Understanding metric-related pitfalls in image analysis validation.

Validation metrics are key for tracking scientific progress and bridging the current chasm between artificial intelligence research and its translation into practice. However, increasing evidence shows that, particularly in image analysis, metrics are often chosen inadequately. Although taking into account the individual strengths, weaknesses and limitations of validation metrics is a critical prerequisite to making educated choices, the relevant knowledge is currently scattered and poorly accessible to individual researchers. Based on a multistage Delphi process conducted by a multidisciplinary expert consortium as well as extensive community feedback, the present work provides a reliable and comprehensive common point of access to information on pitfalls related to validation metrics in image analysis. Although focused on biomedical image analysis, the addressed pitfalls generalize across application domains and are categorized according to a newly created, domain-agnostic taxonomy. The work serves to enhance global comprehension of a key topic in image analysis validation.

Metrics reloaded: recommendations for image analysis validation.

Increasing evidence shows that flaws in machine learning (ML) algorithm validation are an underestimated global problem. In biomedical image analysis, chosen performance metrics often do not reflect the domain interest, and thus fail to adequately measure scientific progress and hinder translation of ML techniques into practice. To overcome this, we created Metrics Reloaded, a comprehensive framework guiding researchers in the problem-aware selection of metrics. Developed by a large international consortium in a multistage Delphi process, it is based on the novel concept of a problem fingerprint-a structured representation of the given problem that captures all aspects that are relevant for metric selection, from the domain interest to the properties of the target structure(s), dataset and algorithm output. On the basis of the problem fingerprint, users are guided through the process of choosing and applying appropriate validation metrics while being made aware of potential pitfalls. Metrics Reloaded targets image analysis problems that can be interpreted as classification tasks at image, object or pixel level, namely image-level classification, object detection, semantic segmentation and instance segmentation tasks. To improve the user experience, we implemented the framework in the Metrics Reloaded online tool. Following the convergence of ML methodology across application domains, Metrics Reloaded fosters the convergence of validation methodology. Its applicability is demonstrated for various biomedical use cases.

Symptoms before and after COVID-19: a population and case-control study using prospective data.

BACKGROUND: Some individuals experience prolonged illness after acute coronavirus disease 2019 (COVID-19). We assessed whether pre-infection symptoms affected post-acute COVID illness duration. METHODS: Survival analysis was performed in adults (n=23 452) with community-managed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection prospectively self-logging data through the ZOE COVID Symptom Study app, at least weekly, from 8 weeks before to 12 weeks after COVID-19 onset, conditioned on presence versus absence of baseline symptoms (4-8 weeks before COVID-19). A case-control study was performed in 1350 individuals with long illness (≥8 weeks, including 906 individuals (67.1%) with illness ≥12 weeks), matched 1:1 (for age, sex, body mass index, testing week, prior infection, vaccination, smoking, index of multiple deprivation) with 1350 individuals with short illness (<4 weeks). Baseline symptoms were compared between the two groups, and against post-COVID symptoms. RESULTS: Individuals reporting baseline symptoms had longer COVID-related symptom duration (median 15 days versus 10 days for individuals without baseline symptoms) with baseline fatigue nearly doubling duration. Two-thirds (910 (67.4%) of 1350) of individuals with long illness were asymptomatic beforehand. However, 440 (32.6%) had baseline symptoms, versus 255 (18.9%) of 1350 individuals with short illness (p<0.0001). Baseline symptoms doubled the odds ratio for long illness (2.14, 95% CI 1.78-2.57). Prior comorbidities were more common in individuals with long versus short illness. In individuals with long illness, baseline symptomatic (versus asymptomatic) individuals were more likely to be female, younger, and have prior comorbidities; and baseline and post-acute symptoms, and symptom burden, correlated strongly. CONCLUSIONS: Individuals experiencing symptoms before COVID-19 had longer illness duration and increased odds of long illness. However, many individuals with long illness were well before SARS-CoV-2 infection.

Biomarkers of Migraine and Cluster Headache: Differences and Similarities.

