Test-retest Variability Research Articles

Quantifying Improvement in V˙ o2peak and Exercise Thresholds in Cardiovascular Disease Using Reliable Change Indices.

Improving aerobic fitness through exercise training is recommended for the treatment of cardiovascular disease (CVD). However, strong justifications for the criteria of assessing improvement in key parameters of aerobic function including estimated lactate threshold (θ LT ), respiratory compensation point (RCP), and peak oxygen uptake (V˙ o2peak ) at the individual level are not established. We applied reliable change index (RCI) statistics to determine minimal meaningful change (MMC RCI ) cutoffs of θ LT , RCP, and V˙ o2peak for individual patients with CVD. Sixty-six stable patients post-cardiac event performed three exhaustive treadmill-based incremental exercise tests (modified Bruce) ∼1 wk apart (T1-T3). Breath-by-breath gas exchange and ventilatory variables were measured by metabolic cart and used to identify θ LT , RCP, and V˙ o2peak . Using test-retest reliability and mean difference scores to estimate error and test practice/exposure, respectively, MMC RCI values were calculated for V˙ o2 (mL·min -1. kg -1 ) at θ LT , RCP, and V˙ o2peak . There were no significant between-trial differences in V˙ o2 at θ LT ( P = .78), RCP ( P = .08), or V˙ o2peak ( P = .74) and each variable exhibited excellent test-retest variability (intraclass correlation: 0.97, 0.98, and 0.99; coefficient of variation: 6.5, 5.4, and 4.9% for θ LT , RCP, and V˙ o2peak , respectively). Derived from comparing T1-T2, T1-T3, and T2-T3, the MMC RCI for θ LT were 3.91, 3.56, and 2.64 mL·min -1. kg -1 ; 4.01, 2.80, and 2.79 mL·min -1. kg -1 for RCP; and 3.61, 3.83, and 2.81 mL·min -1. kg -1 for V˙ o2peak . For each variable, MMC RCI scores were lowest for T2-T3 comparisons. These MMC RCI scores may be used to establish cutoff criteria for determining meaningful changes for interventions designed to improve aerobic function in individuals with CVD.

ASD-GResTM: Deep Learning Framework for ASD classification using Gramian Angular Field.

Autism Spectrum Disorder (ASD) is a heterogeneous disorder in children, and the current clinical diagnosis is accomplished using behavioral, cognitive, developmental, and language metrics. These clinical metrics can be imperfect measures as they are subject to high test-retest variability, and are influenced by assessment factors such as environment, social structure, or comorbid disorders. Advances in neuroimaging coupled with machine-learning provides an opportunity to develop methods that are more quantifiable, and reliable than existing clinical techniques. In this paper, we design and develop a deep-learning model that operates on functional magnetic resonance imaging (fMRI) data, and can classify between ASD and neurotypical brains. We introduce a novel strategy to transform time-series data extracted from fMRI signals into Gramian Angular Field (GAF) while locking in the temporal and spatial patterns in the data. Our motivation is to design and develop a novel framework that could encode the time-series, acquired from fMRI data, into images that can be used by deep-learning architectures that have been successful in computer vision. In our proposed framework called ASD-GResTM, we used a Convolutional Neural Network (CNN) to extract useful features from GAF images. We then used a Long Short-Term Memory (LSTM) layer to learn the activities between the regions. Finally, the output representations of the last LSTM layer are applied to a single-layer perceptron (SPL) to get the final classification. Our extensive experimentation demonstrates high accuracy across 4 centers, and outperforms state-of-the-art models on two centers with an increase in the accuracy of 17.58% and 6.7%, respectively as compared to the state of the art. Our model achieved the maximum accuracy of 81.78% with high degree of sensitivity and specificity. All training, validation, and testing was accomplished using openly available ABIDE-I benchmarking dataset.

Short-term effects of cyclopentolate and tropicamide eye drops on macular choroidal thickness in myopic children.

