: 23908183
pointwise linear regression; glaucoma progression; perimetry; trend analysis; visual field
5.  Longitudinal and Cross-Sectional Analyses of Visual Field Progression in Participants of the Ocular Hypertension Treatment Study (OHTS) 
Archives of ophthalmology  2010;128(12):1528-1532.
Purpose
Visual field progression can be determined by evaluating the visual field by serial examinations (longitudinal analysis), or by a change in classification derived from comparison to age-matched normal data in single examinations (cross-sectional analysis). We determined the agreement between these two approaches in data from the Ocular Hypertension Treatment Study (OHTS).
Methods
Visual field data from 3088 eyes of 1570 OHTS participants (median follow-up 7 yrs, 15 tests with static automated perimetry) were analysed. Longitudinal analyses were performed with change probability with total and pattern deviation, and cross-sectional analysis with Glaucoma Hemifield Test, Corrected Pattern Standard Deviation, and Mean Deviation. The rates of Mean Deviation and General Height change were compared to estimate the degree of diffuse loss in emerging glaucoma.
Results
The agreement on progression in longitudinal and cross-sectional analyses ranged from 50% to 61% and remained nearly constant across a wide range of criteria. In contrast, the agreement on absence of progression ranged from 97% to 99.7%, being highest for the stricter criteria. Analyses of pattern deviation were more conservative than total deviation, with a 3 to 5 times lesser incidence of progression. Most participants developing field loss had both diffuse and focal change.
Conclusions
Despite considerable overall agreement, between 40 to 50% of eyes identified as having progressed with either longitudinal or cross-sectional analyses were identified with only one of the analyses. Because diffuse change is part of early glaucomatous damage, pattern deviation analyses may underestimate progression in patients with ocular hypertension.
doi:10.1001/archophthalmol.2010.292
PMCID: PMC3914151  PMID: 21149774
glaucoma; progression; visual field; change probability; ocular hypertension
6.  Uncertainty Visualization in HARDI based on Ensembles of ODFs 
In this paper, we propose a new and accurate technique for uncertainty analysis and uncertainty visualization based on fiber orientation distribution function (ODF) glyphs, associated with high angular resolution diffusion imaging (HARDI). Our visualization applies volume rendering techniques to an ensemble of 3D ODF glyphs, which we call SIP functions of diffusion shapes, to capture their variability due to underlying uncertainty. This rendering elucidates the complex heteroscedastic structural variation in these shapes. Furthermore, we quantify the extent of this variation by measuring the fraction of the volume of these shapes, which is consistent across all noise levels, the certain volume ratio. Our uncertainty analysis and visualization framework is then applied to synthetic data, as well as to HARDI human-brain data, to study the impact of various image acquisition parameters and background noise levels on the diffusion shapes.
doi:10.1109/PacificVis.2012.6183591
PMCID: PMC3898522  PMID: 24466504
DT-MRI; Uncertainty; HARDI; Rank-k tensor decomp
7.  The Effect of Test Variability on the Structure-Function Relation in Early Glaucoma 
Purpose
To determine whether the weakness of the structure-function relation could be produced by test variability alone, without implying underlying dissociation between the true rates of structural and functional change.
Methods
Perimetric Mean Deviation (MD), and Rim Area (RA) and Cup Volume (CV) from confocal scanning laser ophthalmoscopy, over six visits, were taken from 166 eyes of 92 participants with high risk ocular hypertension or suspected / early glaucoma in the Portland Progression Project. Models were created of each measure’s variability. A further model predicted the rate of functional change from the rate of structural change. These were used to generate realistic simulated sequences of both functional and structural data with different standard deviations σ between the underlying rates of change. ‘Observed’ structure-function relations were calculated. An empirical p-value was derived, equaling the proportion of simulated series for which the ‘observed’ structure-function dissociation was greater than that seen in patient data.
Results
The correlation between the rates of structural (RA) and functional (MD) change was 0.171, consistent with σ<0.02dB/yr. Using CV, the correlation was −0.091, consistent with σ<0.01dB/yr. By comparison, the models predicted that the standard deviation of the rate of functional change for a healthy eye due to test variability would be 0.18dB/yr.