OBJECTIVE: This study was undertaken to identify magnetic resonance imaging (MRI) biomarkers that differentiate migraine from cluster headache patients and imaging features that are shared. METHODS: Clinical, functional, and structural MRI data were obtained from 20 migraineurs, 20 cluster headache patients, and 15 healthy controls. Support vector machine algorithms and a stepwise removal process were used to discriminate headache patients from controls, and subgroups of patients. Regional between-group differences and association between imaging features and patients' clinical characteristics were also investigated. RESULTS: The accuracy for classifying headache patients from controls was 80%. The classification accuracy for discrimination between migraine and controls was 89%, and for cluster headache and controls it was 98%. For distinguishing cluster headache from migraine patients, the MRI classifier yielded an accuracy of 78%, whereas MRI-clinical combined classification model achieved an accuracy of 99%. Bilateral hypothalamic and periaqueductal gray (PAG) functional networks were the most important MRI features in classifying migraine and cluster headache patients from controls. The left thalamic network was the most discriminative MRI feature in classifying migraine from cluster headache patients. Compared to migraine, cluster headache patients showed decreased functional interaction between the left thalamus and cortical areas mediating interoception and sensory integration. The presence of restlessness was the most important clinical feature in discriminating the two groups of patients. INTERPRETATION: Functional biomarkers, including the hypothalamic and PAG networks, are shared by migraine and cluster headache patients. The thalamocortical pathway may be the neural substrate that differentiates migraine from cluster headache attacks with their distinct clinical features. ANN NEUROL 2023;93:729-742.

Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with ß-amyloid status in cognitively normal adults at age 70.

BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.

Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

Common infections and neuroimaging markers of dementia in three UK cohort studies.

INTRODUCTION: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. METHODS: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain  = 2632; NAPOE-interaction  = 1810). RESULTS: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (ß = -3.89 mL [-5.81, -1.97], Padjusted  < 0.05); these were largely attenuated in fully adjusted models (ß = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed. DISCUSSION: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication.

Biomarker pathway heterogeneity of amyloid-positive individuals.

INTRODUCTION: In amyloid-positive individuals, disease-related biomarker heterogeneity is understudied. METHODS: We used Subtype and Stage Inference (SuStaIn) to identify data-driven subtypes among cerebrospinal fluid (CSF) amyloid beta (1-42)-positive individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNIGO/2 [n = 376]). Variables included: CSF phosphorylated tau (p-tau181), hippocampal and whole-brain volume, logical memory (LM), composite Trail Making Test score, and white matter hyperintensity (WMH) volumes. CSF amyloid-negative, apolipoprotein E ε4 non-carrier cognitively unimpaired controls (n = 86) were used to calculate z scores. RESULTS: One subtype (n = 145) had early LM changes, with later p-tau and WMH changes. A second subtype (n = 88) had early WMH changes, were older, and more hypertensive. A third subtype (n = 100) had early p-tau changes, and reflected typical Alzheimer's disease. Some amyloid positive (n = 43) individuals were similar to the amyloid-negative group. DISCUSSION: This work identified heterogeneity in individuals who are conventionally considered homogeneous, which is likely driven by co-pathologies including cerebrovascular disease. HIGHLIGHTS: Data-driven modeling identified marker heterogeneity in amyloid-positive individuals. Heterogeneity reflected Alzheimer's disease-like, vascular-like, and mixed pathology presentations. Some amyloid-positive individuals were more similar to amyloid-negative controls. Vascular pathology plays a key role in understanding heterogeneity in those on the amyloid pathway.

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study.

BACKGROUND: The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population. METHODS: In this prospective longitudinal observational study, we collected data from participants who were self-reporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16-99 years, based in the UK, with a body-mass index between 15 and 55 kg/m2, had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence. FINDINGS: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16-0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43-1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57-0·98, p=0·03). INTERPRETATION: The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work-health policies and public health advice. FUNDING: Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, and Medical Research Council.

Neuroimaging correlates of brain injury in Wilson's disease: a multimodal, whole-brain MRI study.

Wilson's disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focused on specific sequences or regions of interest, often stratifying chronically treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively recruited patients with Wilson's disease (age range 16-68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding 6 months as having 'active' disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound ('free') copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson's disease.

Is the association between blood pressure and cognition in the oldest-old modified by physical, vascular or brain pathology markers? The EMIF-AD 90 + Study.

