GEDEVO: An Evolutionary Graph Edit Distance Algorithm for Biological Network Alignment

Introduction: With the so-called OMICS technology the scientific community has generated huge amounts of data that allow us to reconstruct the interplay of all kinds of biological entities. The emerging interaction networks are usually modeled as graphs with thousands of nodes and tens of thousands of edges between them. In addition to sequence alignment, the comparison of biological networks has proven great potential to infer the biological function of proteins and genes. However, the corresponding network alignment problem is computationally hard and theoretically intractable for real world instances. Results: We therefore developed GEDEVO, a novel tool for efficient graph comparison dedicated to real-world size biological networks. Underlying our approach is the so-called Graph Edit Distance (GED) model, where one graph is to be transferred into another one, with a minimal number of (or more general: minimal costs for) edge insertions and deletions. We present a novel evolutionary algorithm aiming to minimize the GED, and we compare our implementation against state of the art tools: SPINAL, GHOST, CGRAAL, and MIGRAAL. On a set of protein-protein interaction networks from different organisms we demonstrate that GEDEVO outperforms the current methods. It thus refines the previously suggested alignments based on topological information only. Conclusion: With GEDEVO, we account for the constantly exploding number and size of available biological networks. The software as well as all used data sets are publicly available at http://gedevo.mpi-inf.mpg.de

Level-Specific Volumetric BMD Threshold Values for the Prediction of Incident Vertebral Fractures Using Opportunistic QCT: A Case-Control Study

Purpose: To establish and evaluate the diagnostic accuracy of volumetric bone mineral density (vBMD) threshold values at different spinal levels, derived from opportunistic quantitative computed tomography (QCT), for the prediction of incident vertebral fractures (VF). Materials and Methods: In this case-control study, 35 incident VF cases (23 women, 12 men; mean age: 67 years) and 70 sex- and age-matched controls were included, based on routine multi detector CT (MDCT) scans of the thoracolumbar spine. Trabecular vBMD was measured from routine baseline CT scans of the thoracolumbar spine using an automated pipeline including vertebral segmentation, asynchronous calibration for HU-to-vBMD conversion, and correction of intravenous contrast medium (https://anduin.bonescreen.de). Threshold values at T1-L5 were calculated for the optimal operating point according to the Youden index and for fixed sensitivities (60 – 85%) in receiver operating characteristic (ROC) curves. Results: vBMD at each single level of the thoracolumbar spine was significantly associated with incident VFs (odds ratio per SD decrease [OR], 95% confidence interval [CI] at T1-T4: 3.28, 1.66–6.49; at T5-T8: 3.28, 1.72–6.26; at T9-T12: 3.37, 1.78–6.36; and at L1-L4: 3.98, 1.97–8.06), independent of adjustment for age, sex, and prevalent VF. AUC showed no significant difference between vertebral levels and was highest at the thoracolumbar junction (AUC = 0.75, 95%-CI = 0.63 - 0.85 for T11-L2). Optimal threshold values increased from lumbar (L1-L4: 52.0 mg/cm³) to upper thoracic spine (T1-T4: 69.3 mg/cm³). At T11-L2, T12-L3 and L1-L4, a threshold of 80.0 mg/cm³ showed sensitivities of 85 - 88%, and specificities of 41 - 49%. To achieve comparable sensitivity (85%) at more superior spinal levels, resulting thresholds were higher: 114.1 mg/cm³ (T1-T4), 92.0 mg/cm³ (T5-T8), 88.2 mg/cm³ (T9-T12). Conclusions: At all levels of the thoracolumbar spine, lower vBMD was associated with incident VFs in an elderly, predominantly oncologic patient population. Automated opportunistic osteoporosis screening of vBMD along the entire thoracolumbar spine allows for risk assessment of imminent VFs. We propose level-specific vBMD threshold at the thoracolumbar spine to identify individuals at high fracture risk

Proposed diagnostic volumetric bone mineral density thresholds for osteoporosis and osteopenia at the cervicothoracic spine in correlation to the lumbar spine

Objectives: To determine the correlation between cervicothoracic and lumbar volumetric bone mineral density (vBMD) in an average cohort of adults and to identify specific diagnostic thresholds for the cervicothoracic spine on the individual subject level. Methods: In this HIPPA–compliant study, we retrospectively included 260 patients (59.7 ± 18.3 years, 105 women), who received a contrast-enhanced or non-contrast-enhanced CT scan. vBMD was extracted using an automated pipeline (https://anduin.bonescreen.de). The association of vBMD between each vertebra spanning C2–T12 and the averaged values at the lumbar spine (L1–L3) was analyzed before and after semiquantitative assessment of fracture status and degeneration, and respective vertebra-specific cut-off values for osteoporosis were calculated using linear regression. Results: In both women and men, trabecular vBMD decreased with age in the cervical, thoracic, and lumbar regions. vBMD values of cervicothoracic vertebrae showed strong correlations with lumbar vertebrae (L1–L3), with a median Pearson value of r = 0.87 (range: r$_{C2}$ = 0.76 to r$_{T12}$ = 0.96). The correlation coefficients were significantly lower (p < 0.0001) without excluding fractured and degenerated vertebrae, median r = 0.82 (range: r$_{C2}$ = 0.69 to r$_{T12}$ = 0.93). Respective cut-off values for osteoporosis peaked at C4 (209.2 mg/ml) and decreased to 83.8 mg/ml at T12. Conclusion: Our data show a high correlation between clinically used mean L1–L3 values and vBMD values elsewhere in the spine, independent of age. The proposed cut-off values for the cervicothoracic spine therefore may allow the determination of low bone mass even in clinical cases where only parts of the spine are imaged. Key Points: vBMD of all cervicothoracic vertebrae showed strong correlation with lumbar vertebrae (L1–L3), with a median Pearson’s correlation coefficient of r = 0.87 (range: r$_{C2}$ = 0.76 to r$_{T12}$ = 0.96). The correlation coefficients were significantly lower (p < 0.0001) without excluding fractured and moderate to severely degenerated vertebrae, median r = 0.82 (range: r$_{C2}$ = 0.69 to r$_{T12}$ = 0.93). We postulate that trabecular vBMD < 200 mg/ml for the cervical spine and < 100 mg/ml for the thoracic spine are strong indicators of osteoporosis, similar to < 80 mg/ml at the lumbar spine

Incidental vertebral fracture prediction using neuronal network-based automatic spine segmentation and volumetric bone mineral density extraction from routine clinical CT scans.

OBJECTIVES To investigate vertebral osteoporotic fracture (VF) prediction by automatically extracted trabecular volumetric bone mineral density (vBMD) from routine CT, and to compare the model with fracture prevalence-based prediction models. METHODS This single-center retrospective study included patients who underwent two thoraco-abdominal CT scans during clinical routine with an average inter-scan interval of 21.7 ± 13.1 months (range 5-52 months). Automatic spine segmentation and vBMD extraction was performed by a convolutional neural network framework (anduin.bonescreen.de). Mean vBMD was calculated for levels T5-8, T9-12, and L1-5. VFs were identified by an expert in spine imaging. Odds ratios (ORs) for prevalent and incident VFs were calculated for vBMD (per standard deviation decrease) at each level, for baseline VF prevalence (yes/no), and for baseline VF count (n) using logistic regression models, adjusted for age and sex. Models were compared using Akaike's and Bayesian information criteria (AIC & BIC). RESULTS 420 patients (mean age, 63 years ± 9, 276 males) were included in this study. 40 (25 female) had prevalent and 24 (13 female) had incident VFs. Individuals with lower vBMD at any spine level had higher odds for VFs (L1-5, prevalent VF: OR,95%-CI,p: 2.2, 1.4-3.5,p=0.001; incident VF: 3.5, 1.8-6.9,p<0.001). In contrast, VF status (2.15, 0.72-6.43,p=0.170) and count (1.38, 0.89-2.12,p=0.147) performed worse in incident VF prediction. Information criteria revealed best fit for vBMD-based models (AIC vBMD=165.2; VF status=181.0; count=180.7). CONCLUSIONS VF prediction based on automatically extracted vBMD from routine clinical MDCT outperforms prediction models based on VF status and count. These findings underline the importance of opportunistic quantitative osteoporosis screening in clinical routine MDCT data

Automated Opportunistic Osteoporosis Screening in Routine Computed Tomography of the Spine: Comparison With Dedicated Quantitative CT

Opportunistic osteoporosis screening in nondedicated routine computed tomography (CT) is of increasing importance. The purpose of this study was to compare lumbar volumetric bone mineral density (vBMD) assessed by a convolutional neural network (CNN)-based framework in routine CT to vBMD from dedicated quantitative CT (QCT), and to evaluate the ability of vBMD and surrogate measurements of Hounsfield units (HU) to distinguish between patients with and without osteoporotic vertebral fractures (VFs). A total of 144 patients (median age: 70.7 years, 93 females) with clinical routine CT (eight different CT scanners, 120 kVp or 140 kVp, with and without intravenous contrast medium) and dedicated QCT acquired within ≤30 days were included. Vertebral measurements included (i) vBMD from the CNN-based approach including automated vertebral body labeling, segmentation, and correction of the contrast media phase for routine CT data (vBMD_OPP), (ii) vBMD from dedicated QCT (vBMD_QCT), and (iii) noncalibrated HU from vertebral bodies of routine CT data as previously proposed for immanent opportunistic osteoporosis screening based on CT attenuation. The intraclass correlation coefficient (ICC) for vBMD_QCT versus vBMD_OPP indicated better agreement (ICC = 0.913) than the ICC for vBMD_QCT versus noncalibrated HU (ICC = 0.704). Bland-Altman analysis showed data points from 137 patients (95.1%) within the limits of agreement (LOA) of -23.2 to 25.0 mg/cm3 for vBMD_QCT versus vBMD_OPP. Osteoporosis (vBMD <80 mg/cm3 ) was detected in 89 patients (vBMD_QCT) and 88 patients (vBMD_OPP), whereas no patient crossed the diagnostic thresholds from normal vBMD to osteoporosis or vice versa. In a subcohort of 88 patients (thoracolumbar spine covered by imaging for VF reading), 69 patients showed one or more prevalent VFs, and the performance for discrimination between patients with and without VFs was best for vBMD_OPP (area under the curve [AUC] = 0.862; 95% confidence interval [CI], 0.771-0.953). In conclusion, automated opportunistic osteoporosis screening in routine CT of various scanner setups is feasible and may demonstrate high diagnostic accuracy for prevalent VFs. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

