key: cord-0962805-00d386vb
authors: Basty, N.; Sorokin, E. P.; Thanaj, M.; Srinivasan, R.; Whitcher, B.; Bell, J. D.; Cule, M.; Thomas, E. L.
title: Abdominal Imaging Associates Body Composition with COVID-19 Severity
date: 2022-02-24
journal: nan
DOI: 10.1101/2022.02.22.22270091
sha: 1b12d12e8912ce839d0cf5e1e137f3fc9ff5d7cd
doc_id: 962805
cord_uid: 00d386vb

The main drivers of COVID-19 disease severity and the impact of COVID-19 on long-term health after recovery are yet to be fully understood. Medical imaging studies investigating COVID-19 to date have mostly been limited to small datasets and post-hoc analyses of severe cases. The UK Biobank recruited recovered SARS-CoV-2 positive individuals (n=967) and matched controls (n=913) who were extensively imaged prior to the pandemic and underwent follow-up scanning. In this study, we investigated longitudinal changes in body composition, as well as the associations of pre-pandemic image-derived phenotypes with COVID-19 severity. Our longitudinal analysis, in a population of mostly mild cases, associated a decrease in lung volume with SARS-CoV-2 positivity. We also observed that increased visceral adipose tissue and liver fat, and reduced muscle volume, prior to COVID-19, were associated with COVID-19 disease severity. Finally, we trained a machine classifier with demographic, anthropometric and imaging traits, and showed that visceral fat, liver fat and muscle volume have prognostic value for COVID-19 disease severity beyond the standard demographic and anthropometric measurements. This combination of image-derived phenotypes from abdominal MRI scans and ensemble learning to predict risk may have future clinical utility in identifying populations at-risk for a severe COVID-19 outcome.

Introduction COVID-19, the disease caused by the virus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), impacts human health and has debilitating effects in both the short-and longer term [1] . A complex array of sequelae associated with COVID-19 have been reported [2] , confirming earlier hypotheses that the commonly observed COVID-19 hyperinflammatory response results in damage to multiple systems and organs [3] . Individuals with both advanced age as well as chronic comorbidities such as obesity and diabetes are known to be at higher risk of severe disease and poorer prognosis following COVID-19 infection [4] , with adverse COVID-19 outcomes thought to be associated with markers of accelerated aging [5, 6] .

Whilst there are few imaging studies that prospectively delineate the impact of COVID-19 on organ health, there are multiple case reports and imaging studies using computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound to assess patients post-infection, with some showing consistent changes characteristic of the response to COVID-19 infection. These include cardiac changes in inflammatory edema, fibrosis, impaired ventricular function, and mass [7] [8] [9] [10] , with acute myocardial injury and myocarditis reported in 8-12% patients discharged post COVID-19 and consequently increased risk of heart failure and cardiac arrhythmias [11, 12] . Characteristic damage to the lungs such as the widely reported "ground-glass opacification" due to interstitial thickening, parenchymal abnormalities, edema, and reduced vital capacity, have also been reported [9, 10, 13] . A significant proportion of patients hospitalized with COVID-19 have developed moderate or severe kidney damage, resulting in dialysis [14] [15] [16] , with reported imaging findings including renal infarcts, increased cortical echogenicity (a marker of renal disease), increased T1 (reported to indicate declining kidney function), reduced renal perfusion and increased perinephric fat stranding [9, 10, 17, 18] . Reported changes in the liver include inflammation, fibrosis, elasticity, with conflicting reports regarding changes in liver fat and the biliary system including cholangiopathy, and presence of gallbladder 'sludge' [10, [19] [20] [21] [22] . Despite biochemical changes suggesting pancreatic involvement, imaging observations have been few, with reports of a 'bulky' pancreas and peripancreatic fat stranding and inflammation [10, 23] . Muscle involvement is frequently reported, from acute imaging observations, such as edema and myositis, which appear to be more common in patients with myalgia and long-term muscular changes such as sarcopenia and cachexia [24] . However, it is difficult to definitively discern from many of these studies whether the findings arise directly from SARS-CoV-2 infection, relate to the demographics of the patient population, or are in part related to the actual clinical treatment, including mechanical ventilation/hypoxia, effects of systemic inflammation, drug toxicity or changes relating to prolonged inactivity [24, 25] .

