Functional protein representations from biological networks enable diverse cross-species inference.

Transferring knowledge between species is key for many biological applications, but is complicated by divergent and convergent evolution. Many current approaches for this problem leverage sequence and interaction network data to transfer knowledge across species, exemplified by network alignment methods. While these techniques do well, they are limited in scope, creating metrics to address one specific problem or task. We take a different approach by creating an environment where multiple knowledge transfer tasks can be performed using the same protein representations. Specifically, our kernel-based method, MUNK, integrates sequence and network structure to create functional protein representations, embedding proteins from different species in the same vector space. First we show proteins in different species that are close in MUNK-space are functionally similar. Next, we use these representations to share knowledge of synthetic lethal interactions between species. Importantly, we find that the results using MUNK-representations are at least as accurate as existing algorithms for these tasks. Finally, we generalize the notion of a phenolog ('orthologous phenotype') to use functionally similar proteins (i.e. those with similar representations). We demonstrate the utility of this broadened notion by using it to identify known phenologs and novel non-obvious ones supported by current research.

Amniotic fluid transcriptomics reflects novel disease mechanisms in fetuses with myelomeningocele.

BACKGROUND: Cell-free RNA in amniotic fluid supernatant reflects developmental changes in gene expression in the living fetus, which includes genes that are specific to the central nervous system. Although it has been previously shown that central nervous system-specific transcripts are present in amniotic fluid supernatant, it is not known whether changes in the amniotic fluid supernatant transcriptome reflect the specific pathophysiologic condition of fetal central nervous system disorders. In myelomeningocele, there is open communication between the central nervous system and amniotic fluid. OBJECTIVES: The purpose of this study was to identify molecular pathophysiologic changes and novel disease mechanisms that are specific to myelomeningocele by the analysis of amniotic fluid supernatant cell-free RNA in fetuses with open myelomeningocele. STUDY DESIGN: Amniotic fluid supernatant was collected from 10 pregnant women at the time of the open myelomeningocele repair in the second trimester (24.5±1.0 weeks); 10 archived amniotic fluid supernatant from sex and gestational age-matched euploid fetuses without myelomeningocele were used as controls (20.9±0.9 weeks). Differentially regulated gene expression patterns were analyzed with the use of human genome expression arrays. RESULTS: Fetuses with myelomeningocele had 284 differentially regulated genes (176 up- and 108 down-regulated) in amniotic fluid supernatant. Known genes that were associated with myelomeningocele (PRICKLE2, GLI3, RAB23, HES1, FOLR1) and novel dysregulated genes were identified in association with neurodevelopment and neuronal regeneration (up-regulated, GAP43 and ZEB1) or axonal growth and guidance (down-regulated, ACAP1). Pathway analysis demonstrated a significant contribution of inflammation to disease and a broad influence of Wnt signaling pathways (Wnt1, Wnt5A, ITPR1). CONCLUSION: Transcriptomic analyses of living fetuses with myelomeningocele with the use of amniotic fluid supernatant cell-free RNA demonstrated differential regulation of specific genes and molecular pathways relevant to this central nervous system disorder, which resulted in a new understanding of pathophysiologic changes. The data also suggested the importance of pathways that involve secondary disease, such as inflammation, in myelomeningocele. These newly identified pathways may lead to hypotheses that can test novel therapeutic targets as adjuncts to fetal surgical repair.

Landmark Based Bronchoscope Localization for Needle Insertion Under Respiratory Deformation.

Bronchoscopy is currently the least invasive method for definitively diagnosing lung cancer, which kills more people in the United States than any other form of cancer. Successfully diagnosing suspicious lung nodules requires accurate localization of the bronchoscope relative to a planned biopsy site in the airways. This task is challenging because the lung deforms intraoperatively due to respiratory motion, the airways lack photometric features, and the anatomy's appearance is repetitive. In this paper, we introduce a real-time camera-based method for accurately localizing a bronchoscope with respect to a planned needle insertion pose. Our approach uses deep learning and accounts for deformations and overcomes limitations of global pose estimation by estimating pose relative to anatomical landmarks. Specifically, our learned model considers airway bifurcations along the airway wall as landmarks because they are distinct geometric features that do not vary significantly with respiratory motion. We evaluate our method in a simulated dataset of lungs undergoing respiratory motion. The results show that our method generalizes across patients and localizes the bronchoscope with accuracy sufficient to access the smallest clinically-relevant nodules across all levels of respiratory deformation, even in challenging distal airways. Our method could enable physicians to perform more accurate biopsies and serve as a key building block toward accurate autonomous robotic bronchoscopy.