Incidental vertebral fracture prediction using neuronal network-based automatic spine segmentation and volumetric bone mineral density extraction from routine clinical CT scans

ObjectivesTo investigate vertebral osteoporotic fracture (VF) prediction by automatically extracted trabecular volumetric bone mineral density (vBMD) from routine CT, and to compare the model with fracture prevalence-based prediction models.MethodsThis single-center retrospective study included patients who underwent two thoraco-abdominal CT scans during clinical routine with an average inter-scan interval of 21.7 ± 13.1 months (range 5–52 months). Automatic spine segmentation and vBMD extraction was performed by a convolutional neural network framework (anduin.bonescreen.de). Mean vBMD was calculated for levels T5-8, T9-12, and L1-5. VFs were identified by an expert in spine imaging. Odds ratios (ORs) for prevalent and incident VFs were calculated for vBMD (per standard deviation decrease) at each level, for baseline VF prevalence (yes/no), and for baseline VF count (n) using logistic regression models, adjusted for age and sex. Models were compared using Akaike’s and Bayesian information criteria (AIC &amp; BIC).Results420 patients (mean age, 63 years ± 9, 276 males) were included in this study. 40 (25 female) had prevalent and 24 (13 female) had incident VFs. Individuals with lower vBMD at any spine level had higher odds for VFs (L1-5, prevalent VF: OR,95%-CI,p: 2.2, 1.4–3.5,p=0.001; incident VF: 3.5, 1.8–6.9,p&lt;0.001). In contrast, VF status (2.15, 0.72–6.43,p=0.170) and count (1.38, 0.89–2.12,p=0.147) performed worse in incident VF prediction. Information criteria revealed best fit for vBMD-based models (AIC vBMD=165.2; VF status=181.0; count=180.7).ConclusionsVF prediction based on automatically extracted vBMD from routine clinical MDCT outperforms prediction models based on VF status and count. These findings underline the importance of opportunistic quantitative osteoporosis screening in clinical routine MDCT data

Sex differences and age-related changes in vertebral body volume and volumetric bone mineral density at the thoracolumbar spine using opportunistic QCT

ObjectivesTo quantitatively investigate the age- and sex-related longitudinal changes in trabecular volumetric bone mineral density (vBMD) and vertebral body volume at the thoracolumbar spine in adults.MethodsWe retrospectively included 168 adults (mean age 58.7 ± 9.8 years, 51 women) who received ≥7 MDCT scans over a period of ≥6.5 years (mean follow-up 9.0 ± 2.1 years) for clinical reasons. Level-wise vBMD and vertebral body volume were extracted from 22720 thoracolumbar vertebrae using a convolutional neural network (CNN)-based framework with asynchronous calibration and correction of the contrast media phase. Human readers conducted semiquantitative assessment of fracture status and bony degenerations.ResultsIn the 40-60 years age group, women had a significantly higher trabecular vBMD than men at all thoracolumbar levels (p&lt;0.05 to p&lt;0.001). Conversely, men, on average, had larger vertebrae with lower vBMD. This sex difference in vBMD did not persist in the 60-80 years age group. While the lumbar (T12-L5) vBMD slopes in women only showed a non-significant trend of accelerated decline with age, vertebrae T1-11 displayed a distinct pattern, with women demonstrating a significantly accelerated decline compared to men (p&lt;0.01 to p&lt;0.0001). Between baseline and last follow-up examinations, the vertebral body volume slightly increased in women (T1-12: 1.1 ± 1.0 cm3; L1-5: 1.0 ± 1.4 cm3) and men (T1-12: 1.2 ± 1.3 cm3; L1-5: 1.5 ± 1.6 cm3). After excluding vertebrae with bony degenerations, the residual increase was only small in women (T1-12: 0.6 ± 0.6 cm3; L1-5: 0.7 ± 0.7 cm3) and men (T1-12: 0.7 ± 0.6 cm3; L1-5: 1.2 ± 0.8 cm3). In non-degenerated vertebrae, the mean change in volume was &lt;5% of the respective vertebral body volumes.ConclusionSex differences in thoracolumbar vBMD were apparent before menopause, and disappeared after menopause, likely attributable to an accelerated and more profound vBMD decline in women at the thoracic spine. In patients without advanced spine degeneration, the overall volumetric changes in the vertebral body appeared subtle

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements