PARE: A framework for removal of confounding effects from any distance-based dimension reduction method.

Dimension reduction tools preserving similarity and graph structure such as t-SNE and UMAP can capture complex biological patterns in high-dimensional data. However, these tools typically are not designed to separate effects of interest from unwanted effects due to confounders. We introduce the partial embedding (PARE) framework, which enables removal of confounders from any distance-based dimension reduction method. We then develop partial t-SNE and partial UMAP and apply these methods to genomic and neuroimaging data. For lower-dimensional visualization, our results show that the PARE framework can remove batch effects in single-cell sequencing data as well as separate clinical and technical variability in neuroimaging measures. We demonstrate that the PARE framework extends dimension reduction methods to highlight biological patterns of interest while effectively removing confounding effects.

Visual Pathway Involvement in NMDA Receptor Encephalitis: A Clinical, Optical Coherence Tomography, and 18-Fluorodeoxyglucose PET/CT Approach.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis patients have been reported to exhibit visual dysfunction without retinal thinning. The objective of our study was to examine the involvement of the visual pathway structure and function in anti-NMDAR encephalitis by assessing postrecovery visual function and retinal structure, and acute-phase occipital cortex function. METHODS: In this cross-sectional study, patients diagnosed with anti-NMDAR encephalitis per consensus criteria underwent postrecovery visual acuity (VA) testing and optical coherence tomography (OCT) with automated retinal layer segmentation. Clinical data and acute-phase brain 18F-fluorodeoxyglucose (FDG) PET/CT (performed within 90 days of symptom onset, assessed qualitatively and semi-quantitatively) were retrospectively analyzed. VA and OCT measures were compared between anti-NMDAR and age, sex, and race-matched healthy controls (HC). When available, FDG-PET/CT metabolism patterns were analyzed for correlations with VA, and OCT measures. RESULTS: A total of 16 anti-NMDAR (32 eyes) and 32 HC (64 eyes) were included in the study. Anti-NMDAR exhibited lower low-contrast VA (2.5% contrast: -4.4 letters [95% CI; -8.5 to -0.3]; P = 0.04, 1.25% contrast: -6.8 letters [95%CI; -12 to -1.7]; P = 0.01) compared with HC, but no differences were found on OCT-derived retinal layer thicknesses. Acute-phase FDG-PET/CT medial occipital cortex metabolism did not correlate with follow-up low-contrast VA or ganglion cell/inner plexiform layer thickness (GCIPL) (n = 7, 2.5% contrast: r = -0.31; P = 0.50, 1.25% contrast: r = -0.34; P = 0.45, GCIPL: r = -0.04; P = 0.94). CONCLUSIONS: Although the visual system seems to be involved in anti-NMDAR encephalitis, no retinal structural or occipital cortex functional abnormalities seem to be responsible for the visual dysfunction. When detected acutely, occipital lobe hypometabolism in anti-NMDAR encephalitis does not seem to associate with subsequent retrograde trans-synaptic degenerative phenomena, potentially reflecting reversible neuronal/synaptic dysfunction in the acute phase of the illness rather than neuronal degeneration.

Association of body mass index with longitudinal rates of retinal atrophy in multiple sclerosis.

BACKGROUND: Studies evaluating associations between body mass index (BMI) and optical coherence tomography (OCT) measures in multiple sclerosis (MS) are lacking. OBJECTIVE: To assess whether elevated BMI is associated with accelerated retinal atrophy. METHODS: In this observational study, 513 MS patients were followed with serial spectral-domain OCT for a median of 4.4 years. Participants were categorized as normal weight (BMI: 18.5-24.9 kg/m2), overweight (BMI: 25-29.9 kg/m2), and obese (BMI: ⩾30 kg/m2). Participants with diabetes mellitus or uncontrolled hypertension and eyes with optic neuritis (ON) ⩽6 months prior to baseline OCT or during follow-up were excluded. Statistical analyses were performed with mixed-effects linear regression. RESULTS: Obese patients (n = 146) exhibited accelerated rates of ganglion cell + inner plexiform layer (GCIPL) atrophy relative to normal weight patients (n = 214; -0.57%/year (95% confidence interval (CI): -0.65% to -0.48%) versus -0.42%/year (95% CI: -0.49% to -0.35%); p = 0.012). GCIPL atrophy rate did not differ between overweight (n = 153) and normal weight patients (-0.47%/year vs -0.42%/year; p = 0.41). Each 1 kg/m2 higher BMI was associated with accelerated GCIPL (-0.011%/year; 95% CI: -0.019% to -0.004%; p = 0.003) atrophy. Multivariable analyses accounting for age, sex, race, MS subtype, and ON history did not alter the above findings. CONCLUSIONS: Elevated BMI, in the absence of overt metabolic comorbidities, may be associated with accelerated GCIPL atrophy. Obesity, a modifiable risk factor, may be associated with accelerated neurodegeneration in MS.

