Optimizing Design of Genomics Studies for Clonal Evolution Analysis.

Genomic biotechnologies have seen rapid development over the past two decades, allowing for both the inference and modification of genetic and epigenetic information at the single cell level. While these tools present enormous potential for basic research, diagnostics, and treatment, they also raise difficult issues of how to design research studies to deploy these tools most effectively. In designing a study at the population or individual level, a researcher might combine several different sequencing modalities and sampling protocols, each with different utility, costs, and other tradeoffs. The central problem this paper attempts to address is then how one might create an optimal study design for a genomic analysis, with particular focus on studies involving somatic variation, typically for applications in cancer genomics. We pose the study design problem as a stochastic constrained nonlinear optimization problem and introduce a simulation-centered optimization procedure that iteratively optimizes the objective function using surrogate modeling combined with pattern and gradient search. Finally, we demonstrate the use of our procedure on diverse test cases to derive resource and study design allocations optimized for various objectives for the study of somatic cell populations.

A Clonal Evolution Simulator for Planning Somatic Evolution Studies.

Somatic evolution plays a key role in development, cell differentiation, and normal aging, but also in diseases such as cancer. Understanding mechanisms of somatic mutability and how they can vary between cell lineages will likely play a crucial role in biological discovery and medical applications. This need has led to a proliferation of new technologies for profiling single-cell variation, each with distinctive capabilities and limitations that can be leveraged alone or in combination with other technologies. The enormous space of options for assaying somatic variation, however, presents unsolved informatics problems with regard to selecting optimal combinations of technologies for designing appropriate studies for any particular scientific questions. Versatile simulation tools are needed to explore and optimize potential study designs if researchers are to deploy multiomic technologies most effectively. In this study, we present a simulator allowing for the generation of synthetic data from a wide range of clonal lineages, variant classes, and sequencing technology choices, intended to provide a platform for effective study design in somatic lineage analysis. Users can input various properties of the somatic evolutionary system, mutation classes, and biotechnology options, and then generate samples of synthetic sequence reads and their corresponding ground truth parameters for a given study design. We demonstrate the utility of the simulator for testing and optimizing study designs for various experimental queries.

Mynx vascular closure device achieves reliable closure and hemostasis of percutaneous transfemoral venous access in a porcine vascular model.

AIMS: Vascular closure device (VCD)-based venous closure has been anecdotally reported, but systematic evaluation of the reparative response of the vessel wall to venous closure is lacking. The need to control groin complications, and minimize risks associated with postponed sheath removal under conditions of persistent anticoagulation, has generated interest in the role of VCDs for venous access closure. We sought to characterize the vessel wall response to venous closure, both acutely and in delayed fashion at 30 days using angiography, ultrasound, and histology. METHODS: Ten venous 7 Fr sheaths were deployed in the femoral veins of swine. Bilateral venous access sites were subsequently closed utilizing manual compression (MC; control arm: n = 4) or a closure device utilizing an extravascular polyethylene glycol sealant (MynxGrip treatment arm: n = 6). Acute (post closure), 3-day, and 30-day vascular ultrasound, as well as venography (internal jugular approach) were used to assess outcomes. Gross pathology and histology were obtained at the 30-day endpoint for all femoral venous closure sites. RESULTS: Hemostasis was successfully achieved in all cases without access-site complications. Venography and ultrasound confirmed normal ilio-femoral anatomy and flow at all study time points. Gross pathology and histopathology revealed no evidence of deep vein thrombosis, and no abnormalities were seen in the vena cava, heart, or lungs. Histology at 30 days showed complete healing of the vein wall access site, with a small focus of chronic inflammation and fibrosis in the perivascular adventitial tissue of the access tract. There was no microscopic evidence of the sealant. The tissue tract showed mild discrete inflammation (foamy macrophages, lymphocytes, plasma cells) with microgranulomas centered on residual red cells in both treatment and control groups. CONCLUSIONS: This study characterizes the angiographic, ultrasound, and histopathology outcomes of femoral vein closure, and provides insight into the healing mechanisms following venotomy. The bio-resorptive role of MynxGrip extravascular sealant in achieving effective venous closure and preserved long-term vessel patency without venous thromboembolism is demonstrated.