Cell-specific imputation of drug connectivity mapping with incomplete data.

Drug repositioning allows expedited discovery of new applications for existing compounds, but re-screening vast compound libraries is often prohibitively expensive. "Connectivity mapping" is a process that links drugs to diseases by identifying compounds whose impact on expression in a collection of cells reverses the disease's impact on expression in disease-relevant tissues. The LINCS project has expanded the universe of compounds and cells for which data are available, but even with this effort, many clinically useful combinations are missing. To evaluate the possibility of repurposing drugs despite missing data, we compared collaborative filtering using either neighborhood-based or SVD imputation methods to two naive approaches via cross-validation. Methods were evaluated for their ability to predict drug connectivity despite missing data. Predictions improved when cell type was taken into account. Neighborhood collaborative filtering was the most successful method, with the best improvements in non-immortalized primary cells. We also explored which classes of compounds are most and least reliant on cell type for accurate imputation. We conclude that even for cells in which drug responses have not been fully characterized, it is possible to identify unassayed drugs that reverse in those cells the expression signatures observed in disease.

Autonomous medical needle steering in vivo.

The use of needles to access sites within organs is fundamental to many interventional medical procedures both for diagnosis and treatment. Safely and accurately navigating a needle through living tissue to a target is currently often challenging or infeasible because of the presence of anatomical obstacles, high levels of uncertainty, and natural tissue motion. Medical robots capable of automating needle-based procedures have the potential to overcome these challenges and enable enhanced patient care and safety. However, autonomous navigation of a needle around obstacles to a predefined target in vivo has not been shown. Here, we introduce a medical robot that autonomously navigates a needle through living tissue around anatomical obstacles to a target in vivo. Our system leverages a laser-patterned highly flexible steerable needle capable of maneuvering along curvilinear trajectories. The autonomous robot accounts for anatomical obstacles, uncertainty in tissue/needle interaction, and respiratory motion using replanning, control, and safe insertion time windows. We applied the system to lung biopsy, which is critical for diagnosing lung cancer, the leading cause of cancer-related deaths in the United States. We demonstrated successful performance of our system in multiple in vivo porcine studies achieving targeting errors less than the radius of clinically relevant lung nodules. We also demonstrated that our approach offers greater accuracy compared with a standard manual bronchoscopy technique. Our results show the feasibility and advantage of deploying autonomous steerable needle robots in living tissue and how these systems can extend the current capabilities of physicians to further improve patient care.

A Metric for Finding Robust Start Positions for Medical Steerable Needle Automation.

Steerable needles are medical devices with the ability to follow curvilinear paths to reach targets while circumventing obstacles. In the deployment process, a human operator typically places the steerable needle at its start position on a tissue surface and then hands off control to the automation that steers the needle to the target. Due to uncertainty in the placement of the needle by the human operator, choosing a start position that is robust to deviations is crucial since some start positions may make it impossible for the steerable needle to safely reach the target. We introduce a method to efficiently evaluate steerable needle motion plans such that they are safe to variation in the start position. This method can be applied to many steerable needle planners and requires that the needle's orientation angle at insertion can be robotically controlled. Specifically, we introduce a method that builds a funnel around a given plan to determine a safe insertion surface corresponding to insertion points from which it is guaranteed that a collision-free motion plan to the goal can be computed. We use this technique to evaluate multiple feasible plans and select the one that maximizes the size of the safe insertion surface. We evaluate our method through simulation in a lung biopsy scenario and show that the method is able to quickly find needle plans with a large safe insertion surface.

Backward Planning for a Multi-Stage Steerable Needle Lung Robot.