To investigate the short-term effects of cyclopentolate and tropicamide eyedrops on choroidal thickness (ChT) in myopic children using placebo or low-dose atropine eyedrops. The analysis included 242 myopic individuals (7-19 years) enrolled in two randomised placebo-controlled clinical trials of low-dose atropine eyedrops. Cycloplegia was induced using either one drop of 1% cyclopentolate (n = 161), two drops of 1% cyclopentolate (n = 32) or two drops of 1% tropicamide (n = 49). ChT measurements were taken using swept-source optical coherence tomography before and 30 min after administering the cycloplegic eye drops. A subset of 51 participants underwent test-retest measurements prior to cycloplegia. Mean changes in subfoveal ChT after two drops of tropicamide and one and two drops of cyclopentolate were -2.5 μm (p = 0.10), -4.3 μm (p < 0.001) and -9.6 μm (p < 0.001), respectively. Subfoveal ChT changes after one and two drops of cyclopentolate were significantly greater than the test-retest changes (test-retest mean change: -3.1 μm; p < 0.05), while the tropicamide group was not significantly different (p = 0.64). Choroidal thinning post-cyclopentolate was not significantly different between atropine and placebo treatment groups (p > 0.05 for all macular locations). The coefficient of repeatability (CoR) in the tropicamide group (range: 8.2-14.4 μm) was similar to test-retest (range: 7.5-12.2 μm), whereas greater CoR values were observed in the cyclopentolate groups (one drop: range: 10.8-15.3 μm; two drops: range: 12.2-24.6 μm). Cyclopentolate eye drops caused dose-dependent choroidal thinning and increased variation in pre- to post-cycloplegia measurements compared with test-retest variability, whereas tropicamide did not. These findings have practical implications for ChT measurements when cyclopentolate is used, particularly for successive measurements.

Changes in postictal cerebral perfusion are related to the duration of electroconvulsive therapy-induced seizures.

Postictal symptoms may result from cerebral hypoperfusion, which is possibly a consequence of seizure-induced vasoconstriction. Longer seizures have previously been shown to cause more severe postictal hypoperfusion in rats and epilepsy patients. We studied cerebral perfusion after generalized seizures elicited by electroconvulsive therapy (ECT) and its relation to seizure duration. Patients with a major depressive episode who underwent ECT were included. During treatment, 21-channel continuous electroencephalogram (EEG) was recorded. Arterial spin labeling magnetic resonance imaging scans were acquired before the ECT course (baseline) and approximately 1 h after an ECT-induced seizure (postictal) to quantify global and regional gray matter cerebral blood flow (CBF). Seizure duration was assessed from the period of epileptiform discharges on the EEG. Healthy controls were scanned twice to assess test-retest variability. We performed hypothesis-driven Bayesian analyses to study the relation between global and regional perfusion changes and seizure duration. Twenty-four patients and 27 healthy controls were included. Changes in postictal global and regional CBF were correlated with seizure duration. In patients with longer seizure durations, global decrease in CBF reached values up to 28 mL/100 g/min. Regional reductions in CBF were most prominent in the inferior frontal gyrus, cingulate gyrus, and insula (up to 35 mL/100 g/min). In patients with shorter seizures, global and regional perfusion increased (up to 20 mL/100 g/min). These perfusion changes were larger than changes observed in healthy controls, with a maximum median global CBF increase of 12 mL/100 g/min and a maximum median global CBF decrease of 20 mL/100 g/min. Seizure duration is a key factor determining postictal perfusion changes. In future studies, seizure duration needs to be considered as a confounding factor due to its opposite effect on postictal perfusion.

Video Motion Analysis as a Quantitative Evaluation Tool for Essential Tremor during Magnetic Resonance-Guided Focused Ultrasound Thalamotomy.

The Clinical Rating Scale for Tremor (CRST) is commonly used to evaluate essential tremor (ET) during focused ultrasound (FUS) thalamotomy. However, it faces challenges such as the ceiling effect and test-retest variability. This study explored the utility of videographic motion analysis as an evaluation index for ET. Forty-three patients with ET performed postural tremor and line-drawing tasks recorded on video, and the data were analyzed using motion analysis software. The test-retest and inter-rater reliability, correlations with the CRST and tremor scores, and pre/post-FUS treatment comparisons were analyzed. The video motion analysis showed excellent test-retest and inter-rater reliability. In the postural tremor tasks, video parameter amplitude significantly correlated with the CRST and tremor scores. Similarly, for the line-drawing task, video parameter amplitude showed significant correlations with CRST and tremor scores, effectively addressing the ceiling effect. Regarding post-FUS treatment improvements, changes in the CRST and tremor scores were significantly associated with changes in video parameter amplitude. In conclusion, quantitative analysis of the video motion of ET enables precise evaluation of kinematic characteristics and effectively resolves the ceiling effect and test-retest variability. The video motion analysis score accurately reflected the tremor severity and treatment effects, demonstrating its high clinical utility.