The UK Biobank (UKBB) is a prospective cohort study of half a million adults in the UK. Beginning in 2014, the UKBB implemented an extensive standardized imaging protocol covering the abdomen, heart and brain [26] . To investigate longitudinal changes attributable to infection with SARS-CoV-2, the UKBB invited individuals who had recovered from SARS-CoV-2 and individuals who were matched negative controls to attend a re-imaging session to determine the impact of COVID-19 on body composition and organ health. The UKBB has already provided invaluable insights regarding the prevalence of COVID-19 [27] , as well as its associations with cardiometabolic profiles [28] , frailty [29] , and the ability to predict disease severity [30, 31] and mortality [32] . In contrast to the prevailing literature that COVID-19 can result in a number of cardiovascular disorders [33] , an analysis of cardiac MRI found no significant changes between cases before and after infection, compared to controls, which the authors attributed to generally a milder disease in the UKBB cohort compared to most clinical studies [34] . However, a brain MRI study from the same UKBB cohort reported multiple changes including loss of gray matter in several regions of the brain associated with the primary olfactory and gustatory systems [35] .

The aim of the current study is to assess the impact of SARS-CoV-2 infection on abdominal organ health and body composition in 967 cases and 913 controls. Moreover, we assessed the association between severity of COVID-19 disease and multi-organ image-derived phenotypes from the baseline imaging visit. The findings from this study are relevant for determining long-term outcomes and future health needs for both populations and individuals recovering from COVID-19, as well as shedding light on possible factors for disease severity.

Approximately 45,000 UKBB participants have attended a baseline MRI scanning session (brain, heart, and abdomen) prior to the appearance of SARS-CoV-2 in the UK. Starting from February 2021, a total of 1,880 participants who attended the first imaging visit were recruited to a new re-imaging study aiming to determine the impact of COVID-19. Individuals with a confirmed COVID-19 diagnosis (from results available through primary care data, hospital records, antigen tests obtained from Public Health data records, or home-based antibody lateral flow kits sent by the UKBB to participants) were invited to take part in the study, together with a matched control group. The control group was selected based on negative results or no history of positive results from the aforementioned sources. Cases and controls were paired based on sex, ethnicity, age (± 6 months), imaging assessment centre, and date of initial baseline scan (± 6 months). Due to small numbers of non-white participants, ethnic matching was based on a classification of white vs non-white. In line with UK travel restrictions at the time, participants were restricted to those living within 60 km of the UKBB scanning centers at Stockport, Newcastle, and Reading.

Participant data from the UKBB cohort was obtained as previously described [36] through UKBB Access Application number 44584. The UKBB has approval from the North West Multi-Centre Research Ethics Committee (REC reference: 11/NW/0382). All methods were performed under the relevant guidelines and regulations, and informed consent was obtained from all participants. Researchers may apply to use the UKBB data resource by submitting a health-related research proposal that is in the public interest. More information may be found on the UKBB researchers and resource catalogue pages (https://www.ukbiobank.ac.uk).

Full details regarding the UKBB MRI abdominal protocol have previously been reported [26] . The data included in this paper focused on the neck-to-knee Dixon MRI acquisition, separate single-slice quantitative MRI acquisitions of the liver and pancreas, and T1-weighted pancreas volume. We processed all available image data for cases and controls using our previously published image processing pipeline [37] . We subsequently generated image-derived phenotypes (IDPs) of abdominal organs, adipose tissue, and muscles using convolutional neural networks [37] [38] [39] . We included a total of twelve IDPs in this study: volumes of abdominal subcutaneous adipose tissue (ASAT), visceral adipose tissue (VAT), liver, lungs, iliopsoas muscles, kidneys, pancreas, spleen, as well as proton density fat fraction (PDFF) measures of liver and pancreas fat content, and organ iron concentration of the liver and pancreas.