Lung cancer is one of the deadliest types of cancer, and early diagnosis is crucial for successful treatment. Definitively diagnosing lung cancer typically requires biopsy, but current approaches either carry a high procedural risk for the patient or are incapable of reaching many sites of clinical interest in the lung. We present a new sampling-based planning method for a steerable needle lung robot that has the potential to accurately reach targets in most regions of the lung. The robot comprises three stages: a transorally deployed bronchoscope, a sharpened piercing tube (to pierce into the lung parenchyma from the airways), and a steerable needle able to navigate to the target. Planning for the sequential deployment of all three stages under health safety concerns is a challenging task, as each stage depends on the previous one. We introduce a new backward planning approach that starts at the target and advances backwards toward the airways with the goal of finding a piercing site reachable by the bronchoscope. This new strategy enables faster performance by iteratively building a single search tree during the entire computation period, whereas previous forward approaches have relied on repeating this expensive tree construction process many times. Additionally, our method further reduces runtime by employing biased sampling and sample rejection based on geometric constraints. We evaluate this approach using simulation-based studies in anatomical lung models. We demonstrate in comparison with existing techniques that the new approach (i) is more likely to find a path to a target, (ii) is more efficient by reaching targets more than 5 times faster on average, and (iii) arrives at lower-risk paths in shorter time.

Design Considerations for a Steerable Needle Robot to Maximize Reachable Lung Volume.

Steerable needles that are able to follow curvilinear trajectories and steer around anatomical obstacles are a promising solution for many interventional procedures. In the lung, these needles can be deployed from the tip of a conventional bronchoscope to reach lung lesions for diagnosis. The reach of such a device depends on several design parameters including the bronchoscope diameter, the angle of the piercing device relative to the medial axis of the airway, and the needle's minimum radius of curvature while steering. Assessing the effect of these parameters on the overall system's clinical utility is important in informing future design choices and understanding the capabilities and limitations of the system. In this paper, we analyze the effect of various settings for these three robot parameters on the percentage of the lung that the robot can reach. We combine Monte Carlo random sampling of piercing configurations with a Rapidly-exploring Random Trees based steerable needle motion planner in simulated human lung environments to asymptotically accurately estimate the volume of sites in the lung reachable by the robot. We highlight the importance of each parameter on the overall system's reachable workspace in an effort to motivate future device innovation and highlight design trade-offs.

Clinical Concept Embeddings Learned from Massive Sources of Multimodal Medical Data.

Word embeddings are a popular approach to unsupervised learning of word relationships that are widely used in natural language processing. In this article, we present a new set of embeddings for medical concepts learned using an extremely large collection of multimodal medical data. Leaning on recent theoretical insights, we demonstrate how an insurance claims database of 60 million members, a collection of 20 million clinical notes, and 1.7 million full text biomedical journal articles can be combined to embed concepts into a common space, resulting in the largest ever set of embeddings for 108,477 medical concepts. To evaluate our approach, we present a new benchmark methodology based on statistical power specifically designed to test embeddings of medical concepts. Our approach, called cui2vec, attains state-of-the-art performance relative to previous methods in most instances. Finally, we provide a downloadable set of pre-trained embeddings for other researchers to use, as well as an online tool for interactive exploration of the cui2vec embeddings.

STEERABLE NEEDLE TRAJECTORY FOLLOWING IN THE LUNG: TORSIONAL DEADBAND COMPENSATION AND FULL POSE ESTIMATION WITH 5DOF FEEDBACK FOR NEEDLES PASSING THROUGH FLEXIBLE ENDOSCOPES.

Bronchoscopic diagnosis and intervention in the lung is a new frontier for steerable needles, where they have the potential to enable minimally invasive, accurate access to small nodules that cannot be reliably accessed today. However, the curved, flexible bronchoscope requires a much longer needle than prior work has considered, with complex interactions between the needle and bronchoscope channel, introducing new challenges in steerable needle control. In particular, friction between the working channel and needle causes torsional windup along the bronchoscope, the effects of which cannot be directly measured at the tip of thin needles embedded with 5 degree-of-freedom magnetic tracking coils. To compensate for these effects, we propose a new torsional deadband-aware Extended Kalman Filter to estimate the full needle tip pose including the axial angle, which defines its steering direction. We use the Kalman Filter estimates with an established sliding mode controller to steer along desired trajectories in lung tissue. We demonstrate that this simple torsional deadband model is sufficient to account for the complex interactions between the needle and endoscope channel for control purposes. We measure mean final targeting error of 1.36 mm in phantom tissue and 1.84 mm in ex-vivo porcine lung, with mean trajectory following error of 1.28 mm and 1.10 mm, respectively.