An Absorbance Peak Template for Clinical Assessment of Sound Conduction in Newborn Ears.

Power absorbance measures recorded over a wide range of frequencies allow for clinical inferences about the outer/middle ears' acoustic mechanics. A frequency-dependent feature in the newborn wideband absorbance response, the prominent mid-frequency absorbance peak, has been linked to middle-ear resonance. However, current normative methods were not designed to assess subtle changes in such features. This work aims to develop and validate an absorbance peak template (APT) for assessment of absorbance peaks in newborns. Additional objectives are to compare test performance of absorbance peaks and APTs to existing normative methods, to demonstrate APT-based methods for categorization of abnormal absorbance peaks, and to describe absorbance peak test-retest variability. Peak absorbance and peak frequency were analyzed in a training data set (490 measurements in 84 newborn ears who passed transient evoked otoacoustic emissions [TEOAEs] screenings), and an APT was developed by computing normal limits on these two absorbance peak variables. Split-set analysis evaluated the reproducibility of APT, and test-retest analysis was performed. Test performance analysis, conveyed by area under the receiver operating characteristic curve (AROC) and 95% confidence intervals (CIs), compared absorbance peak variables to absorbance area indices (AAIs) in a validation data set (359 ears that passed distortion-product OAE [DPOAE] screening and 64 ears that failed). APT-based assessment paradigms for normal and abnormal ears were compared to the common absorbance normative range paradigm. Split-set analysis demonstrated a good reproducibility of APT, and test-retest of absorbance peak variables showed that they were stable measures for clinical assessment. Test performance of peak absorbance (AROC = 0.83; 95% CI [0.77, 0.88]) was comparable to the top-performing AAI variables (AROC = 0.85; 95% CI [0.80, 0.90]). APT-based assessment categorized measurements based on their peak absorbance and peak frequency and enhanced the detection of subtle frequency changes that were missed by the normative range method. Analysis of absorbance peaks guided by APT has the potential to simplify and improve assessments of sound conduction pathways in newborn ears and can be used together with or in-place of current methods for analysis of wideband absorbance data.

Detection and agreement of event-based OCT and OCTA analysis for glaucoma progression.

To examine event-based glaucoma progression using optical coherence tomography (OCT) and OCT angiography (OCTA). In this retrospective study, glaucoma eyes with ≥2-year and 4-visits of OCT/OCTA imaging were included. Peripapillary capillary density (CD) and retinal nerve fibre layer thickness (RNFL) were obtained from 4.5 mm × 4.5 mm optic nerve head (ONH) scans. Event-based OCT/OCTA progression was defined as decreases in ONH measurements exceeding test-retest variability on ≥2 consecutive visits. Visual field (VF) progression was defined as significant VF mean deviation worsening rates on ≥2 consecutive visits. Inter-instrument agreement on progression detection was compared using kappa(κ) statistics. Among 147 eyes (89 participants), OCTA and OCT identified 33(22%) and 25(17%) progressors, respectively. They showed slight agreement (κ = 0.06), with 7(5%) eyes categorized as progressors by both. When incorporating both instruments, the rate of progressors identified increased to 34%. Similar agreement was observed in diagnosis- and severity-stratified analyses (κ < 0.10). Compared to progressors identified only by OCT, progressors identified only by OCTA tended to have thinner baseline RNFL and worse baseline VF. VF progression was identified in 11(7%) eyes. OCT and VF showed fair agreement (κ = 0.26), with 6(4%) eyes categorized as progressors by both. OCTA and VF showed slight agreement (κ = 0.08), with 4(3%) eyes categorized as progressors by both. OCT and OCTA showed limited agreement on event-based progression detection, with OCT showing better agreement with VF. Both OCT and OCTA detected more progressors than VF. OCT and OCTA may provide valuable, yet different and complementary, information about glaucoma progression.