Conclusion
Test variability is sufficiently large that realistic patient data can be simulated without requiring a large variability between the underlying rates of structural and functional change. This absence of implied dissociation is a necessary condition for it to be valid to combine structural and functional measures to improve estimates of functional change and/or to reduce perimetric variability.
doi:10.1007/s00417-012-2005-9
PMCID: PMC3763816  PMID: 22527311
Glaucoma; Perimetry; Confocal Scanning Laser Ophthalmoscopy; Structure-Function Relation; Simulation; Variability
8.  Reviewing long-term antidepressants can reduce drug burden: a prospective observational cohort study 
The British Journal of General Practice  2012;62(604):e773-e779.
Background
Antidepressant prescribing continues to rise. Contributing factors are increased long-term prescribing and possibly the use of higher selective serotonin re-uptake inhibitor (SSRI) doses.
Aim
To review general practice patients prescribed the same antidepressant long-term (≥2 years) and evaluate prescribing and management pre and post-review.
Design and setting
Prospective observational cohort study using routine data from 78 urban general practices, Scotland.
Method
All patients prescribed antidepressants (excluding amitriptyline) for ≥2 years were identified from records November 2009 to March 2010. GPs selected patients for face-to-face review of clinical condition and medication, December 2009 to September 2010. Pre- and post-review data were collected; average antidepressant doses and changes in prescribed daily doses were calculated. Onward referral to support services was recorded.
Results
8.6% (33 312/388 656) of all registered patients were prescribed an antidepressant, 47.1% (15 689) were defined as long-term users and 2849 (18.2%) were reviewed. 811 (28.5%) patients reviewed had a change in antidepressant therapy: 7.0% stopped, 12.8% reduced dose, 5.3% increased dose, and 3.4% changed antidepressant, resulting in 9.5% (95% CI = 9.1% to 9.8% P<0.001) reduction in prescribed daily dose and 8.1% reduction in prescribing costs. 6.3% were referred onwards, half to NHS Mental Health Services. Pre-review SSRI doses were 10–30% higher than previously reported.
Conclusion
Almost half of all people prescribed antidepressants were long-term users. Appropriate reductions in prescribing can be achieved by reviewing patients. Higher SSRI doses may be contributing to current antidepressant growth.
doi:10.3399/bjgp12X658304
PMCID: PMC3481518  PMID: 23211181
antidepressant; drug therapy; depression; primary care
9.  Mammalian Fatty Acid Synthase Activity From Crude Tissue Lysates Tracing [13C]-Substrates Using GC Mass Spectrometry 
Analytical biochemistry  2012;428(2):158-166.
Fatty Acid Synthase (FASN, FAS; EC 2.3.1.85) is the sole mammalian enzyme to synthesize fatty acids de novo from acetyl and malonyl coenzyme A esters. A new method is described that directly quantifies uniformly labeled [13C]16-palmitate by tracing [13C]2-acetyl-CoA and [13C]3-malonyl-CoA using an in vitro FASN assay. This method used GC-MS to detect [13C]16-palmitate carboxylate anions (m/z 271) of pentafluorobenzyl derivatives and was highly sensitive at femtomole quantities. Uniformly incorporated [13C]16-palmitate was the primary product of both recombinant and crude tissue lysate FASN. Quantification of FASN protein within crude tissue lysates assured equal FASN amounts, preserved steady state kinetics, and enabled calculation of FASN specific activity. FASN activity determined by [13C]16-palmitate synthesis was consistent with values obtained from NADPH oxidation assays. Analysis of FASN activity from tissue extracts was not hampered by contaminating enzymes or pre-existing fatty acids. Crude mammary gland and liver lysates had significantly different activities at 82 and 65 nmoles minute−1 mg−1 respectively, suggesting tissue specific activity levels differ in a manner unrelated to FASN amount. GC-MS quantification of [13C]16-palmitate synthesis permits sensitive evaluation of FASN activity from tissues of varied physiologic states, and of purified FASN activity in the presence of modifying proteins, enzymes, or drugs.
doi:10.1016/j.ab.2012.06.013
PMCID: PMC3415257  PMID: 22728958
Fatty Acid Synthase Activity; GC-Mass Spectrometry; Mammary Gland/Liver Lysates; [13C]-substrate incorporation; [13C]16-Palmitic Acid
10.  Perimetric Indices as Predictors of Future Glaucomatous Functional Change 
Purpose
To evaluate the use of global indices summarizing the current status of a patient’s visual field as predictors of their future rate of change.
