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Sequence-to-function deep learning frameworks for engineered riboregulators.

ABSTRACT: While synthetic biology has revolutionized our approaches to medicine, agriculture, and energy, the design of completely novel biological circuit components beyond naturally-derived templates remains challenging due to poorly understood design rules. Toehold switches, which are programmable nucleic acid sensors, face an analogous design bottleneck; our limited understanding of how sequence impacts functionality often necessitates expensive, time-consuming screens to identify effective switches. Here, we introduce Sequence-based Toehold Optimization and Redesign Model (STORM) and Nucleic-Acid Speech (NuSpeak), two orthogonal and synergistic deep learning architectures to characterize and optimize toeholds. Applying techniques from computer vision and natural language processing, we 'un-box' our models using convolutional filters, attention maps, and in silico mutagenesis. Through transfer-learning, we redesign sub-optimal toehold sensors, even with sparse training data, experimentally validating their improved performance. This work provides sequence-to-function deep learning frameworks for toehold selection and design, augmenting our ability to construct potent biological circuit components and precision diagnostics.

SUBMITTER: Valeri JA

PROVIDER: S-EPMC7541510 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Sequence-to-function deep learning frameworks for engineered riboregulators.

Valeri Jacqueline A JA Collins Katherine M KM Ramesh Pradeep P Alcantar Miguel A MA Lepe Bianca A BA Lu Timothy K TK Camacho Diogo M DM

Nature communications 20201007 1

While synthetic biology has revolutionized our approaches to medicine, agriculture, and energy, the design of completely novel biological circuit components beyond naturally-derived templates remains challenging due to poorly understood design rules. Toehold switches, which are programmable nucleic acid sensors, face an analogous design bottleneck; our limited understanding of how sequence impacts functionality often necessitates expensive, time-consuming screens to identify effective switches. ...[more]

PMID: 33028819

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Project description:ImportanceLike other clinical biomarkers, trajectories of estimated glomerular filtration rate (eGFR) after kidney transplant are characterized by intra-individual variability. These fluctuations hamper the distinction between alarming graft functional deterioration or harmless fluctuation within the patient-specific expected reference range of eGFR.ObjectiveTo determine whether a deep learning model could accurately predict the patient-specific expected reference range of eGFR after kidney transplant.Design, setting, and participantsA multicenter diagnostic study consisted of a derivation cohort of 933 patients who received a kidney transplant between 2004 and 2013 with 100 867 eGFR measurements from University Hospitals Leuven, Belgium, and 2 independent test cohorts: with 39 999 eGFR measurements from 1 170 patients, 1 from University Hospitals Leuven, Belgium, receiving transplants between 2013 and 2018 and 1 from Hannover Medical School, Germany, receiving transplants between 2003 and 2007. Patients receiving a single kidney transplant, with consecutive eGFR measurements were included. Data were analyzed from February 2019 to April 2021.ExposuresIn the derivation cohort 100 867 eGFR measurements were available for analysis and 39 999 eGFR measurements from the independent test cohorts.Main outcomes and measuresA sequence-to-sequence model was developed for prediction of a patient-specific expected range of eGFR, based on previous eGFR values. The primary outcome was the performance of the deep learning sequence-to-sequence model in the 2 independent cohorts.ResultsIn this diagnostic study, a total of 933 patients in the training sets (mean [SD] age, 53.5 [13.3] years; 570 male [61.1%]) and 1170 patients in the independent test sets (cohort 1 [n = 621]: mean [SD] age, 58.5 [12.1] years; 400 male [64.4%]; cohort 2 [n = 549]: mean [SD] age, 50.1 [13.0] years; 316 male [57.6%]) who received a single kidney transplant most frequently from deceased donors, the sequence-to-sequence models accurately predicted future patient-specific eGFR trajectories within the first 3 months after transplant, based on the previous graft eGFR values (root mean square error, 6.4-8.9 mL/min/1.73 m2). The sequence-to-sequence model predictions outperformed the more conventional autoregressive integrated moving average prediction model, at all input/output number of eGFR values.Conclusions and relevanceIn this diagnostic study, a sequence-to-sequence deep learning model was developed and validated for individual forecasting of kidney transplant function. The patient-specific sequence predictions could be used in clinical practice to guide physicians on deviations from the expected intra-individual variability, rather than relating the individual results to the reference range of the healthy population.

Project description:Diabetic Retinopathy (DR) may result in various degrees of vision loss and even blindness if not diagnosed in a timely manner. Therefore, having an annual eye exam helps early detection to prevent vision loss in earlier stages, especially for diabetic patients. Recent technological advances made smartphone-based retinal imaging systems available on the market to perform small-sized, low-powered, and affordable DR screening in diverse environments. However, the accuracy of DR detection depends on the field of view and image quality. Since smartphone-based retinal imaging systems have much more compact designs than a traditional fundus camera, captured images are likely to be the low quality with a smaller field of view. Our motivation in this paper is to develop an automatic DR detection model for smartphone-based retinal images using the deep learning approach with the ResNet50 network. This study first utilized the well-known AlexNet, GoogLeNet, and ResNet50 architectures, using the transfer learning approach. Second, these frameworks were retrained with retina images from several datasets including EyePACS, Messidor, IDRiD, and Messidor-2 to investigate the effect of using images from the single, cross, and multiple datasets. Third, the proposed ResNet50 model is applied to smartphone-based synthetic images to explore the DR detection accuracy of smartphone-based retinal imaging systems. Based on the vision-threatening diabetic retinopathy detection results, the proposed approach achieved a high classification accuracy of 98.6%, with a 98.2% sensitivity and a 99.1% specificity while its AUC was 0.9978 on the independent test dataset. As the main contributions, DR detection accuracy was improved using the deep transfer learning approach for the ResNet50 network with publicly available datasets and the effect of the field of view in smartphone-based retinal imaging was studied. Although a smaller number of images were used in the training set compared with the existing studies, considerably acceptable high accuracies for validation and testing data were obtained.

Dataset Information

Sequence-to-function deep learning frameworks for engineered riboregulators.

Publications

Sequence-to-function deep learning frameworks for engineered riboregulators.

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