Cortical excitation/inhibition ratios in patients with major depression treated with electroconvulsive therapy: an EEG analysis

Electroconvulsive therapy (ECT) is an effective treatment for major depression, but its working mechanisms are poorly understood. Modulation of excitation/inhibition (E/I) ratios may be a driving factor. Here, we estimate cortical E/I ratios in depressed patients and study whether these ratios change over the course of ECT in relation to clinical effectiveness. Five-minute resting-state electroencephalography (EEG) recordings of 28 depressed patients were recorded before and after their ECT course. Using a novel method based on critical dynamics, functional E/I (fE/I) ratios in the frequency range of 0.5–30 Hz were estimated in frequency bins of 1 Hz for the whole brain and for pre-defined brain regions. Change in Hamilton Depression Rating Scale (HDRS) score was used to estimate clinical effectiveness. To account for test–retest variability, repeated EEG recordings from an independent sample of 31 healthy controls (HC) were included. At baseline, no differences in whole brain and regional fE/I ratios were found between patients and HC. At group level, whole brain and regional fE/I ratios did not change over the ECT course. However, in responders, frontal fE/I ratios in the frequencies 12–28 Hz increased significantly (pFDR < 0.05 [FDR = false discovery rate]) over the ECT course. In non-responders and HC, no changes occurred over time. In this sample, frontal fE/I ratios increased over the ECT course in relation to treatment response. Modulation of frontal fE/I ratios may be an important mechanism of action of ECT.

Validating Trend-Based End Points for Neuroprotection Trials in Glaucoma.

The purpose of this study was to evaluate the power of trend-based visual field (VF) progression end points against long-term development of event-based end points accepted by the US Food and Drug Administration (FDA). One eye from 3352 patients with ≥10 24-2 VFs (median = 11 years) follow-up were analyzed. Two FDA-compatible criteria were applied to these series to label "true-progressed" eyes: ≥5 locations changing from baseline by more than 7 dB (FDA-7) or by more than the expected test-retest variability (GPA-like) in 2 consecutive tests. Observed rates of progression (RoP) were used to simulate trial-like series (2 years) randomly assigned (1000 times) to a "placebo" or a "treatment" arm. We simulated neuroprotective "treatment" effects by changing the proportion of "true progressed" eyes in the two arms. Two trend-based methods for mean deviation (MD) were assessed: (1) linear mixed model (LMM), testing average difference in RoP between the two arms, and (2) time-to-progression (TTP), calculated by linear regression as time needed for MD to decline by predefined cutoffs from baseline. Power curves with 95% confidence intervals were calculated for trend and event-based methods on the simulated series. The FDA-7 and GPA-like progression was achieved by 45% and 55% of the eyes in the clinical database. LMM and TTP had similar power, significantly superior to the event-based methods, none of which reached 80% power. All methods had a 5% false-positive rate. The trend-based methods can efficiently detect treatment effects defined by long-term FDA-compatible progression. The assessment of the power of trend-based methods to detect clinically relevant progression end points.

Comparing a head-mounted virtual reality perimeter and the Humphrey Field Analyzer for visual field testing in healthy and glaucoma patients.

To compare clinical visual field outputs in glaucoma and healthy patients returned by the Humphrey Field Analyzer (HFA) and virtual reality (Virtual Field, VF) perimetry. One eye of 54 glaucoma patients and 41 healthy subjects was prospectively tested (three times each in random order) using the HFA and VF perimeters (24-2 test grids). We extracted and compared global indices (mean deviation [MD] and pattern standard deviation [PSD]), pointwise sensitivity (and calculated 'equivalent' sensitivity after accounting for differences in background luminance) and pointwise defects. Bland-Altman (mean difference [Mdiff ] and 95% limits of agreement [LoA]) and intraclass correlation analyses were performed. The VF test was shorter (by 76 s) and had lower fixation losses (by 0.08) and false-positive rate (by 0.01) compared to the HFA (all p < 0.0001). Intraclass correlations were 0.86, 0.82 and 0.47 for MD, PSD and pointwise sensitivity between devices, respectively. Test-retest variability was higher for VF (Mdiff 0.3 dB, LoA -7.6 to 8.2 dB) compared to the HFA (Mdiff -0.3 dB, LoA -6.4 to 5.9 dB), indicating greater test-retest variability. When using each device's underlying normative database, the HFA detected, on average, 7 more defects (at the p < 0.05 level) out of the 52 test locations compared to this iteration of VF in the glaucoma cohort. Virtual Field returns global results that are correlated with the HFA, but pointwise sensitivities were more variable. Differences in test-retest variability and defect detection by its current normative database raise questions about the widespread adoption of VF in lieu of the HFA.

Multicenter Evaluation of the Feasibility of Clinical Implementation of SPECT Myocardial Blood Flow Measurement: Intersite Variability and Imaging Time.