Methods
Ninety-five subjects with early or suspected glaucoma were studied, of whom 50 exhibited glaucomatous optic neuropathy (GON) at baseline. Subjects underwent seven annual visual field tests. Results from the first test in the sequence were used to predict their subsequent rate of change. Two global indices were considered: mean deviation (MD) and pattern standard deviation (PSD).
Results
Using multiple linear regression, baseline MD predicted subsequent slope of MD significantly better than baseline PSD predicted subsequent slope of PSD (p = 0.017). Using multiple logistic regression, a worse initial MD was predictive of being in the worst tertile for subsequent change in MD (pseudo-R2 = 0.33 for subjects with GON at baseline and 0.31 for those without). Worse initial PSD was not predictive of being in the worst tertile for subsequent change in PSD (pseudo-R2 = 0.09 with GON at baseline, 0.10 without).
Conclusions
Among patients with otherwise similar clinical profiles, a worse visual field at baseline, as measured by the global index MD, is predictive of a more rapid future rate of change. This should be taken into account when clinical decisions are made concerning management of patients who already have some visual field damage at presentation.
doi:10.1097/OPX.0b013e3181fc30b6
PMCID: PMC3746834  PMID: 20966804
glaucoma; perimetry; visual field; progression; data analysis
11.  The Development of a Decision Analytic Model of Changes in Mean Deviation in People with Glaucoma: The COA Model 
Ophthalmology  2012;119(7):1367-1374.
Purpose
To create and validate a statistical model predicting progression of primary open angle glaucoma (POAG) assessed by loss of visual field as measured in mean deviation (MD) using three landmark studies of glaucoma progression and treatment.
Design
A Markov decision analytic model using patient level data described longitudinal MD changes over seven years.
Participants
Patient level data from the Collaborative Initial Glaucoma Treatment Study (CIGTS, n=607), the Ocular Hypertension Treatment Study (OHTS, n=148, only those who developed POAG in the first five years of OHTS) and Advanced Glaucoma Intervention Study (AGIS, n=591), the COA model.
Methods
We developed a Markov model with transition matrices stratified by current MD, age, race and intraocular pressure categories and used a microsimulation approach to estimate change in MD over seven years. Internal validation compared model prediction for seven years to actual MD for COA participants. External validation used a cohort of glaucoma patients drawn from university clinical practices.
Main Outcome Measures
Change in visual field as measured in MD in decibels (dB).
Results
Regressing the actual MD against the predicted produced an R2 of 0.68 for the right eye and 0.63 for the left. The model predicted ending MD for right eyes of 65% of participants and for 63% of left eyes within 3 dB of actual results at seven years. In external validation the model had an R2 of 0.79 in the right eye and 0.77 in the left at five years.
Conclusion
The COA model is a validated tool for clinicians, patients and health policy makers seeking to understand longitudinal changes in mean deviation in people with glaucoma..
doi:10.1016/j.ophtha.2012.01.054
PMCID: PMC3389134  PMID: 22537616
12.  Morphometric Analysis and Classification of Glaucomatous Optic Neuropathy using Radial Polynomials 
Journal of Glaucoma  2012;21(5):302-312.
Purpose
To quantify the morphological features of the optic nerve head using radial polynomials, to use these morphometric models as the basis for classification of glaucomatous optic neuropathy glaucomatous optic neuropathy via an automated decision tree induction algorithm, and to compare these classification results with established methods.
Methods
A cohort of patients with high-risk ocular hypertension or early glaucoma (n = 179) and a second cohort of normal subjects (n = 96) were evaluated for glaucomatous optic neuropathy using stereographic disc photography and confocal scanning laser tomography. Morphological features of the optic nerve head region were modeled from the tomography data using pseudo-Zernike radial polynomials and features derived from these models were used as the basis for classification by a decision tree induction algorithm. Decision tree classification performance was compared with expert classification of stereographic disc photos and analysis of neural retinal rim thickness by Moorfields Regression Analysis (MRA).