All summary statistics, hypothesis tests, models were performed using the R3.6.3 software environment for statistical computing and graphics [40] . Visualization was performed using the ggplot2 v3.3.5 package. Descriptive statistics are provided as mean, standard deviation, and range for continuous traits, and as mean, standard deviation, and 95% confidence interval for binary traits. Differences between groups were assessed for statistical significance using a Chi-squared goodness-of-fit test for binary traits, and Student's t-test for continuous traits.

In our analyses, we assessed the longitudinal effects of SARS-CoV-2 infection as well as the severity of COVID-19 based on pre-pandemic imaging alone. We determined COVID-19 severity based upon hospitalization with International Classification of Diseases 10th Revision (ICD-10) diagnosis codes U071.1 or U071.2, plus a positive test status from one of the available sources. We also filtered severe cases by pneumonia diagnosis (J128.2) and by placement on a ventilator (Z99.11). For the severity analyses of first imaging visit data only, a second category of COVID-19 severe outcomes also included death with a recorded cause of death as COVID-19 (U07.1). Follow-up analysis of pulmonary diseases was conducted using hospital billing codes J00-J99. The severity analysis included 140 additional SARS-CoV-2 positive samples beyond the matched case/control design in the first analysis, of participants who had attended the first imaging visit but were not recruited as part of the re-imaging study.

Associations between changes in imaging phenotypes and COVID-19 diagnosis required calculating the age difference between the two imaging visits: ∆age = (age rescan -age baseline ). To capture quadratic effects of age, (∆age) 2 was calculated as the difference of the squared age at rescanning and the squared age at baseline: ∆age 2 = (age rescan -age baseline ) 2 . The following model was selected to associate changes in abdominal IDPs with COVID-19 diagnosis:

= β + β + ∆ · β + ∆ 2 · β 2 + · β describes fixed effects: sex, ethnicity, height, BMI, smoking status, alcohol consumption, and Townsend deprivation index. Baseline and rescan IDP values were standardized. During model selection, we initially included an interaction term between COVID positivity and sex but did not observe that any significant interactions (p>0.05), so the interaction term was dropped from the final model above.

As a logistic regression model, COVID-19 severity was regressed on standardized baseline IDP values and fixed effect covariates:

Here, included imaging age, imaging age squared, sex, ethnicity, Townsend deprivation index, height, BMI, smoking status, alcohol consumption, and baseline imaging center location. Baseline imaging center was encoded as a categorical variable. During model selection we tested whether baseline IDP association with severity differed by sex but the interaction term was not significant for any of the baseline IDPs (p>0.05). We modeled severity as hospitalized and non-hospitalized outcomes; severe (hospitalization + death) and non-severe outcomes; and death vs hospitalization. For multiple test correction of independent traits, a Bonferroni adjustment was used to determine a significance threshold, where alpha was set at 0.05. For dependent traits, false discovery rate (FDR) was estimated from p-values using the Benjamini-Hochberg method [41] , and a threshold of FDR ≤ 0.05 determined significance.

A multivariate model was also developed for COVID-19 severity with a penalty term added to the least-squares loss function to implement LASSO L1-regularization.

Here, included twelve IDPs adjusted for covariates. LASSO was implemented using the glmnet package. The shrinkage parameter was set as 0.0238, its minimum value during λ cross-validation.

We developed random forest [42] classifiers for COVID-19 severity prediction in python 3.7.2 using the scikit-learn 1.0.2 package [43] . We tested an increasing number of forests, doubling the estimator number from 1 to 1024, and found the best results with 128 trees. Model training was conducted with 10-fold cross-validation on an 80% randomized data split for training, with the remaining 20% kept aside as a testing set used to assess model performance. Area under the receiver operating characteristic (ROC) curve (AUC) and F1 score were used as performance metrics. We trained three kinds of models, two without IDPs and one with IDP, in order to assess potentially added value from IDPs on top of standard anthropometric traits.

An example of the 3D segmentations obtained from the neck-to-knee Dixon MRI acquisition for one of the COVID-19 rescan participants is shown in Figure 1 (generated using 3D Slicer [44] ), including the liver (yellow), lungs (blue), spleen (purple), kidneys (green), ASAT (white), VAT (orange transparent, making internal organs visible), iliopsoas muscles (pink), and the pancreas (red).

renderings of image-derived phenotypes obtained after image preprocessing and segmentation pipelines for that same participant. 3D segmentations: Liver (yellow), lungs (blue), spleen (purple), kidneys (green), abdominal subcutaneous adipose tissue (white), visceral adipose tissue (orange transparent), iliopsoas muscles (pink), pancreas (red).