Single-center studies have shown that single photon emission computed tomography myocardial blood flow (MBF) measurement is accurate compared with MBF measured with microspheres in a porcine model, positron emission tomography, and angiography. Clinical implementation requires consistency across multiple sites. The study goal is to determine the intersite processing repeatability of single photon emission computed tomography MBF and the additional camera time required. Five sites (Canada, Italy, Japan, Germany, and Singapore) each acquired 25 to 35 MBF studies at rest and with pharmacological stress using technetium-99m-tetrofosmin on a pinhole-collimated cadmium-zinc-telluride-based cardiac single photon emission computed tomography camera with standardized list-mode imaging and processing protocols. Patients had intermediate to high pretest probability of coronary artery disease. MBF was measured locally and at a core laboratory using commercially available software. The time a room was occupied for an MBF study was compared with that for a standard rest/stress myocardial perfusion study. With motion correction, the overall correlation in MBF between core laboratory and local site was 0.93 (range, 0.87-0.97) at rest, 0.90 (range, 0.84-0.96) at stress, and 0.84 (range, 0.70-0.92) for myocardial flow reserve. The local-to-core difference in global MBF (bias-MBF) was 5.4% (-3.8% to 14.8%; median [interquartile range]) at rest and 5.4% (-6.2% to 19.4%) at stress. Between the 5 sites, bias-MBF ranged from -1.6% to 11.0% at rest and from -1.9% to 16.3% at stress; the interquartile range in bias-MBF was between 9.3% (4.8%-14.0%) and 22.3% (-10.3% to 12.0%) at rest and between 17.0% (-11.3% to 5.6%) and 33.3% (-10.4% to 22.9%) at stress and was not significantly different between most sites. Both bias and interquartile range were like previously reported interobserver variability and less than the SD of the test-retest difference of 30%. The overall difference in myocardial flow reserve was 1.52% (-10.6% to 11.3%). There were no significant differences between with and without motion correction. The average additional acquisition time varied between sites from 44 to 79 minutes. The average bias-MBF and bias-MFR values were small with standard deviations substantially less than the test-retest variability. This demonstrates that MBF can be measured consistently across multiple sites and further supports that this technique can be reliably implemented. URL: https://www. gov; Unique identifier: NCT03427749.

Clinical Characterization of [18F]T-008, a Cholesterol 24-Hydroxylase PET Ligand: Dosimetry, Kinetic Modeling, Variability, and Soticlestat Occupancy.

This series of studies characterized [18F]T-008, a PET radiotracer for imaging cholesterol 24-hydroxylase (CH24H), in healthy volunteers (ClinicalTrials.gov identifier NCT02497235). Assessments included radiation dosimetry, kinetic modeling, test-retest variability (TRT) evaluation, and a dose occupancy evaluation using soticlestat, a selective CH24H inhibitor. Soticlestat is currently in phase 3 development for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome. Methods: In the dosimetry study, 5 participants (3 men) underwent serial whole-body scans to estimate organ-absorbed doses and effective doses of [18F]T-008 using OLINDA/EXM 1.1. For the kinetic modeling and TRT study, 6 participants (all men) underwent two 210-min dynamic [18F]T-008 PET scans with arterial blood sampling. The regional total volume of distribution was estimated using a 1-tissue-compartment model, a 2-tissue-compartment model, and Logan graphic analysis. In the dose occupancy study, 11 participants (all men) underwent 120-min scans at baseline and 2 time points (peak and trough) after receiving single oral doses of soticlestat (50-600 mg). The relationship between effect-site soticlestat concentration and brain occupancy was evaluated with a specially developed pharmacokinetic model and a saturable maximal occupancy model. Results: The estimated mean whole-body effective dose was 0.0292 mSv/MBq (SD, 0.00147 mSv/MBq). [18F]T-008 entered the brain rapidly, with a distribution consistent with known CH24H distribution densities. The 2-tissue-compartment model and Logan graphic analysis best described the tracer kinetics. The mean TRT for estimating total volume of distribution was 7%-15%. Single doses of soticlestat in the range 50-600 mg resulted in occupancies of 64%-96% at 2 h and 11%-79% at 24 h. The estimated half-maximal effect-site concentration of soticlestat was 5.52 ng/mL. Conclusion: [18F]T-008 is a suitable PET radiotracer for quantitatively analyzing CH24H in the human brain. Using [18F]T-008 and PET, we demonstrated that soticlestat was brain-penetrant and established target engagement by displacing [18F]T-008 in a dose-dependent manner in the brain.