Estimates of healthcare spending for preterm and low-birthweight infants in a commercially insured population: 2008-2016.

The growth in healthcare spending is an important topic in the United States, and preterm and low-birthweight infants have some of the highest healthcare expenditures of any patient population. We performed a retrospective cohort study of spending in this population using a large, national claims database of commercially insured individuals. A total of 763,566 infants with insurance coverage through Aetna, Inc. for the first 6 months of post-natal life were included, and received approximately $8.4 billion (2016 USD) in healthcare services. Infants with billing codes indicating preterm status (<37 weeks, n = 50,511) incurred medical expenditures of $76,153 on average, while low-birthweight status (<2500 g) was associated with average spending of $114,437. Infants born at 24 weeks gestation (n = 418) had the highest per infant average expenditures of $603,778. Understanding the drivers of variation in costs within gestational age and birthweight bands is an important target for future studies.

Decoupling Steerability from Diameter: Helical Dovetail Laser Patterning for Steerable Needles.

The maximum curvature of a steerable needle in soft tissue is highly sensitive to needle shaft stiffness, which has motivated use of small diameter needles in the past. However, desired needle payloads constrain minimum shaft diameters, and shearing along the needle shaft can occur at small diameters and high curvatures. We provide a new way to adjust needle shaft stiffness (thereby enhancing maximum curvature, i.e. "steerability") at diameters selected based on needle payload requirements. We propose helical dovetail laser patterning to increase needle steerability without reducing shaft diameter. Experiments in phantoms and ex vivo animal muscle, brain, liver, and inflated lung tissues demonstrate high steerability in soft tissues. These experiments use needle diameters suitable for various clinical scenarios, and which have been previously limited by steering challenges without helical dovetail patterning. We show that steerable needle targeting remains accurate with established controllers and demonstrate interventional payload delivery (brachytherapy seeds and radiofrequency ablation) through the needle. Helical dovetail patterning decouples steerability from diameter in needle design. It enables diameter to be selected based on clinical requirements rather than being carefully tuned to tissue properties. These results pave the way for new sensors and interventional tools to be integrated into high-curvature steerable needles.

Concordance between gene expression in peripheral whole blood and colonic tissue in children with inflammatory bowel disease.

BACKGROUND: Presenting features of inflammatory bowel disease (IBD) are non-specific. We hypothesized that mRNA profiles could (1) identify genes and pathways involved in disease pathogenesis; (2) identify a molecular signature that differentiates IBD from other conditions; (3) provide insight into systemic and colon-specific dysregulation through study of the concordance of the gene expression. METHODS: Children (8-18 years) were prospectively recruited at the time of diagnostic colonoscopy for possible IBD. We used transcriptome-wide mRNA profiling to study gene expression in colon biopsies and paired whole blood samples. Using blood mRNA measurements, we fit a regression model for disease state prediction that was validated in an independent test set of adult subjects (GSE3365). RESULTS: Ninety-eight children were recruited [39 Crohn's disease, 18 ulcerative colitis, 2 IBDU, 39 non-IBD]. There were 1,118 significantly differentially (IBD vs non-IBD) expressed genes in colon tissue, and 880 in blood. The direction of relative change in expression was concordant for 106/112 genes differentially expressed in both tissue types. The regression model from the blood mRNA measurements distinguished IBD vs non-IBD disease status in the independent test set with 80% accuracy using only 6 genes. The overlap of 5 immune and metabolic pathways in the two tissue types was significant (p<0.001). CONCLUSIONS: Blood and colon tissue from patients with IBD share a common transcriptional profile dominated by immune and metabolic pathways. Our results suggest that peripheral blood expression levels of as few as 6 genes (IL7R, UBB, TXNIP, S100A8, ALAS2, and SLC2A3) may distinguish patients with IBD from non-IBD.