Of 1,955 matched cases and controls recruited in the COVID-19 study, 51.2% (n=1,000) tested positive for SARS-CoV-2 via one of four assays, and 48.8% (n=955) tested negative. We examined baseline demographics of the COVID-19 study cohort with complete covariates (n=1,880) including age, sex, ethnicity, height, BMI, waist/hip ratio, blood 6 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted February 24, 2022. ; pressure, Townsend deprivation index, smoking status, and diagnosis rate of several common diseases. The largest difference observed was in non-alcoholic fatty liver disease (NAFLD) diagnosis (p chisq =0.02), but as with all other demographic parameters, this difference did not achieve the threshold for statistical significance, indicating effective case-control matching ( Table 1) To identify changes in abdominal IDPs associated with SARS-CoV-2 test positivity, we first examined the distributions in abdominal IDPs between the baseline scan and repeat scan. We observed differences in the distributions of abdominal IDPs by sex ( Table 2) . To test whether SARS-CoV-2 diagnosis was a significant factor in abdominal IDP changes between the two imaging visits, we developed a multiple linear regression model, adjusting for sex and additional confounding variables (Methods). Sex, age, and BMI were among the demographic parameters most highly associated with changes in abdominal IDPs between baseline and rescan visits (Figure 2 and We tested whether baseline IDP values, assessed before the pandemic, were associated with severity of COVID-19 disease. We defined severity based on first ascertaining for SARS-CoV-2 test positivity during the study period, then combining death, hospitalization, and GP records, including searching for hospitalization with COVID-19, critical care treatment, pneumonia diagnosis, and/or placement on a ventilator during the study period.

Of the baseline imaging cohort with a positive SARS-CoV-2 test result included in this study (n=1,107), 16.1% were accompanied by severe disease, comprising hospitalized cases (n=149) and deaths (n=30) from COVID-19. The remaining participants who tested positive for SARS-CoV-2 in this study did not have severe disease (n=928).

In univariate regression modeling of hospitalization versus death from COVID-19, the group that died was significantly older than the hospitalized group (mean difference = 4.7 years; FDR=0.009) (Supplementary Table 2) . In univariate models of all severe cases (n=179) tested against non-severe SARS-CoV-2 infections (n=928), we found that increased age, male sex, increased BMI, increased waist/hip ratio, increased blood pressure, being a smoker, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, myocardial infarction, and type 2 diabetes were all associated with increased risk of having a severe outcome (Supplementary Table 2 ).

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preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in We observed differences in the distributions of baseline abdominal IDPs by disease severity after stratifying by sex ( Table 4) . To test whether baseline abdominal IDPs were associated with COVID-19 severity, we performed multiple linear regression and found that sex and BMI were predictors of COVID-19 severity (Figure 3 and Supplementary Table 3) . We tested whether any of the twelve IDPs were also associated with any severe outcome in the model and found that iliopsoas muscle volume was negatively associated with severity (beta=-0.68; FDR=0.0057), while two variables were positively associated with severity: VAT volume (beta=0.42; FDR=0.0036) and liver PDFF (beta=0.26; FDR=0.043), even after adjustment for ten possible confounders. When testing a milder severity score measured by hospitalization vs non-hospitalization only, iliopsoas muscle volume was associated (beta=-0.65, FDR=0.012) (Supplementary Table 4) . In a multivariate model of association for COVID-19 severity performed with L1 penalization, visceral fat was significant (beta=2.2e-4, p=4.9e-4) (Supplementary We tested whether IDPs could be used to classify and predict COVID-19 disease severity using machine learning with random forests. We compared the performance of a base demographic model (age, sex) to an anthropometric model (age, sex, height, BMI), and finally a full model containing IDPs in addition to demographic and anthropometric predictors. Age and sex were modestly able to discriminate between severe and non-severe outcomes (AUC=0.67), adding height and BMI as additional predictors performed better (AUC=0.75), and the full model was best able to predict disease severity (AUC=0.82) ( Table  5 and Figure 4A) . The best-performing model contained age, sex, height, BMI as well as visceral fat, iliopsoas muscle volume, and liver fat. Investigating feature importances showed that the most significant feature contribution to the random forest classifier came from VAT (19.7%) ( Figure 4B) . Finally, we used the best-performing random forest classifier to predict severity in the remaining UKBB baseline imaging cohort (n=43,464), and estimated that 2,309 individuals (5.31%) would have severe disease.