Improved assessment of left ventricular ejection fraction using artificial intelligence in echocardiography: A comparative analysis with cardiac magnetic resonance imaging

BackgroundLeft ventricular ejection fraction (LVEF) measurement in echocardiography (Echo) using the recommended modified biplane Simpson (MBS) method is operator-dependent and exhibits variability. We aimed to assess the accuracy of a novel fully automated (Auto) artificial intelligence (AI) in view selection and biplane LVEF calculation compared to MBS-Echo, with cardiac magnetic resonance imaging (CMR) as reference. MethodsEach of the 301 consecutive patients underwent CMR and Echo on the same day. LVEF was measured independently by Auto-Echo, MBS-Echo and CMR. Interobserver (n = 40) and test-retest (n = 14) analysis followed. ResultsA total of 229 patients (76%) underwent complete analysis. Auto-Echo and MBS-Echo showed high correlations with CMR (R = 0.89 and 0.89) and with each other (R = 0.93). Auto underestimated LVEF (bias: 2.2%; limits of agreement [LOA]: −13.5 to 17.9%), while MBS overestimated it (bias: -2.2%; LOA: 18.6 to 14.1%). Despite comparable areas under the curves of Auto- and MBS-Echo (0.93 and 0.92), 46% (n = 70) of MBS-Echo misclassified LVEF by ≥5% units in patients with a reduced CMR-LVEF <51%.Although LVEF bias variability across different LV function ranges was significant (p < 0.001), Auto-Echo was closer to CMR for patients with reduced LVEF, wall motion abnormalities, and poor image quality than MBS-Echo. The interobserver correlation coefficient of Auto-Echo was excellent compared to MBS-Echo (1.00 vs. <0.91) for different readers. True test-retest variability was higher for MBS-Echo than for Auto-Echo (7.9% vs. 2.5%). ConclusionThe tested AI has the potential to improve the clinical utility of Echo by reducing user-related variability, providing more accurate and reliable results than MBS.

Reliability of gaze-contingent perimetry.

Standard automated perimetry, a psychophysical task performed routinely in eyecare clinics, requires observers to maintain fixation for several minutes at a time in order to measure visual field sensitivity. Detection of visual field damage is confounded by eye movements, making the technique unreliable in poorly attentive individuals and those with pathologically unstable fixation, such as nystagmus. Microperimetry, which utilizes 'partial gaze-contingency' (PGC), aims to counteract eye movements but only corrects for gaze position errors prior to each stimulus onset. Here, we present a novel method of visual field examination in which stimulus position is updated during presentation, which we refer to as 'continuous gaze-contingency' (CGC). In the first part of this study, we present three case examples that demonstrate the ability of CGC to measure the edges of the physiological blind spot in infantile nystagmus with greater accuracy than PGC and standard 'no gaze-contingency' (NoGC), as initial proof-of-concept for the utility of the paradigm in measurements of absolute scotomas in these individuals. The second part of this study focused on healthy observers, in which we demonstrate that CGC has the lowest stimulus positional error (gaze-contingent precision: CGC = ± 0.29°, PGC = ± 0.54°, NoGC = ± 0.81°). CGC test-retest variability was shown to be at least as good as both PGC and NoGC. Overall, CGC is supported as a reliable method of visual field examination in healthy observers. Preliminary findings demonstrate the spatially accurate estimation of visual field thresholds related to retinal structure using CGC in individuals with infantile nystagmus.

Assessment of Remote Training, At-Home Testing, and Test-Retest Variability of a Novel Test for Clustered Virtual Reality Perimetry