BACKGROUND: Prior studies suggest a changing association between blood pressure (BP) and cognition with aging, however work in the oldest-old has yielded ambiguous results. Potentially, these mixed results can be explained by modifying factors. The aim of this study was to establish whether physical, vascular or brain pathology markers that describe a state of increased vulnerability, affect the association between BP and cognition in the oldest-old. Results may influence clinicians' decisions regarding the use of antihypertensives in this age group. METHODS: We included 122 individuals (84 without cognitive impairment and 38 with cognitive impairment) from the EMIF-AD 90 + Study (mean age 92.4 years). First, we tested cross-sectional associations of systolic and diastolic BP with a cognitive composite score. Second, we tested whether these associations were modified by physical markers (waist circumference, muscle mass, gait speed and handgrip strength), vascular markers (history of cardiac disease, carotid intima media thickness as a proxy for atherosclerosis and carotid distensibility coefficient as a proxy for arterial stiffness) or brain pathology markers (white matter hyperintensities and cortical thickness). RESULTS: In the total sample, there was no association between BP and cognition, however, waist circumference modified this association (p-value for interaction with systolic BP: 0.03, with diastolic BP: 0.01). In individuals with a high waist circumference, higher systolic and diastolic BP tended to be associated with worse cognition, while in individuals with a low waist circumference, higher systolic BP was associated with better cognition. The others physical, vascular and brain pathology markers did not modify the association between BP and cognition. CONCLUSIONS: When examining various markers for physical, vascular and brain vulnerability, only waist circumference affected the association between BP and cognition. This warrants further research to evaluate whether waist circumference may be a marker in clinical practice influencing the use of antihypertensives in the oldest-old.

Strategic white matter hyperintensity locations for cognitive impairment: A multicenter lesion-symptom mapping study in 3525 memory clinic patients.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

Neuroimaging Correlates of Cognitive Deficits in Wilson's Disease.

BACKGROUND: Cognitive impairment is common in neurological presentations of Wilson's disease (WD). Various domains can be affected, and subclinical deficits have been reported in patients with hepatic presentations. Associations with imaging abnormalities have not been systematically tested. OBJECTIVE: The aim was to determine the neuroanatomical basis for cognitive deficits in WD. METHODS: We performed a 16-item neuropsychological test battery and magnetic resonance brain imaging in 40 patients with WD. The scores for each test were compared between patients with neurological and hepatic presentations and with normative data. Associations with Unified Wilson's Disease Rating Scale neurological examination subscores were examined. Quantitative, whole-brain, multimodal imaging analyses were used to identify associations with neuroimaging abnormalities in chronically treated stable patients. RESULTS: Abstract reasoning, executive function, processing speed, calculation, and visuospatial function scores were lower in patients with neurological presentations than in those with hepatic presentations and correlated with neurological examination subscores. Deficits in abstract reasoning and phonemic fluency were associated with lower putamen volumes even after controlling for neurological severity. About half of patients with hepatic presentations had poor performance in memory for faces, cognitive flexibility, or associative learning relative to normative data. These deficits were associated with widespread cortical atrophy and/or white matter diffusion abnormalities. CONCLUSIONS: Subtle cognitive deficits in patients with seemingly hepatic presentations represent a distinct neurological phenotype associated with diffuse cortical and white matter pathology. This may precede the classical neurological phenotype characterized by movement disorders and executive dysfunction and be associated with basal ganglia damage. A binary phenotypic classification for WD may no longer be appropriate. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis.

Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [ß = -0.037; 95% credible interval (CI) = -0.075, -0.010]. This suggests that simvastatin's beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.

Cancer and Risk of COVID-19 Through a General Community Survey.

Individuals with cancer may be at high risk for coronavirus disease 2019 (COVID-19) and adverse outcomes. However, evidence from large population-based studies examining whether cancer and cancer-related therapy exacerbates the risk of COVID-19 infection is still limited. Data were collected from the COVID Symptom Study smartphone application since March 29 through May 8, 2020. Among 23,266 participants with cancer and 1,784,293 without cancer, we documented 10,404 reports of a positive COVID-19 test. Compared with participants without cancer, those living with cancer had a 60% increased risk of a positive COVID-19 test. Among patients with cancer, current treatment with chemotherapy or immunotherapy was associated with a 2.2-fold increased risk of a positive test. The association between cancer and COVID-19 infection was stronger among participants >65 years and males. Future studies are needed to identify subgroups by tumor types and treatment regimens who are particularly at risk for COVID-19 infection and adverse outcomes.