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preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Table 5 : Severity predictions using random forest. Training was performed using random forests, considering three models. AUC: area under the curve. 

The UK Biobank (UKBB) spearheaded an ambitious endeavor to acquire extensive imaging data for over 100,000 subjects since 2014, and conceived the COVID-19 study to enable this unique longitudinal precision phenotyping research program. For this study, we produced and analyzed abdominal IDPs for 967 cases and 913 matched controls of the UKBB longitudinal COVID-19 study, as well as another 140 severe cases of participants who attended the first imaging visit, identified from hospital records and the death register available from UKBB.

Our longitudinal analysis, examining body composition via twelve IDPs before and after COVID-19, showed a significant decrease in lung volume associated with SARS-CoV-2 positivity. The gold standard measure of lung function is spirometry, with lung volumes generally assessed using whole-body plethysmography or single-breath helium dilution [45, 46] . MRI has previously been used to measure lung volume, but this generally involves acquisition of images during breath-hold at full inflation [47] . Although the neck-to-knee MRI acquisition in the UKBB is not conventionally used for measurements of lung volumes, it 13 All rights reserved. No reuse allowed without permission.

perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in

The copyright holder for this this version posted February 24, 2022. ;

does allow opportunistic assessment of this organ [37] . Thus, our observation of a reduction in lung volume following COVID-19 is consistent with published studies that have shown persistent lung abnormalities following COVID-19 infection, including reduced forced expiratory volume, vital capacity, and forced vital capacity measured by spirometry [48, 49] . Moreover, CT scans showing both reduced lung volume [50] and impaired functional lung volume related to disease severity [51] have been reported. Other studies using pulmonary function tests have reported that lung volumes in patients with mild/moderate COVID-19 are normal [52] . However, most of these studies have assessed patients during/immediately following acute disease followed by a longer-term follow-up, lacking pre-infection information. This clearly is not the case with the current study where pre-infection imaging information was available for both the case and control cohorts. Although the MRI sequences employed in this study were not designed to detect radiological changes such as the characteristic ground-glass opacification, consolidation and lesions [9, 13] , they may be able to provide additional insight into changes occurring as a consequence of infection with SARS-CoV-2. It is worth noting that contrary to most other imaging-based studies relating to COVID-19, which recruited predominantly hospitalized or severe cases, the UKBB longitudinal COVID-19 study deals predominantly (96% or 928 out of 967) with mild cases of the disease. It is therefore interesting that the longitudinal analysis showed significant decrease in lung volume in a population of mostly mild cases, after adjusting for possible confounding factors, potentially shedding some additional insight into mild or asymptomatic response to the disease.

No other significant longitudinal changes were observed in any of our twelve IDPs following COVID-19 infection, despite previous case-control studies reporting differences detectable by MRI attributed to COVID-19 in multiple organs including the liver, kidneys, pancreas, spleen, and muscle [9, 10, 19, 20, 24] . Similarly, there are numerous case reports of individual patients which describe changes in organs throughout the body, although these are mostly linked to severe disease, where it is not always clear whether the reported changes relate to viral infection per se, hypoxia/mechanical ventilation or drug treatments. Interestingly, the first longitudinal study of cardiac phenotypes, also using the UKBB dedicated cardiac imaging dataset, reported no significant changes in cases vs controls, which they attributed to a generally higher prevalence of milder/non-hospitalized disease in this population [34] . However, brain MRI in the same cohort revealed significant gray matter loss in several brain areas [35] , suggesting that even a non-severe COVID-19 infection can cause changes in the brain. The availability of pre-pandemic data in the current abdominal study, and also previous UKBB brain and cardiac studies, reduces the risk of misattributing effects of pre-existing conditions or risk factors to COVID-19, and enables a better insight into the disease. Interestingly, of the three UKBB-based COVID-19 studies, the most significant changes appear to be associated with the brain. This may in part reflect the reportedly higher susceptibility of brain tissue to inflammatory disruption [53] and/or the higher resolution of the brain MRI acquired by the UKBB which make it more likely to detect small anatomical changes.

Our analyses evaluating COVID-19 severity based on body composition prior to infection revealed that severity was associated with elevated visceral adipose tissue and liver fat content as well as smaller iliopsoas muscle volume. It should be noted that participants were 14 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted February 24, 2022. ; not recruited for the COVID-19 re-imaging study based on disease severity, and only a small proportion of the responding participants (4% or 39 out of 967), were classified as having severe disease. However, we determined that 140 UKBB participants who had undergone a baseline imaging visit but not recruited to the re-imaging study had severe COVID-19 based on hospital records and the death register. This enabled the relationship between IDPs and disease severity to be established.

Previous studies have suggested that elevated visceral fat may affect the severity of COVID-19, associated with prognosis and requirement for intensive care [54] [55] [56] [57] . This may be due to higher expression of angiotensin-II (ACE2) in visceral fat (compared with subcutaneous adipose tissue depots), resulting in elevated production of inflammatory cytokines [56] . In our random forest model, visceral fat was the most important feature contributing to disease severity. Like visceral fat, liver fat is known to be an independent risk factor for several conditions, including type 2 diabetes and cardiometabolic disease. More recently, elevated liver fat has been shown to be more prevalent in COVID-19 patients and also indicative of severity and length of hospitalization [58] [59] [60] . Our results confirm these findings, with cases with elevated liver fat showing more severe response to COVID-19 infection, as well as the third most important feature picked up by the random forest disease severity model being liver fat. The mechanism(s) underpinning this effect is unclear, but may entail several interlinked factors, including an intensification of the "cytokine storm" by the pro-inflammatory state of fatty liver [61] , a reduction in an individuals' vitamin D levels, which would make subjects more susceptible to organ damage [62] , enhancement of viral replication arising from increased levels of ACE2 receptor observed in hepatic steatosis [63] and/or the fact that viral replication may be utilizing intracellular lipid stores for its propagation, making tissues with elevated levels of lipid droplets more amenable to viral damage.

Out of all of the 1,107 positive individuals with first imaging visit data, 565 (51%) were female and 542 (49%) were male. It is worth noting that of the 179 severe cases, 72.1% were male and 27.9% were female. This means that men account for more than twice as many severe cases than women in our study even though the case population is evenly distributed between men and women, which matches previous reports of male sex being a risk factor of severe illness and death from COVID-19 [64] . Men are known to accumulate more visceral fat than women, who accumulate more subcutaneous fat [65] . With COVID-19 severity being higher in men, and also significantly associated with higher visceral fat (but not higher abdominal subcutaneous fat) in our study, it is possible that visceral fat is a main risk factor for disease severity, driven by the fact that the disease appears to be targeting adipose tissue cells [66, 67] . We show that image-derived phenotypes are useful biomarkers for identifying at-risk subpopulations. Although the severity estimate in the current study may be lower in post-vaccination populations, our research pinpoints underlining risk factors.

In our analysis, we observed that a smaller iliopsoas volume was associated with a more severe disease outcome. The psoas muscle is a well-recognized marker of frailty and health outcomes [68] , with a small psoas muscle area index measured by ultrasound linked to increased mortality in COVID-19 [69] . However, most studies attempting to determine the relationship between muscle mass and COVID-19 outcomes have repurposed chest images obtained during clinical CT/MRI investigations [70] [71] [72] , whereas our study relies upon standardized research protocols and muscle volumes.

Disease outcome prediction analysis ( Table 5) suggested that body composition IDPs from pre-pandemic imaging improved prediction of COVID-19 severity status. We found that abdominal IDPs improved performance accuracy of a model considering only demographic and anthropometric parameters. In addition to established risk factors of BMI, sex, and age, body composition IDPs therefore have prognostic value for COVID-19 disease severity.