Results
Root mean squared (RMS) error of the morphometric models decreased asymptotically with additional polynomial coefficients, from 62 ± 0.5 μm (32 coefficients) to 32 ± 5.7 μm (256 coefficients). Optimal morphometric classification was derived from a subset of 64 total features and had low sensitivity (69%), high specificity (88%), very good accuracy (80%), and area under the ROC curve (AUROC) was 88% (95% CI = 78 to 98%). By comparison, MRA classification of the same records had a comparatively poorer sensitivity (55%), but had higher specificity (95%), with similar overall accuracy (78%) and AUROC curve, 83% (95 % CI = 70 to 96%).
Conclusions
Pseudo-Zernike radial polynomials provide a mathematically compact and faithful morphological representation of the structural features of the optic nerve head. This morphometric method of glaucomatous optic neuropathy classification has greater sensitivity, and similar overall classification performance (AUROC) when compared with classification by neural retinal rim thickness by MRA in patients with high-risk ocular hypertension and early glaucoma.
doi:10.1097/IJG.0b013e31820d7e6a
PMCID: PMC3163012  PMID: 21423035
Glaucoma; Optic Nerve; Modeling; Classification; Machine Learning
13.  THE 5-LIPOXYGENASE PATHWAY IS REQUIRED FOR ACUTE LUNG INJURY FOLLOWING HEMORRHAGIC SHOCK 
Shock (Augusta, Ga.)  2012;37(6):599-604.
The cellular and biochemical mechanisms leading to acute lung injury and subsequent multiple organ failure are only partially understood. In order to study the potential role of eicosanoids, particularly leukotrienes, as possible mediators of acute lung injury, we used a murine experimental model of acute lung injury induced by hemorrhagic shock after blood removal via cardiac puncture. Neutrophil sequestration as shown by immunofluorescence, and protein leakage into the alveolar space, were measured as markers of injury. We used liquid chromatography coupled to tandem mass spectrometry to unequivocally identify several eicosanoids in the bronchoalveolar lavage fluid of experimental animals. MK886, a specific inhibitor of the 5-lipoxygenase pathway, as well as transgenic mice deficient in 5-lipoxygenase, were used to determine the role of this enzymatic pathway in this model. Leukotriene B4 and leukotriene C4 were consistently elevated in shock-treated mice compared to sham-treated mice. MK886 attenuated neutrophil infiltration and protein extravasation induced by hemorrhagic shock. 5-lipoxygenase-deficient mice showed reduced neutrophil infiltration and protein extravasation after shock treatment, indicating greatly reduced lung injury. These results support the hypothesis that 5-lipoxygenase, most likely through the generation of leukotrienes, plays an important role in the pathogenesis of acute lung injury induced by hemorrhagic shock in mice. This pathway could represent a new target for pharmacological intervention to reduce lung damage following severe primary injury.
doi:10.1097/SHK.0b013e31824ee7bc
PMCID: PMC3357208  PMID: 22392149
multiple organ failure; eicosanoids; leukotrienes; mass spectrometry; inflammation; pharmacological inhibition; transgenic mice
14.  The Nature of Macular Damage in Glaucoma as Revealed by Averaging Optical Coherence Tomography Data 
Purpose
To better understand the nature of glaucomatous damage, especially to the macula, the inner retinal thickness maps obtained with frequency domain optical coherence tomography (fdOCT) were averaged.
Methods
Frequency domain optical coherence tomography macular and optic disc cube scans were obtained from 54 healthy eyes and 156 eyes with glaucomatous optic neuropathy. A manually corrected algorithm was used for layer segmentation. Patients’ eyes were grouped both by mean deviation (MD) and hemifield classification using standard categories and 24-2 (6° grid) visual fields (VFs). To obtain average difference maps, the thickness of retinal nerve fiber (RNF) and retinal ganglion cell plus inner plexiform (RGC+) layers were averaged and subtracted from the average control values.
Results
On the average difference maps, RGC+ and RNF layer thinning was seen in the patient groups with VFs classified as normal. The pattern of the thinning was the same, but the degree of thinning increased with decreased MD and with classification category (from normal to arcuate). This RGC+ thinning was largely within the central four points of the 24-2 (6° grid) field, after correcting for RGC displacement.