To assess the feasibility of remotely training glaucoma patients to take a 10-session clustered virtual reality (VR) visual field (VF) test (Vivid Vision Perimetry [VVP-10]) at home, analyze results for test-retest variability, and assess correspondence with conventional perimetry. Cross-sectional study. Twenty-one subjects with glaucoma were enrolled and included in the feasibility assessment of remote training. Thirty-six eyes were used for test-retest analysis and determination of concordance with the Humphrey Field Analyzer (HFA). Subjects were provided with a mobile VR headset containing the VVP-10 test software and trained remotely via video conferencing. Subjects were instructed to complete 10 sessions over a 14-day period. Feasibility was determined by the number of subjects who were able to independently complete VVP-10 over the 14-day period after 1 remote training session. The intraclass correlation coefficient (ICC) for average fraction seen across 10 sessions and the standard error (SE) of the mean were primary outcome measures for assessing test-retest variability. Correlation with HFA mean sensitivity (MS) across eyes, was a secondary outcome measure. Twenty subjects (95%) successfully completed the VVP-10 test series after 1 training session. The ICC for VVP-10 was 0.95 (95% confidence interval [CI], 0.92-0.97). The mean SE in units of fraction seen was 0.012. The Spearman correlations between VVP-10 average fraction seen and HFA MS were 0.87 (95% CI, 0.66-0.98) for moderate-to-advanced glaucoma eyes, and decreased to 0.67 (95% CI, 0.28-0.94) when all eyes were included. Remote training of patients at home is feasible, and subsequent remote clustered VF testing using VVP-10 by patients on their own, without any further interactions with caregivers or study staff, was possible. At-home VVP-10 results demonstrated low test-retest variability. Future studies must be conducted to determine if VVP-10, taken at home as convenient for the patient, may be a viable supplement to provide equivalent or complementary results to that of standard in-clinic assessment of visual function in glaucoma. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Detectability of Visual Field Defects in Glaucoma Using Moving Versus Static Stimuli for Perimetry.

We have previously shown that using moving, instead of static, stimuli extends the effective dynamic range of automated perimetry in glaucoma. In this study, we further investigate the effect of using moving stimuli on the detectability of functional loss. We used two experimental perimetry paradigms to test 155 subjects with a diagnosis of glaucoma or glaucoma suspect, and 34 healthy control subjects. One test used stimuli moving parallel to the average nerve fiber bundle orientation at each location; the other used static stimuli. Algorithms were otherwise identical. Sensitivities to moving stimuli were transformed to the equivalent values for static stimuli based on a Bland-Altman plot. The proportions of locations outside age-corrected normative limits were compared, and test-retest variability was compared against defect depth for each stimulus type. More tested locations were below the fifth percentile of the normative range for that location using static stimuli. However, among locations abnormal according to standard clinical perimetry on the same day, 19.2% were abnormal using static stimuli, versus 20.5% using moving stimuli (P = 0.372). Test-retest variability was 44% lower for moving stimuli across the range of defect depths. When compared with static automated perimetry and expressed on a common scale, moving stimuli extend the effective dynamic range and decrease variability, without decreasing the detectability of known functional defects. Moving stimuli provide a method to improve known problems of current clinical perimetry.

Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET

IntroductionP-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer’s disease and Parkinson’s disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[11C]verapamil PET. (R)-[11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [18F]MC225 was developed to measure both increases and decreases in P-gp function.AimThe aim of this study was (1) to identify the pharmacokinetic model that best describes [18F]MC225 kinetics in the human brain and (2) to determine test-retest variability.MethodsFive (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (VT), Ki, and the rate constants K1 and k2). In addition, a reversible two-tissue compartment model with fixed k3/k4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility.ResultsSixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (VB) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the VT for [18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model.Conclusion[18F]MC225 VT, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%.Trial registrationEudraCT 2020-001564-28. Registered 25 May 2020.

Test-Retest Variability and Discriminatory Power of Measurements From Microperimetry and Dark Adaptation Assessment in People With Intermediate Age-Related Macular Degeneration - A MACUSTAR Study Report.

The purpose of this study was to assess test-retest variability and discriminatory power of measures from macular integrity assessment (S-MAIA) and AdaptDx. This is a cross-sectional study of 167 people with intermediate age-related macular degeneration (iAMD), no AMD (controls; n = 54), early AMD (n = 28), and late AMD (n = 41), recruited across 18 European ophthalmology centers. Repeat measures of mesopic and scotopic S-MAIA average (mean) threshold (MMAT decibels [dB] and SMAT [dB]) and rod intercept time (RIT [mins]) at 2 visits 14 (±7) days apart were recorded. Repeat measures were assessed by Bland-Altman analysis, intra-class correlation coefficients (ICCs) and variability ratios. Secondary analysis assessed the area under the receiver operating characteristic curves (AUC) to determine the ability to distinguish people as having no AMD, early AMD, or iAMD. Data were available for 128, 131, and 103 iAMD participants for the mesopic and scotopic S-MAIA and AdaptDx, respectively. MMAT and SMAT demonstrate similar test-retest variability in iAMD (95% confidence interval [CI] ICC of 0.79-0.89 and 0.78-0.89, respectively). ICCs were worse in RIT (95% CI ICC = 0.55-0.77). All tests had equivalent AUCs (approximately 70%) distinguishing between subjects with iAMD and controls, whereas early AMD was indistinguishable from iAMD on all measures (AUC = <55%). A learning effect was not seen in these assessments under the operating procedures used. MMAT, SMAT, and RIT have adequate test-retest variability and are all moderately good at separating people with iAMD from controls. Expected levels of test-retest variability and discriminatory power of the AdaptDx and MAIA devices in a clinical study setting must be considered when designing future trials for people with AMD.