A limitation of the study related to the relative time between scans, which ranged between 1.0-7.3 years (3.2 on average), though we adjusted our models for the difference in age between scans. Although this was a prospective study, subjects were not recruited for baseline MRI scanning in anticipation of the COVID-19 pandemic, therefore changes in the body composition could have arisen from changes in lifestyle or disease progression, unrelated to COVID-19. However, our analysis controlled for multiple confounding factors. Moreover, in a previous separate longitudinal study using a larger UKBB cohort, we reported small but significant changes in several tissues and organs [73] , although none of these were further altered by COVID-19 in our current study. Thus, the fact that in our previous longitudinal study, we did not observe changes in lung volume further increases confidence in our current findings. A further limitation of the study is that the UKBB population does not include younger people or children, with initial recruitment in 2007 covering participants aged 40 to 69 of age, therefore it is unclear whether our observations can be extrapolated to other age groups.

In conclusion, body composition assessed via MRI and image-derived phenotypes can provide significant insight into the impact of COVID-19 and could help to understand its long -term impact on those suffering its aftermath. Our study showed a significant decrease in lung volume in SARS-CoV-2 infected cases. We also showed that increased COVID-19 disease severity is associated with smaller iliopsoas muscle volume, higher liver fat as well as higher visceral adipose tissue. Risk estimates of infectious disease severity using MRI-derived measurements of body muscularity and fat can add precision to risk determined by binary assessment of disease diagnosis and may have clinical utility in the future to stratify at-risk populations.

Through an agreement with the UK Biobank, and to expedite and enable further COVID-19 research, we have made all the image-derived phenotypes obtained from our pipeline [37] available to other researchers. discovery rate. Three associations with baseline IDPs passed significance (FDR<=0.05): Liver PDFF, VAT volume, and iliopsoas muscle volume. Table 4 : Association study of COVID-19 severity (defined as hospitalized cases) and baseline abdominal image-derived phenotypes. This study defined cases as all hospitalized cases but not deaths. Standardized betas, standard errors, Z-scores, and p-values are shown. For details on the regression model, see Methods. FDR, false discovery rate. One association with baseline IDPs passed significance (FDR<=0.05): iliopsoas muscle volume.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted February 24, 2022. ; https://doi.org/10.1101/2022.02.22.22270091 doi: medRxiv preprint

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This work was made possible by the UK Biobank, including staff, funders, and study volunteers. We thank Alan Young and Howard Callen at UK Biobank for facilitating data access, and Amoolya Singh, Chang-Heok Soh and Neha Murad for helpful feedback on the manuscript. This research has been conducted using the UK Biobank Resource under Application Number 44584 and was funded by Calico Life Sciences LLC.

NB, EPS, ELT designed the study. NB and BW implemented the image processing methods. MC, EPS, and RS performed the data processing. EPS designed and performed regression modeling of IDP data, NB, EPS, and RS designed and performed predictive modeling. ELT, EPS, JDB, MT, BW, and NB drafted the manuscript. All authors edited, read, and approved the manuscript.Competing interests EPS, RS, and MC are employees of Calico Life Sciences LLC. NB, BW, JDB, MT, and ELT have no competing interests.

Supplementary Table 1 : Association study of changes in abdominal image-derived phenotypes and SARS-CoV-2 infection. Standardized betas, standard errors, Z-scores, and p-values are shown. For details on the regression models, see Methods. VAT, visceral adipose tissue. ASAT, abdominal subcutaneous adipose tissue. PDFF, proton density fat fraction. FDR, false discovery rate.

Baseline image-derived phenotypes in COVID-19 cases were stratified by disease severity, including separately death, hospitalization, and non-severe outcomes. There were n=515 non-hospitalized female cases and n=413 non-hospitalized male cases, n=43 hospitalized female cases, n=106 hospitalized male cases. For the death data, 7 were female and 23 were male. ASAT: Abdominal subcutaneous adipose tissue, VAT: visceral adipose tissue, PDFF: proton density fat fraction of fat content estimated from MRI and presented as a percentage. For each variable, the mean and standard deviation are shown.