Aquaporin-4 IgG seropositivity is associated with worse visual outcomes after optic neuritis than MOG-IgG seropositivity and multiple sclerosis, independent of macular ganglion cell layer thinning.

BACKGROUND: Comparative studies of characteristics of optic neuritis (ON) associated with myelin oligodendrocyte glycoprotein-IgG (MOG-ON) and aquaporin-4-IgG (AQP4-ON) seropositivity are limited. OBJECTIVE: To compare visual and optical coherence tomography (OCT) measures following AQP4-ON, MOG-ON, and multiple sclerosis associated ON (MS-ON). METHODS: In this cross-sectional study, 48 AQP4-ON, 16 MOG-ON, 40 MS-ON, and 31 healthy control participants underwent monocular letter-acuity assessment and spectral-domain OCT. Eyes with a history of ON >3 months prior to evaluation were analyzed. RESULTS: AQP4-ON eyes exhibited worse high-contrast letter acuity (HCLA) compared to MOG-ON (-22.3 ± 3.9 letters; p < 0.001) and MS-ON eyes (-21.7 ± 4.0 letters; p < 0.001). Macular ganglion cell + inner plexiform layer (GCIPL) thickness was lower, as compared to MS-ON, in AQP4-ON (-9.1 ± 2.0 µm; p < 0.001) and MOG-ON (-7.6 ± 2.2 µm; p = 0.001) eyes. Lower GCIPL thickness was associated with worse HCLA in AQP4-ON (-16.5 ± 1.5 letters per 10 µm decrease; p < 0.001) and MS-ON eyes (-8.5 ± 2.3 letters per 10 µm decrease; p < 0.001), but not in MOG-ON eyes (-5.2 ± 3.8 letters per 10 µm decrease; p = 0.17), and these relationships differed between the AQP4-ON and other ON groups (p < 0.01 for interaction). CONCLUSION: AQP4-IgG seropositivity is associated with worse visual outcomes after ON compared with MOG-ON and MS-ON, even with similar severity of macular GCIPL thinning.

Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures.

BACKGROUND: The retinal vasculature may be altered in multiple sclerosis (MS), potentially acting as a biomarker of disease processes. OBJECTIVE: To compare retinal vascular plexus densities in people with MS (PwMS) and healthy controls (HCs), and examine correlations with visual function and global disability. METHODS: In this cross-sectional study, 111 PwMS (201 eyes) and 50 HCs (97 eyes) underwent optical coherence tomography angiography (OCTA). Macular superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified, and poor quality images were excluded according to an artifact-rating protocol. RESULTS: Mean SVP density was 24.1% (SD = 5.5) in MS eyes (26.0% (SD = 4.7) in non-optic neuritis (ON) eyes vs. 21.7% (SD = 5.5) in ON eyes, p < 0.001), as compared to 29.2% (SD = 3.3) in HC eyes (p < 0.001 for all MS eyes and multiple sclerosis optic neuritis (MSON) eyes vs. HC eyes, p = 0.03 for MS non-ON eyes vs. HC eyes). DVP density did not differ between groups. In PwMS, lower SVP density was associated with higher levels of disability (expanded disability status scale (EDSS): R2 = 0.26, p = 0.004; multiple sclerosis functional composite (MSFC): R2 = 0.27, p = 0.03) and lower letter acuity scores (100% contrast: R2 = 0.29; 2.5% contrast: R2 = 0.40; 1.25% contrast: R2 = 0.31; p < 0.001 for all). CONCLUSIONS: Retinal SVP density measured by OCTA is reduced across MS eyes, and correlates with visual function, EDSS, and MSFC scores.