Conclusion
1. VF categories represent different degrees of the same pattern of RGC+ and RNFL layer thinning. 2. RGC+ damage occurs in the central macula even in patients with VFs classified as normal. 3. The 6° grid (24-2) pattern is not optimally designed to detect macular damage. 4. A schematic model of RGC projections is proposed to explain the pattern of macular loss, including the greater vulnerability of the inferior retinal region.
Translational relevance
The 24-2 is not an optimal test pattern for detecting or following glaucomatous damage. Further, we suggest clinical fdOCT reports include RGC+ and RNFL probability plots combined with VF information.
doi:10.1167/tvst.1.1.3
PMCID: PMC3634586  PMID: 23626924
glaucoma; optical coherence tomography; perimetry; visual fields; macula
15.  INTERACTIVE VISUALIZATION OF PROBABILITY AND CUMULATIVE DENSITY FUNCTIONS 
The probability density function (PDF), and its corresponding cumulative density function (CDF), provide direct statistical insight into the characterization of a random process or field. Typically displayed as a histogram, one can infer probabilities of the occurrence of particular events. When examining a field over some two-dimensional domain in which at each point a PDF of the function values is available, it is challenging to assess the global (stochastic) features present within the field. In this paper, we present a visualization system that allows the user to examine two-dimensional data sets in which PDF (or CDF) information is available at any position within the domain. The tool provides a contour display showing the normed difference between the PDFs and an ansatz PDF selected by the user and, furthermore, allows the user to interactively examine the PDF at any particular position. Canonical examples of the tool are provided to help guide the reader into the mapping of stochastic information to visual cues along with a description of the use of the tool for examining data generated from an uncertainty quantification exercise accomplished within the field of electrophysiology.
doi:10.1615/Int.J.UncertaintyQuantification.2012004074
PMCID: PMC3609671  PMID: 23543120
visualization; probability density function; cumulative density function; generalized polynomial chaos; stochastic Galerkin methods; stochastic collocation methods
16.  Cup Size Predicts Subsequent Functional Change in Early Glaucoma 
Purpose
To identify structural predictors of functional change in patients with early glaucoma or risk factors for development of glaucoma.
Methods
129 participants with either high-risk ocular hypertension, suspected or early glaucoma were followed for ten annual visits. Standard Automated Perimetry was performed at each visit, together with Confocal Scanning Laser Ophthalmoscopy (CSLO). Mean Deviation (MD) at the same visit, and the subsequent rate of change in MD, were predicted by linear regression models based on CSLO parameters together with intraocular pressure, central corneal thickness and treatment status. Models were assessed by comparing the correlations between predicted and observed perimetric results.
Results
The model using rim area predicted MD at the same visit with correlation 0.445. Using cup area the equivalent correlation was r=0.411, lower than the model using rim area with p=0.096. Using cup volume the correlation was r=0.436, and the comparison had p=0.714; using disc area r=0.396 and p=0.011. The model using rim area to predict the subsequent rate of change of MD had r=0.539. Models using cup area (r=0.631), cup volume (r=0.649) or disc area (r=0.602) were significantly better; p=0.003, p=0.001 and p=0.044 respectively.
Conclusions
Lower rim area, as measured by CSLO, is predictive of worse function when measured on the same date in participants with high-risk ocular hypertension, suspected and early glaucoma. However, cup area, cup volume and disc area may all be more predictive of the rate of subsequent functional change. Parameters should be chosen based on the specific purpose intended and questions asked, rather than using the same parameters in all circumstances.
doi:10.1097/OPX.0b013e3182303644
PMCID: PMC3223562  PMID: 21912304
glaucoma; progression; perimetry; confocal scanning laser ophthalmoscopy
17.  Factors Predicting the Rate of Functional Progression in Early and Suspected Glaucoma 
Purpose.
Clinical trials in glaucoma have often sought to predict whether a patient will progress or remain stable. This study proposes to combine and support results from earlier studies, forming a model to predict the actual rate of functional change in glaucoma.
Methods.
Data were taken from 259 eyes of 150 participants with early or suspected glaucoma in the ongoing Portland Progression Project. A total of 3854 study visits were available, each consisting of visual acuity, confocal scanning laser ophthalmoscopy (CSLO), and perimetry. The rate of functional change was calculated over each of 1541 series of six consecutive visits. Mixed effects models were formed to predict these rates using baseline perimetric measurements and CSLO parameters, together with IOP, age, and change in visual acuity through the series (to remove any confound from media changes).
