skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: Variant Effect Prediction in the Age of Machine Learning
Over the years, many computational methods have been created for the analysis of the impact of single amino acid substitutions resulting from single-nucleotide variants in genome coding regions. Historically, all methods have been supervised and thus limited by the inadequate sizes of experimentally curated data sets and by the lack of a standardized definition of variant effect. The emergence of unsupervised, deep learning (DL)-based methods raised an important question: Canmachines learn the language of life fromthe unannotated protein sequence data well enough to identify significant errors in the protein “sentences”? Our analysis suggests that some unsupervised methods perform as well or better than existing supervised methods. Unsupervised methods are also faster and can, thus, be useful in large-scale variant evaluations. For all other methods, however, their performance varies by both evaluation metrics and by the type of variant effect being predicted.We also note that the evaluation of method performance is still lacking on less-studied, nonhuman proteins where unsupervised methods hold the most promise.  more » « less
Award ID(s):
2318829 2310114 2310113
PAR ID:
10523474
Author(s) / Creator(s):
; ; ;
Publisher / Repository:
Cold Spring Harbor: Perspectives in Biology
Date Published:
Journal Name:
Cold Spring Harbor Perspectives in Biology
Volume:
16
Issue:
7
ISSN:
1943-0264
Page Range / eLocation ID:
a041467
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Unsupervised denoising is a crucial challenge in real-world imaging applications. Unsupervised deep-learning methods have demonstrated impressive performance on benchmarks based on synthetic noise. However, no metrics are available to evaluate these methods in an unsupervised fashion. This is highly problematic for the many practical applications where ground-truth clean images are not available. In this work, we propose two novel metrics: the unsupervised mean squared error (MSE) and the unsupervised peak signal-to-noise ratio (PSNR), which are computed using only noisy data. We provide a theoretical analysis of these metrics, showing that they are asymptotically consistent estimators of the supervised MSE and PSNR. Controlled numerical experiments with synthetic noise confirm that they provide accurate approximations in practice. We validate our approach on real-world data from two imaging modalities: videos in raw format and transmission electron microscopy. Our results demonstrate that the proposed metrics enable unsupervised evaluation of denoising methods based exclusively on noisy data. 
    more » « less
  2. Unsupervised denoising is a crucial challenge in real-world imaging applications. Unsupervised deep-learning methods have demonstrated impressive performance on benchmarks based on synthetic noise. However, no metrics are available to evaluate these methods in an unsupervised fashion. This is highly problematic for the many practical applications where ground-truth clean images are not available. In this work, we propose two novel metrics: the unsupervised mean squared error (MSE) and the unsupervised peak signal-to-noise ratio (PSNR), which are computed using only noisy data. We provide a theoretical analysis of these metrics, showing that they are asymptotically consistent estimators of the supervised MSE and PSNR. Controlled numerical experiments with synthetic noise confirm that they provide accurate approximations in practice. We validate our approach on real-world data from two imaging modalities: videos in raw format and transmission electron microscopy. Our results demonstrate that the proposed metrics enable unsupervised evaluation of denoising methods based exclusively on noisy data. 
    more » « less
  3. Unsupervised denoising is a crucial challenge in real-world imaging applications. Unsupervised deep-learning methods have demonstrated impressive performance on benchmarks based on synthetic noise. However, no metrics exist to evaluate these methods in an unsupervised fashion. This is highly problematic for the many practical applications where ground-truth clean images are not available. In this work, we propose two novel metrics: the unsupervised mean squared error (MSE) and the unsupervised peak signalto-noise ratio (PSNR), which are computed using only noisy data. We provide a theoretical analysis of these metrics, showing that they are asymptotically consistent estimators of the supervised MSE and PSNR. Controlled numerical experiments with synthetic noise confirm that they provide accurate approximations in practice. We validate our approach on real-world data from two imaging modalities: videos in raw format and transmission electron microscopy. Our results demonstrate that the proposed metrics enable unsupervised evaluation of denoising methods based exclusively on noisy data. 
    more » « less
  4. Unsupervised denoising is a crucial challenge in real-world imaging applications. Unsupervised deep-learning methods have demonstrated impressive performance on benchmarks based on synthetic noise. However, no metrics exist to evaluate these methods in an unsupervised fashion. This is highly problematic for the many practical applications where ground-truth clean images are not available. In this work, we propose two novel metrics: the unsupervised mean squared error (MSE) and the unsupervised peak signal-to-noise ratio (PSNR), which are computed using only noisy data. We provide a theoretical analysis of these metrics, showing that they are asymptotically consistent estimators of the supervised MSE and PSNR. Controlled numerical experiments with synthetic noise confirm that they provide accurate approximations in practice. We validate our approach on real-world data from two imaging modalities: videos in raw format and transmission electron microscopy. Our results demonstrate that the proposed metrics enable unsupervised evaluation of denoising methods based exclusively on noisy data. 
    more » « less
  5. null (Ed.)
    Egocentric perception has grown rapidly with the advent of immersive computing devices. Human gaze prediction is an important problem in analyzing egocentric videos and has primarily been tackled through either saliency-based modeling or highly supervised learning. We quantitatively analyze the generalization capabilities of supervised, deep learning models on the egocentric gaze prediction task on unseen, out-of-domain data. We find that their performance is highly dependent on the training data and is restricted to the domains specified in the training annotations. In this work, we tackle the problem of jointly predicting human gaze points and temporal segmentation of egocentric videos without using any training data. We introduce an unsupervised computational model that draws inspiration from cognitive psychology models of event perception. We use Grenander's pattern theory formalism to represent spatial-temporal features and model surprise as a mechanism to predict gaze fixation points. Extensive evaluation on two publicly available datasets - GTEA and GTEA+ datasets-shows that the proposed model can significantly outperform all unsupervised baselines and some supervised gaze prediction baselines. Finally, we show that the model can also temporally segment egocentric videos with a performance comparable to more complex, fully supervised deep learning baselines. 
    more » « less