18F]FNDP PET neuroimaging test-retest repeatability and whole-body dosimetry in humans.

Soluble epoxide hydrolase (sEH) is an enzyme that shapes immune signaling through its role in maintaining the homeostasis of polyunsaturated fatty acids and their related byproducts. [18F]FNDP is a radiotracer developed for use with positron emission tomography (PET) to image sEH, which has been applied to imaging sEH in the brains of healthy individuals. Here, we report the test-retest repeatability of [18F]FNDP brain PET binding and [18F]FNDP whole-body dosimetry in healthy individuals. Seven healthy adults (4 men, 3 women, ages 40.1 ± 4.6years) completed [18F]FNDP brain PET on two occasions within a period of 14days in a test-retest study design. [18F]FNDP regional total distribution volume (VT) values were derived from modeling time-activity data with a metabolite-corrected arterial input function. Test-retest variability, mean absolute deviation, and intraclass correlation coefficient (ICC) were investigated. Six other healthy adults (3 men, 3 women, ages 46.0 ± 7.0years) underwent [18F]FNDP PET/CT for whole-body dosimetry, which was acquired over 4.5h, starting immediately after radiotracer administration. Organ-absorbed doses and the effective dose were then estimated. The mean test-retest difference in regional VT (ΔVT) was 0.82 ± 5.17%. The mean absolute difference in regional VT was 4.01 ± 3.33%. The ICC across different brain regions ranged from 0.92 to 0.99. The organs with the greatest radiation-absorbed doses included the gallbladder (0.081 ± 0.024mSv/MBq), followed by liver (0.077 ± 0.018mSv/MBq) and kidneys (0.063 ± 0.006mSv/MBq). The effective dose was 0.020 ± 0.003mSv/MBq. These data support a favorable test-retest repeatability of [18F]FNDP brain PET regional VT. The radiation dose to humans from each [18F]FNDP PET scan is similar to that of other 18F-based PET radiotracers.

Paradoxical increase in global longitudinal strain by handgrip exercise despite left ventricular diastolic dysfunction.

Although global longitudinal strain (GLS) is recognized as a sensitive marker of intrinsic left ventricular (LV) dysfunction, its afterload dependency has also been pointed. We hypothesized that decrease in GLS during handgrip exercise could be more sensitive marker of intrinsic myocardial dysfunction. Handgrip exercise-stress echocardiography was performed in 90 cardiovascular disease patients with preserved LV ejection fraction. LV diastolic function was graded according to the guidelines. Diastolic wall stress (DWS) and ratio of left atrial (LA) volume index to late-diastolic mitral annular velocity (LAVI/a') were measured at rest as LV stiffness. As well, LA strains were measured to assess LA function. GLS was expressed as absolute value and significant changes in GLS by handgrip exercise was defined as changes over prespecified mean absolute test-retest variability (2.65%). While mean value of GLS did not change by the exercise, substantial patients showed significant changes in GLS: decreased (group I, n=28), unchanged (group II, n=34), and increased (group III, n=28). Unexpectedly, patients in group I did not show any clinical and echocardiographic characteristics, while those in group III were characterized by elevated natriuretic peptide levels, blunted heart rate response to handgrip exercise, and advanced LV diastolic dysfunction. Multivariable analyses revealed that DWS, left atrial booster strain, and grade II or more diastolic dysfunction determined the increase in GLS even after adjustment for elevated natriuretic peptides and the changes in heart rate by the exercise. In contrast to our hypothesis, paradoxical increase in GLS by handgrip exercise could be associated with advanced LV diastolic dysfunction in cardiovascular patients with preserved LV ejection fraction. Our findings suggest that HG exercise for heart failure patients does not enhance the afterload straightforward, resulting in variable changes of GLS according to the individual conditions.