Deconfounded Dimension Reduction via Partial Embeddings.

Dimension reduction tools preserving similarity and graph structure such as t-SNE and UMAP can capture complex biological patterns in high-dimensional data. However, these tools typically are not designed to separate effects of interest from unwanted effects due to confounders. We introduce the partial embedding (PARE) framework, which enables removal of confounders from any distance-based dimension reduction method. We then develop partial t-SNE and partial UMAP and apply these methods to genomic and neuroimaging data. Our results show that the PARE framework can remove batch effects in single-cell sequencing data as well as separate clinical and technical variability in neuroimaging measures. We demonstrate that the PARE framework extends dimension reduction methods to highlight biological patterns of interest while effectively removing confounding effects.

Intersite brain MRI volumetric biases persist even in a harmonized multisubject study of multiple sclerosis.

BACKGROUND AND PURPOSE: Multicenter study designs involving a variety of MRI scanners have become increasingly common. However, these present the issue of biases in image-based measures due to scanner or site differences. To assess these biases, we imaged 11 volunteers with multiple sclerosis (MS) with scan and rescan data at four sites. METHODS: Images were acquired on Siemens or Philips scanners at 3 Tesla. Automated white matter lesion detection and whole-brain, gray and white matter, and thalamic volumetry were performed, as well as expert manual delineations of T1 magnetization-prepared rapid acquisition gradient echo and T2 fluid-attenuated inversion recovery lesions. Random-effect and permutation-based nonparametric modeling was performed to assess differences in estimated volumes within and across sites. RESULTS: Random-effect modeling demonstrated model assumption violations for most comparisons of interest. Nonparametric modeling indicated that site explained >50% of the variation for most estimated volumes. This expanded to >75% when data from both Siemens and Philips scanners were included. Permutation tests revealed significant differences between average inter- and intrasite differences in most estimated brain volumes (P < .05). The automatic activation of spine coil elements during some acquisitions resulted in a shading artifact in these images. Permutation tests revealed significant differences between thalamic volume measurements from acquisitions with and without this artifact. CONCLUSION: Differences in brain volumetry persisted across MR scanners despite protocol harmonization. These differences were not well explained by variance component modeling; however, statistical innovations for mitigating intersite differences show promise in reducing biases in multicenter studies of MS.

Effects of Myopia on Rates of Change in Optical Coherence Tomography Measured Retinal Layer Thicknesses in People with Multiple Sclerosis and Healthy Controls.

PURPOSE: To quantify the associations of myopia with longitudinal changes in retinal layer thicknesses in people with multiple sclerosis (PwMS) and healthy controls (HC). METHODS: A cohort of PwMS and HC with recorded refractive error (RE) prospectively scanned on Cirrus HD-OCT at the Johns Hopkins MS Center was assessed for inclusion. Exclusion criteria included OCT follow-up < 6 months, ocular comorbidities, incidental OCT pathologies, and inadequate scan quality. Eyes were classified as having high myopia (HM) (RE≤ -6 diopters), low myopia (LM) (RE> -6 and ≤ -3 diopters), or no myopia (NM) (RE> -3 and ≤ +2.75). Linear mixed-effects regression models were used in analyses. RESULTS: A total of 213 PwMS (eyes: 67 HM, 98 LM, 207 NM) and 80 HC (eyes: 26 HM, 37 LM, 93 NM) were included. Baseline average ganglion cell/inner plexiform (GCIPL) and peri-papillary retinal nerve fiber layer (pRNFL) thicknesses were lower in MS HM compared with MS NM (diff: -3.2 µm, 95% CI: -5.5 to -0.8, p = 0.008 and -5.3 µm, 95% CI: -9.0 to -1.7, p = 0.004, respectively), and similarly in HC HM, as compared with HC NM. Baseline superior, inferior, and nasal pRNFL thicknesses were lower in HM compared with NM, while temporal pRNFL thickness was higher, both in MS and HC (MS: 7.1 µm, 95% CI: 2.7-11.6, p = 0.002; HC: 4.7 µm, 95% CI: -0.3 to 9.7, p = 0.07). No longitudinal differences in rates of GCIPL change were noted between HM and LM vs. NM, either in MS or HC. CONCLUSION: Cross-sectional differences in average GCIPL and pRNFL thicknesses are commonly seen in people with HM as compared to reference normative values from people with NM and can lead to false attribution of pathology if RE is not taken into account. However, our study suggests that longitudinal changes in average GCIPL thickness in PwMS with myopia are similar in magnitude to PwMS with NM, and therefore are appropriate for monitoring disease-related pathology.

Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

BACKGROUND AND OBJECTIVES: Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. METHODS: In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. RESULTS: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. DISCUSSION: Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

Modulation of Retinal Atrophy With Rituximab in Multiple Sclerosis.

OBJECTIVE: To investigate the effects of rituximab on retinal atrophy in patients with relapsing-remitting multiple sclerosis (RRMS), we performed serial optical coherence tomography (OCT) scans among a cohort of patients with RRMS on rituximab and compared rates of ganglion cell + inner plexiform layer (GCIPL) atrophy to those observed among age- and sex-matched glatiramer acetate (GA)-and natalizumab-treated patients with RRMS and healthy controls (HCs). METHODS: In this observational study, patients with RRMS treated with a single disease-modifying therapy and HCs were followed with serial OCT for a median duration of 2.8 years. Participants with uncontrolled hypertension, diabetes mellitus, or glaucoma, and eyes with optic neuritis ≤6 months prior to baseline OCT, or during follow-up, were excluded. Statistical analyses were performed using linear mixed-effects regression. RESULTS: During the overall follow-up period, rates of GCIPL atrophy were -0.28 ± 0.11 µm/y among rituximab-treated patients with RRMS (n = 35). This was similar to GA-treated (n = 49; -0.33 ± 0.05 µm/y; p = 0.69) and natalizumab-treated patients (n = 88; -0.17 ± 0.10 µm/y; p = 0.13) and faster than HCs (n = 78; -0.15 ± 0.03 µm/y; p = 0.006). Rituximab-treated patients exhibited 0.55 ± 0.23 µm/y faster rates of GCIPL atrophy during the first 12 months of treatment, relative to afterwards (n = 25; p = 0.02), during which period GCIPL atrophy rates were -0.14 ± 0.13 µm/y. CONCLUSIONS: Retinal atrophy in RRMS is modulated by rituximab. Greater attenuation of retinal atrophy may occur after 12 months of rituximab treatment, following which time GCIPL atrophy rates are similar to those observed among natalizumab-treated patients with RRMS and HCs. Our findings raise the possibility that the neuroprotective therapeutic response with rituximab in RRMS may take up to 12 months, which should be confirmed by larger studies. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the difference in rate of change of the GCIPL thickness in patients with RRMS comparing rituximab to other disease-modifying therapies.

Association of Spectral-Domain OCT With Long-term Disability Worsening in Multiple Sclerosis.

OBJECTIVE: To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later. METHODS: In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was <6.0 or an increase of ≥1.0 if baseline EDSS score was ≥6.0. RESULTS: A total of 132 PwMS (mean age 43 years; 106 patients with relapsing-remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell + inner plexiform layer (GCIPL) thickness ≥70 µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness <70 µm was associated with a 4-fold increased odds of meaningful EDSS worsening (adjusted odds ratio [OR] 3.97, 95% confidence interval [CI] 1.24-12.70; p = 0.02) and an almost 3-fold increased odds of low-contrast VA worsening (adjusted OR 2.93, 95% CI 1.40-6.13; p = 0.04). CONCLUSIONS: Lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time point may help guide therapeutic decision-making among individual PwMS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.

