Genetic prediction of quantitative traits: a machine learner's guide focused on height

Machine learning and deep learning have been celebrating many successes in the application to biological problems, especially in the domain of protein folding. Another equally complex and important question has received relatively little attention by the machine learning community, namely the one of prediction of complex traits from genetics. Tackling this problem requires in-depth knowledge of the related genetics literature and awareness of various subtleties associated with genetic data. In this guide, we provide an overview for the machine learning community on current state of the art models and associated subtleties which need to be taken into consideration when developing new models for phenotype prediction. We use height as an example of a continuous-valued phenotype and provide an introduction to benchmark datasets, confounders, feature selection, and common metrics

Not Hot, but Sharp: Dissociation of Pinprick and Heat Perception in Snake Eye Appearance Myelopathy

Following a traumatic spinal cord injury, a 53-year-old male developed a central cord syndrome with at-level neuropathic pain. Magnetic resonance imaging revealed a classical “snake eye” appearance myelopathy, with marked hyperintensities at C5-C7. Clinical examination revealed intact pinprick sensation coupled with lost or diminished thermal/heat sensation. This dissociation could be objectively confirmed through multi-modal neurophysiological assessments. Specifically, contact heat evoked potentials were lost at-level, while pinprick evoked potentials were preserved. This pattern corresponds with that seen after surgical commissural myelotomy. To our knowledge, this is the first time such a dissociation has been objectively documented, highlighting the diagnostic potential of multi-modal neurophysiological assessments. In future studies, a comprehensive assessment of different nociceptive modalities may help elucidate the pathophysiology of neuropathic pain

Tracking Changes in Neuropathic Pain After Acute Spinal Cord Injury

Neuropathic pain represents a primary detrimental outcome of spinal cord injury. A major challenge facing effective management is a lack of surrogate measures to examine the physiology and anatomy of neuropathic pain. To this end, we investigated the relationship between psychophysical responses to tonic heat stimulation and neuropathic pain rating after traumatic spinal cord injury. Subjects provided a continuous rating to 2 min of tonic heat at admission to rehabilitation and again at discharge. Adaptation, temporal summation of pain, and modulation profile (i.e., the relationship between adaptation and temporal summation of pain) were extracted from tonic heat curves for each subject. There was no association between any of the tonic heat outcomes and neuropathic pain severity at admission. The degree of adaptation, the degree of temporal summation of pain, and the modulation profile did not change significantly from admission to discharge. However, changes in modulation profiles between admission and discharge were significantly correlated with changes in neuropathic pain severity (p = 0.027; R2 = 0.323). The modulation profile may represent an effective measure to track changes in neuropathic pain severity from early to later stages of spinal cord injury

Exercise and aerobic capacity in individuals with spinal cord injury:A systematic review with meta-analysis and meta-regression

BACKGROUND: A low level of cardiorespiratory fitness [CRF; defined as peak oxygen uptake (V̇O2peak) or peak power output (PPO)] is a widely reported consequence of spinal cord injury (SCI) and a major risk factor associated with chronic disease. However, CRF can be modified by exercise. This systematic review with meta-analysis and meta-regression aimed to assess whether certain SCI characteristics and/or specific exercise considerations are moderators of changes in CRF.METHODS AND FINDINGS: Databases (MEDLINE, EMBASE, CENTRAL, and Web of Science) were searched from inception to March 2023. A primary meta-analysis was conducted including randomised controlled trials (RCTs; exercise interventions lasting &gt;2 weeks relative to control groups). A secondary meta-analysis pooled independent exercise interventions &gt;2 weeks from longitudinal pre-post and RCT studies to explore whether subgroup differences in injury characteristics and/or exercise intervention parameters explained CRF changes. Further analyses included cohort, cross-sectional, and observational study designs. Outcome measures of interest were absolute (AV̇O2peak) or relative V̇O2peak (RV̇O2peak), and/or PPO. Bias/quality was assessed via The Cochrane Risk of Bias 2 and the National Institute of Health Quality Assessment Tools. Certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Random effects models were used in all meta-analyses and meta-regressions. Of 21,020 identified records, 120 studies comprising 29 RCTs, 67 pre-post studies, 11 cohort, 7 cross-sectional, and 6 observational studies were included. The primary meta-analysis revealed significant improvements in AV̇O2peak [0.16 (0.07, 0.25) L/min], RV̇O2peak [2.9 (1.8, 3.9) mL/kg/min], and PPO [9 (5, 14) W] with exercise, relative to controls (p &lt; 0.001). Ninety-six studies (117 independent exercise interventions comprising 1,331 adults with SCI) were included in the secondary, pooled meta-analysis which demonstrated significant increases in AV̇O2peak [0.22 (0.17, 0.26) L/min], RV̇O2peak [2.8 (2.2, 3.3) mL/kg/min], and PPO [11 (9, 13) W] (p &lt; 0.001) following exercise interventions. There were subgroup differences for RV̇O2peak based on exercise modality (p = 0.002) and intervention length (p = 0.01), but there were no differences for AV̇O2peak. There were subgroup differences (p ≤ 0.018) for PPO based on time since injury, neurological level of injury, exercise modality, and frequency. The meta-regression found that studies with a higher mean age of participants were associated with smaller changes in AV̇O2peak and RV̇O2peak (p &lt; 0.10). GRADE indicated a moderate level of certainty in the estimated effect for RV̇O2peak, but low levels for AV̇O2peak and PPO. This review may be limited by the small number of RCTs, which prevented a subgroup analysis within this specific study design.CONCLUSIONS: Our primary meta-analysis confirms that performing exercise &gt;2 weeks results in significant improvements to AV̇O2peak, RV̇O2peak, and PPO in individuals with SCI. The pooled meta-analysis subgroup comparisons identified that exercise interventions lasting up to 12 weeks yield the greatest change in RV̇O2peak. Upper-body aerobic exercise and resistance training also appear the most effective at improving RV̇O2peak and PPO. Furthermore, acutely injured, individuals with paraplegia, exercising for ≥3 sessions/week will likely experience the greatest change in PPO. Ageing seemingly diminishes the adaptive CRF responses to exercise training in individuals with SCI.REGISTRATION: PROSPERO: CRD42018104342.</p