Results.
Cup volume from CSLO was predictive of subsequent rate of functional change (P = 0.036), together with baseline mean deviation (P < 0.001) and pattern standard deviation (P = 0.097), age (P = 0.013), maximum IOP during the sequence (P = 0.004), and change in acuity during the sequence (P = 0.022). In a similar model, rim area was less predictive of functional change (P = 0.066).
Conclusions.
A larger optic cup and/or a more damaged visual field are predictive of more rapid perimetric sensitivity loss. The structural parameters most closely correlated with current functional status may not be the parameters that are most useful for predicting the future course of a patient's disease. Maximum IOP may be a more important risk factor than mean IOP over the same time period.
In glaucoma, larger optic cup size, greater current functional damage, and greater maximum IOP during follow-up are all predictive of a more rapid rate of functional change. The structural parameters most closely correlated with current functional status may not be the parameters that are most useful for predicting the future course of a patient's disease.
doi:10.1167/iovs.11-9065
PMCID: PMC3406886  PMID: 22570353
18.  Assessment of linear-scale indices for perimetry in terms of progression in early glaucoma 
Vision research  2011;51(16):1801-1810.
Currently, global indices that summarize the visual field combine sensitivities on a logarithmic (decibel) scale. Recent structure-function models for glaucoma suggest that contrast sensitivity should be converted to a linear scale before averaging across visual field locations, to better relate sensitivity with the number of surviving retinal ganglion cells (RGCs). New indices designed to represent the number of RGCs already lost are described. At least one was found to be a significantly better predictor of subsequent rate of change than traditional Mean Deviation (p=0.014) in participants with glaucomatous optic neuropathy. Issues concerning the creation of optimal global indices are discussed.
doi:10.1016/j.visres.2011.06.009
PMCID: PMC3152648  PMID: 21704057
Glaucoma; Perimetry; Quantification; Visual Field; Progression
19.  Measuring Visual Function in AMD with Frequency-Doubling (Matrix) Perimetry 
Purpose
To determine the agreement between the Humphrey Matrix perimeter 10-2 test and the 10-2 Humphrey Field Analyzer (HFA) test when assessing visual function in patients with age-related macular degeneration (AMD).
Methods
Forty-two eyes of 42 subjects with AMD (average 75.0 years, sd= 6.2: median visual acuity in logMAR of 0.26, range -0.12 to 1.04) were evaluated with the Matrix and HFA 10-2 visual field tests. Mean Deviation (MD), Pattern Standard Deviation (PSD), and test time were recorded. We calculated spatial concordance of individual test locations, being the proportion of spatially agreeing locations with identical classification (normal vs abnormal, p<5%) on the pattern deviation plot. As multiple HFA stimuli overlapped with some Matrix locations, several criteria for grouping HFA data into locations were investigated.
Results
Both MD and PSD were significantly correlated for the two devices (r2=0.79 and r2=0.80 respectively, p<0.0001). Using our standard criterion for abnormal HFA locations (≥50% stimuli abnormal) the median spatial concordance was 0.76, with 95% of tests giving a concordance of ≥0.59. A small, but significant, increase in concordance occurred when a stricter criterion (all stimuli abnormal at a location) was applied. Median fixation loss percentages were 7% and 0% for the HFA and Matrix, respectively. Visual acuity in logMAR showed modest correlations with both defect depth (HFA MD; r2=0.39, p<0.0001) and size of defect (number of abnormal points on the HFA: r2=0.24, p<0.0001).
Conclusions
Using a simple metric to calculate spatial concordance, the Matrix 10-2 test quantifies the spatial extent of significant depression of the central visual fields in AMD in a manner similar to the HFA 10-2. The spatial extent and depth of central visual field loss in AMD are only modestly predicted by visual acuity measurements.
doi:10.1097/OPX.0b013e31821861bd
PMCID: PMC3132570  PMID: 21478785
age-related macular degeneration; automated perimetry; visual field; psychophysics; frequency doubling; visual acuity; contrast
20.  Design preferences and cognitive styles: experimentation by automated website synthesis 
Background
This article aims to demonstrate computational synthesis of Web-based experiments in undertaking experimentation on relationships among the participants' design preference, rationale, and cognitive test performance. The exemplified experiments were computationally synthesised, including the websites as materials, experiment protocols as methods, and cognitive tests as protocol modules. This work also exemplifies the use of a website synthesiser as an essential instrument enabling the participants to explore different possible designs, which were generated on the fly, before selection of preferred designs.
Methods
The participants were given interactive tree and table generators so that they could explore some different ways of presenting causality information in tables and trees as the visualisation formats. The participants gave their preference ratings for the available designs, as well as their rationale (criteria) for their design decisions. The participants were also asked to take four cognitive tests, which focus on the aspects of visualisation and analogy-making. The relationships among preference ratings, rationale, and the results of cognitive tests were analysed by conservative non-parametric statistics including Wilcoxon test, Krustal-Wallis test, and Kendall correlation.
Results
In the test, 41 of the total 64 participants preferred graphical (tree-form) to tabular presentation. Despite the popular preference for graphical presentation, the given tabular presentation was generally rated to be easier than graphical presentation to interpret, especially by those who were scored lower in the visualization and analogy-making tests.
Conclusions
This piece of evidence helps generate a hypothesis that design preferences are related to specific cognitive abilities. Without the use of computational synthesis, the experiment setup and scientific results would be impractical to obtain.
doi:10.1186/1759-4499-4-2
PMCID: PMC3386886  PMID: 22748000
21.  The Nature of Macular Damage in Glaucoma as Revealed by Averaging Optical Coherence Tomography Data 
Purpose
To better understand the nature of glaucomatous damage, especially to the macula, the inner retinal thickness maps obtained with frequency domain optical coherence tomography (fdOCT) were averaged.
Methods
Frequency domain optical coherence tomography macular and optic disc cube scans were obtained from 54 healthy eyes and 156 eyes with glaucomatous optic neuropathy. A manually corrected algorithm was used for layer segmentation. Patients' eyes were grouped both by mean deviation (MD) and hemifield classification using standard categories and 24-2 (6° grid) visual fields (VFs). To obtain average difference maps, the thickness of retinal nerve fiber (RNF) and retinal ganglion cell plus inner plexiform (RGC+) layers were averaged and subtracted from the average control values.
Results
On the average difference maps, RGC+ and RNF layer thinning was seen in the patient groups with VFs classified as normal. The pattern of the thinning was the same, but the degree of thinning increased with decreased MD and with classification category (from normal to arcuate). This RGC+ thinning was largely within the central four points of the 24-2 (6° grid) field, after correcting for RGC displacement.
Conclusion
1. VF categories represent different degrees of the same pattern of RGC+ and RNFL layer thinning. 2. RGC+ damage occurs in the central macula even in patients with VFs classified as normal. 3. The 6° grid (24-2) pattern is not optimally designed to detect macular damage. 4. A schematic model of RGC projections is proposed to explain the pattern of macular loss, including the greater vulnerability of the inferior retinal region.
Translational relevance
The 24-2 is not an optimal test pattern for detecting or following glaucomatous damage. Further, we suggest clinical fdOCT reports include RGC+ and RNFL probability plots combined with VF information.
doi:10.1167/tvst.1.1.3
PMCID: PMC3634586  PMID: 23626924
glaucoma; optical coherence tomography; perimetry; visual fields; macula
22.  Biomedical Visual Computing: Case Studies and Challenges 
Advances in computational geometric modeling, imaging, and simulation let researchers build and test models of increasing complexity, generating unprecedented amounts of data. As recent research in biomedical applications illustrates, visualization will be critical in making this vast amount of data usable; it’s also fundamental to understanding models of complex phenomena.
doi:10.1109/MCSE.2011.92
PMCID: PMC3336198  PMID: 22545005
23.  An Optimization Framework for Inversely Estimating Myocardial Transmembrane Potentials and Localizing Ischemia 
Conference Proceedings  2011;2011:1680-1683.
By combining a static bidomain heart model with a torso conduction model, we studied the inverse electrocardiographic problem of computing the transmembrane potentials (TMPs) throughout the myocardium from a body-surface potential map, and then used the recovered potentials to localize myocardial ischemia. Our main contribution is solving the inverse problem within a constrained optimization framework, which is a generalization of previous methods for calculating transmembrane potentials. The framework offers ample flexibility for users to apply various physiologically-based constraints, and is well supported by mature algorithms and solvers developed by the optimization community. By avoiding the traditional inverse ECG approach of building the lead-field matrix, the framework greatly reduces computation cost and, by setting the associated forward problem as a constraint, the framework enables one to flexibly set individualized resolutions for each physical variable, a desirable feature for balancing model accuracy, ill-conditioning and computation tractability. Although the task of computing myocardial TMPs at an arbitrary time instance remains an open problem, we showed that it is possible to obtain TMPs with moderate accuracy during the ST segment by assuming all cardiac cells are at the plateau phase. Moreover, the calculated TMPs yielded a good estimate of ischemic regions, which was of more clinical interest than the voltage values themselves. We conducted finite element simulations of a phantom experiment over a 2D torso model with synthetic ischemic data. Preliminary results indicated that our approach is feasible and suitably accurate for the common case of transmural myocardial ischemia.
doi:10.1109/IEMBS.2011.6090483
PMCID: PMC3336368  PMID: 22254648
Inverse Problem; Electrocardiography; Finite Element Method; Myocardial Ischemia; Constrained Optimization
24.  Detection of crossing white matter fibers with high-order tensors and rank-k decompositions 
Fundamental to high angular resolution diffusion imaging (HARDI), is the estimation of a positive-semidefinite orientation distribution function (ODF) and extracting the diffusion properties (e.g., fiber directions). In this work we show that these two goals can be achieved efficiently by using homogeneous polynomials to represent the ODF in the spherical deconvolution approach, as was proposed in the Cartesian Tensor-ODF (CT-ODF) formulation. Based on this formulation we first suggest an estimation method for positive-semidefinite ODF by solving a linear programming problem that does not require special parameterization of the ODF. We also propose a rank-k tensor decomposition, known as CP decomposition, to extract the fibers information from the estimated ODF. We show that this decomposition is superior to the fiber direction estimation via ODF maxima detection as it enables one to reach the full fiber separation resolution of the estimation technique. We assess the accuracy of this new framework by applying it to synthetic and experimentally obtained HARDI data.
doi:10.1007/978-3-642-22092-0_44
PMCID: PMC3327305  PMID: 21761684
25.  Maternal Health Status Correlates with Nest Success of Leatherback Sea Turtles (Dermochelys coriacea) from Florida 
PLoS ONE  2012;7(2):e31841.
Of the seven sea turtle species, the critically endangered leatherback sea turtle (Dermochelys coriacea) exhibits the lowest and most variable nest success (i.e., hatching success and emergence success) for reasons that remain largely unknown. In an attempt to identify or rule out causes of low reproductive success in this species, we established the largest sample size (n = 60–70 for most values) of baseline blood parameters (protein electrophoresis, hematology, plasma biochemistry) for this species to date. Hematologic, protein electrophoretic and biochemical values are important tools that can provide information regarding the physiological condition of an individual and population health as a whole. It has been proposed that the health of nesting individuals affects their reproductive output. In order to establish correlations with low reproductive success in leatherback sea turtles from Florida, we compared maternal health indices to hatching success and emergence success of their nests. As expected, hatching success (median = 57.4%) and emergence success (median = 49.1%) in Floridian leatherbacks were low during the study period (2007–2008 nesting seasons), a trend common in most nesting leatherback populations (average global hatching success = ∼50%). One protein electrophoretic value (gamma globulin protein) and one hematologic value (red blood cell count) significantly correlated with hatching success and emergence success. Several maternal biochemical parameters correlated with hatching success and/or emergence success including alkaline phosphatase activity, blood urea nitrogen, calcium, calcium∶phosphorus ratio, carbon dioxide, cholesterol, creatinine, and phosphorus. Our results suggest that in leatherbacks, physiological parameters correlate with hatching success and emergence success of their nests. We conclude that long-term and comparative studies are needed to determine if certain individuals produce nests with lower hatching success and emergence success than others, and if those individuals with evidence of chronic suboptimal health have lower reproductive success.
doi:10.1371/journal.pone.0031841
PMCID: PMC3281022  PMID: 22359635

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