Optical Coherence Tomography and Optical Coherence Tomography Angiography Findings After Optic Neuritis in Multiple Sclerosis.

Background: In people with multiple sclerosis (MS), optic neuritis (ON) results in inner retinal layer thinning, and reduced density of the retinal microvasculature. Objective: To compare inter-eye differences (IEDs) in macular optical coherence tomography (OCT) and OCT angiography (OCTA) measures in MS patients with a history of unilateral ON (MS ON) vs. MS patients with no history of ON (MS non-ON), and to assess how these measures correlate with visual function outcomes after ON. Methods: In this cross-sectional study, people with MS underwent OCT and OCTA. Superficial vascular plexus (SVP) density of each eye was quantified using a deep neural network. IEDs were calculated with respect to the ON eye in MS ON patients, and with respect to the right eye in MS non-ON patients. Statistical analyses used mixed-effect regression models accounting for intra-subject correlations. Results: We included 43 MS ON patients (with 92 discrete OCT/OCTA visits) and 14 MS non-ON patients (with 24 OCT/OCTA visits). Across the cohorts, mean IED in SVP density was -2.69% (SD 3.23) in MS ON patients, as compared to 0.17% (SD 2.39) in MS non-ON patients (p = 0.002). When the MS ON patients were further stratified according to time from ON and compared to MS non-ON patients with multiple cross-sectional analyses, we identified that IED in SVP density was significantly increased in MS ON patients at 1-3 years (p = < 0.001) and >3 years post-ON (p < 0.001), but not at <3 months (p = 0.21) or 3-12 months post-ON (p = 0.07), while IED in ganglion cell + inner plexiform layer (GCIPL) thickness was significantly increased in MS ON patients at all time points post-ON (p ≦ 0.01 for all). IED in SVP density and IED in GCIPL thickness demonstrated significant relationships with IEDs in 100% contrast, 2.5% contrast, and 1.25% contrast letter acuity in MS ON patients (p < 0.001 for all). Conclusions: Our findings suggest that increased IED in SVP density can be detected after ON in MS using OCTA, and detectable changes in SVP density after ON may occur after changes in GCIPL thickness. IED in SVP density and IED in GCIPL thickness correlate well with visual function outcomes in MS ON patients.

The impact of replacing heavy passenger vehicles (LTVs and SUVs) in the British Columbia fleet with lighter versions.

OBJECTIVE: The study reported in this article addressed the potential safety impact of consumer movement toward smaller vehicle choices by examining the makeup of the full British Columbia (BC) vehicle fleet--from smaller cars to heavy commercial vehicles. The basic assumption made was that some operators of heavy light trucks/vans (LTVs) or sport utility vehicles (SUVs) would, in the short term, be induced to downsize to lighter vehicles of the same type. METHOD: The 2000-2007 BC crash-claim data at the Insurance Corporation of British Columbia (ICBC) was used to create matrices of average information by culpable and nonculpable entities in two-vehicle collisions in 15 weight categories. Models for the effects of various driver/crash characteristics on injury potential were created and used to adjust the effect calculated solely on the basis of weight change. Levels of heavy LTV/SUV replacement from 0.05 to 0.95 of the current population were tested and the redistribution of vehicles was done in such a way that the relationship between small-large vehicle injury ratio and large-small vehicle mass ratio over the whole fleet remained constant as did the relative proportions of culpable and nonculpable involvements. RESULTS: The net effect of downsizing in the manner assumed for this study was mildly positive in terms of overall injury risk--that is, downsizing resulted in slightly fewer total injuries--but not in the case of fatalities, which tended to be increased by a more substantial margin. However, the results showed that even replacing substantial proportions of the heavy LTV/SUV population would not result in a large impact on safety. CONCLUSIONS: Replacing almost all the heavy LTV/SUVs with lighter versions should reduce injuries by less than 1 percent and increase fatalities by 3.5 percent percent. Nevertheless, in terms of persons impacted and the associated costs, the effects would be noticeable. The issue for policy-makers is to judge how the environmental benefits associated with encouraging such change compare with the net costs in terms of safety outcomes.