Geo-social gradients in predicted COVID-19 prevalence in Great Britain: results from 1 960 242 users of the COVID-19 Symptoms Study app.

Understanding the geographical distribution of COVID-19 through the general population is key to the provision of adequate healthcare services. Using self-reported data from 1 960 242 unique users in Great Britain (GB) of the COVID-19 Symptom Study app, we estimated that, concurrent to the GB government sanctioning lockdown, COVID-19 was distributed across GB, with evidence of 'urban hotspots'. We found a geo-social gradient associated with predicted disease prevalence suggesting urban areas and areas of higher deprivation are most affected. Our results demonstrate use of self-reported symptoms data to provide focus on geographical areas with identified risk factors.

Late onset depression: dopaminergic deficit and clinical features of prodromal Parkinson's disease: a cross-sectional study.

BACKGROUND: Late onset depression (LOD) may precede the diagnosis of Parkinson's disease (PD) or dementia with Lewy bodies (DLB). We aimed to determine the rate of clinical and imaging features associated with prodromal PD/DLB in patients with LOD. METHODS: In a cross-sectional design, 36 patients with first onset of a depressive disorder (Diagnostic and Statistical Manual of Mental Disorders IV criteria) diagnosed after the age of 55 (LOD group) and 30 healthy controls (HC) underwent a detailed clinical assessment. In addition, 28/36 patients with LOD and 20/30 HC underwent a head MRI and 29/36 and 25/30, respectively, had dopamine transporter imaging by 123I-ioflupane single-photon emission computed tomography (SPECT) imaging. Image analysis of both scans was performed by a rater blind to the participant group. Results of clinical assessments and imaging results were compared between the two groups. RESULTS: Patients with LOD (n=36) had significantly worse scores than HC (n=30) on the PD screening questionnaire (mean (SD) 1.8 (1.9) vs 0.8 (1.2); p=0.01), Movement Disorder Society Unified Parkinson's Disease Rating Scale total (mean (SD) 19.2 (12.7) vs 6.1 (5.7); p<0.001), REM-sleep behaviour disorder screening questionnaire (mean (SD) 4.3 (3.2) vs 2.1 (2.1); p=0.001), Lille Apathy Rating Scale (mean (SD) -23.3 (9.6) vs -27.0 (4.7); p=0.04) and the Scales for Outcomes in PD-Autonomic (mean (SD) 14.9 (8.7) vs 7.7 (4.9); p<0.001). Twenty-four per cent of patients with LOD versus 4% HC had an abnormal 123I-ioflupane SPECT scan (p=0.04). CONCLUSIONS: LOD is associated with increased rates of motor and non-motor features of PD/DLB and of abnormal 123I-ioflupane SPECTs. These results suggest that patients with LOD should be considered at increased risk of PD/DLB.

Anxiety and depression symptoms after COVID-19 infection: results from the COVID Symptom Study app.

BACKGROUND: Mental health issues have been reported after SARS-CoV-2 infection. However, comparison to prevalence in uninfected individuals and contribution from common risk factors (eg, obesity and comorbidities) have not been examined. We identified how COVID-19 relates to mental health in the large community-based COVID Symptom Study. METHODS: We assessed anxiety and depression symptoms using two validated questionnaires in 413148 individuals between February and April 2021; 26998 had tested positive for SARS-CoV-2. We adjusted for physical and mental prepandemic comorbidities, body mass index (BMI), age and sex. FINDINGS: Overall, 26.4% of participants met screening criteria for general anxiety and depression. Anxiety and depression were slightly more prevalent in previously SARS-CoV-2-positive (30.4%) vs SARS-CoV-2-negative (26.1%) individuals. This association was small compared with the effect of an unhealthy BMI and the presence of other comorbidities, and not evident in younger participants (≤40 years). Findings were robust to multiple sensitivity analyses. Association between SARS-CoV-2 infection and anxiety and depression was stronger in individuals with recent (<30 days) versus more distant (>120 days) infection, suggesting a short-term effect. INTERPRETATION: A small association was identified between SARS-CoV-2 infection and anxiety and depression symptoms. The proportion meeting criteria for self-reported anxiety and depression disorders is only slightly higher than prepandemic.