Automatic Calculation of Cervical Spine Parameters Using Deep Learning: Development and Validation on an External Dataset

STUDY DESIGN Retrospective data analysis. OBJECTIVES This study aims to develop a deep learning model for the automatic calculation of some important spine parameters from lateral cervical radiographs. METHODS We collected two datasets from two different institutions. The first dataset of 1498 images was used to train and optimize the model to find the best hyperparameters while the second dataset of 79 images was used as an external validation set to evaluate the robustness and generalizability of our model. The performance of the model was assessed by calculating the median absolute errors between the model prediction and the ground truth for the following parameters: T1 slope, C7 slope, C2-C7 angle, C2-C6 angle, Sagittal Vertical Axis (SVA), C0-C2, Redlund-Johnell distance (RJD), the cranial tilting (CT) and the craniocervical angle (CCA). RESULTS Regarding the angles, we found median errors of 1.66° (SD 2.46°), 1.56° (1.95°), 2.46° (SD 2.55), 1.85° (SD 3.93°), 1.25° (SD 1.83°), .29° (SD .31°) and .67° (SD .77°) for T1 slope, C7 slope, C2-C7, C2-C6, C0-C2, CT, and CCA respectively. As concerns the distances, we found median errors of .55 mm (SD .47 mm) and .47 mm (.62 mm) for SVA and RJD respectively. CONCLUSIONS In this work, we developed a model that was able to accurately predict cervical spine parameters from lateral cervical radiographs. In particular, the performances on the external validation set demonstrate the robustness and the high degree of generalizability of our model on images acquired in a different institution

Walking Outcome After Traumatic Paraplegic Spinal Cord Injury: The Function of Which Myotomes Makes a Difference?

BACKGROUND: Accurate prediction of walking function after a traumatic spinal cord injury (SCI) is crucial for an appropriate tailoring and application of therapeutical interventions. Long-term outcome of ambulation is strongly related to residual muscle function acutely after injury and its recovery potential. The identification of the underlying determinants of ambulation, however, remains a challenging task in SCI, a neurological disorder presented with heterogeneous clinical manifestations and recovery trajectories. OBJECTIVES: Stratification of walking function and determination of its most relevant underlying muscle functions based on stratified homogeneous patient subgroups. METHODS: Data from individuals with paraplegic SCI were used to develop a prediction-based stratification model, applying unbiased recursive partitioning conditional inference tree (URP-CTREE). The primary outcome was the 6-minute walk test at 6 months after injury. Standardized neurological assessments ≤15 days after injury were chosen as predictors. Resulting subgroups were incorporated into a subsequent node-specific analysis to attribute the role of individual lower extremity myotomes for the prognosis of walking function. RESULTS: Using URP-CTREE, the study group of 361 SCI patients was divided into 8 homogeneous subgroups. The node specific analysis uncovered that proximal myotomes L2 and L3 were driving factors for the differentiation between walkers and non-walkers. Distal myotomes L4-S1 were revealed to be responsible for the prognostic distinction of indoor and outdoor walkers (with and without aids). CONCLUSION: Stratification of a heterogeneous population with paraplegic SCI into more homogeneous subgroups, combined with the identification of underlying muscle functions prospectively determining the walking outcome, enable potential benefit for application in clinical trials and practice

Sensorimotor plasticity after spinal cord injury: a longitudinal and translational study

Objective The objective was to track and compare the progression of neuroplastic changes in a large animal model and humans with spinal cord injury. Methods A total of 37 individuals with acute traumatic spinal cord injury were followed over time (1, 3, 6, and 12 months post-injury) with repeated neurophysiological assessments. Somatosensory and motor evoked potentials were recorded in the upper extremities above the level of injury. In a reverse-translational approach, similar neurophysiological techniques were examined in a porcine model of thoracic spinal cord injury. Twelve Yucatan mini-pigs underwent a contusive spinal cord injury at T10 and tracked with somatosensory and motor evoked potentials assessments in the fore- and hind limbs pre- (baseline, post-laminectomy) and post-injury (10 min, 3 h, 12 weeks). Results In both humans and pigs, the sensory responses in the cranial coordinates of upper extremities/forelimbs progressively increased from immediately post-injury to later time points. Motor responses in the forelimbs increased immediately after experimental injury in pigs, remaining elevated at 12 weeks. In humans, motor evoked potentials were significantly higher at 1-month (and remained so at 1 year) compared to normative values. Conclusions Despite notable differences between experimental models and the human condition, the brain's response to spinal cord injury is remarkably similar between humans and pigs. Our findings further underscore the utility of this large animal model in translational spinal cord injury research

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe