Tag Archives: genomics

Analyzing genomic data in families with deep learning

The Genomics team at Google Health is excited to share our latest expansion to DeepVariant - DeepTrio.

First released in 2017, DeepVariant is an open source tool that enables researchers and clinicians to analyze an individual’s genome sequencing data and identify genetic variants, such as those that may cause disease. Our continued work on DeepVariant has been recognized for its top-of-class accuracy. With DeepTrio, we have expanded DeepVariant to be able to consider the genetic variants in the sequence data of a mother-father-child trio.

Humans are diploid organisms, carrying two copies of the human genome. Every individual inherits one copy of the genome from their mother, and the other from their father. Parental inheritance informs analysis of traits and diseases that follow Mendelian inheritance. DeepTrio learns to use the properties of Mendelian inheritance directly from sequencing data in order to more accurately identify genetic variants in cases when both parent and a child sample can be co-analyzed.

Modifying DeepVariant to analyze trio samples

DeepVariant learns to classify positions in a genome as reference or variant using representations of data similar to the “genome browser” which experts use in analysis. “Improving the Accuracy of Genomic Analysis with DeepVariant 1.0” provides a good overview.

DeepVariant receives data as a window of the genome centered on a candidate variant which it is asked to classify as either reference (no variant), heterozygous (one copy of a variant) or homozygous (both copies are variant). DeepVariant sees the sequence evidence as channels representing features of the data (see: “Looking through DeepVariant’s eyes” for a deeper explanation).

We modified DeepTrio to represent the sequence data from a trio in a single image, with a fixed height for each sample and the child in the middle. Using gold standard samples from NIST Genome in a Bottle for truth labels, we train one model to call variants in the child and another to call variants in the top parent. To call both parents, we flip the position of the parent samples.

An image of 4 of the channels that DeepTrio uses in classification (these, and 4 other channels are shown in a stack.

conceptual schematic of how trio files are used to create examples, which are then called by DeepTrio.

Figure 1. (top) An image of 4 of the channels that DeepTrio uses in classification (these, and 4 other channels are shown in a stack. (bottom) conceptual schematic of how trio files are used to create examples, which are then called by DeepTrio.

Measuring DeepTrio’s improved accuracy

We show that DeepTrio is more accurate than DeepVariant for both parent and child variant detection, with an especially pronounced advantage at lower coverages. This enables researchers to either analyze samples at higher accuracy, or to maintain comparable accuracy at a substantially reduced expense.

To assess the accuracy of DeepTrio, we compare its accuracy to DeepVariant using extensively characterized gold standards made available by NIST Genome in a Bottle. In order to have an evaluation dataset which is never seen in training, we exclude chromosome 20 from training and perform evaluations on chromosome 20.

We train DeepVariant and DeepTrio for sequencing data from two different instruments, Illumina and Pacific Biosciences (PacBio), for more information on the differences between these technologies, please see our previous blog. These sequencers both randomly sample the genome in an error-prone manner. To accurately analyze a genome, the same region needs to be sampled repeatedly. The depth of sampling at a position is called coverage. Sequencing to greater coverage is more expensive in an approximately linear manner. This often forces trade-offs between cost, accuracy, and samples sequenced. As a result, in trios parents are often sequenced at lower depth.

In the charts below, we plot the accuracy of DeepTrio and DeepVariant across a range of coverages.

DeepTrio child accuracy

DeepTrio parent accuracy

Figure 2. F1-score for DeepTrio (solid line) and DeepVariant (dashed line) on a child sample (top) and a parent sample (bottom), sequenced with an Illumina (blue) and PacBio (black) instrument. F1 is measured for all types of small variants on chromosome 20, across samples with a range of sequencing coverage (x-axis).

DeepTrio’s performance on de novo variants

Each individual has roughly 5 million variants relative to the human reference genome. The overwhelming majority of these are inherited from their parents. A small number, around 100, are new (referred to as de novo), due to copying errors during DNA replication. We demonstrate that DeepTrio substantially reduces false positives for de novo variants. For Illumina data, this comes with a smaller decrease in recovery of true positives, while for PacBio data, this trade-off does not occur.

To assess accuracy we analyzed sites where both parents are called as non-variant, but the child is called as heterozygous variant. We observe that DeepTrio is more reluctant to call a variant as de novo, which is similar to how a human would require a higher level of evidence for sites violating Mendelian inheritance. This results in a much lower false positive rate for these de novo variants, but a slightly lower recall rate in DeepTrio Illumina. Usually when this occurs, the child is still called as a variant, but the parents are given “no-call” (the classifier is not confident enough to make a call).

Accuracy on de novo calls (child heterozygous variant, parents reference call) for recall of true de novo events


Accuracy on de novo calls (child heterozygous variant, parents reference call) for recall of false positive de novo events

Figure 3. Accuracy on de novo calls (child heterozygous variant, parents reference call) for recall of true de novo events (top) and false positive de novo events (bottom) for DeepTrio (solid line) and DeepVariant (dashed line) on Illumina (blue) and PacBio (black). Accuracy is measured on chromosome 20, across samples with a range of sequencing coverage (x-axis).

Contributing to rare disease research

By releasing DeepTrio as open source software, we hope to improve analysis of genomic data, by allowing scientists to more accurately analyze samples. We hope this will enable research and clinical pipelines, leading to better resolution of rare disease cases, and improve development of therapeutics.

In addition to the release of DeepTrio’s code as open source, we have also released the sequencing data that we generated in order to train these models. That data is described in our pre-print “An Extensive Sequence Dataset of Gold-Standard Samples for Benchmarking and Development”. By releasing both this production model, and the data required to train models of similar complexity, we hope to contribute to methods development by the genomics community.

By Andrew Carroll, Product Lead Genomics and Howard Yang, Program Manager Genomics — Google Health

DeepVariant: Highly Accurate Genomes With Deep Neural Networks

Crossposted on the Google Research Blog

Across many scientific disciplines, but in particular in the field of genomics, major breakthroughs have often resulted from new technologies. From Sanger sequencing, which made it possible to sequence the human genome, to the microarray technologies that enabled the first large-scale genome-wide experiments, new instruments and tools have allowed us to look ever more deeply into the genome and apply the results broadly to health, agriculture and ecology.

One of the most transformative new technologies in genomics was high-throughput sequencing (HTS), which first became commercially available in the early 2000s. HTS allowed scientists and clinicians to produce sequencing data quickly, cheaply, and at scale. However, the output of HTS instruments is not the genome sequence for the individual being analyzed — for humans this is 3 billion paired bases (guanine, cytosine, adenine and thymine) organized into 23 pairs of chromosomes. Instead, these instruments generate ~1 billion short sequences, known as reads. Each read represents just 100 of the 3 billion bases, and per-base error rates range from 0.1-10%. Processing the HTS output into a single, accurate and complete genome sequence is a major outstanding challenge. The importance of this problem, for biomedical applications in particular, has motivated efforts such as the Genome in a Bottle Consortium (GIAB), which produces high confidence human reference genomes that can be used for validation and benchmarking, as well as the precisionFDA community challenges, which are designed to foster innovation that will improve the quality and accuracy of HTS-based genomic tests.

CAPTION: For any given location in the genome, there are multiple reads among the ~1 billion that include a base at that position. Each read is aligned to a reference, and then each of the bases in the read is compared to the base of the reference at that location. When a read includes a base that differs from the reference, it may indicate a variant (a difference in the true sequence), or it may be an error.

Today, we announce the open source release of DeepVariant, a deep learning technology to reconstruct the true genome sequence from HTS sequencer data with significantly greater accuracy than previous classical methods. This work is the product of more than two years of research by the Google Brain team, in collaboration with Verily Life Sciences. DeepVariant transforms the task of variant calling, as this reconstruction problem is known in genomics, into an image classification problem well-suited to Google's existing technology and expertise.

CAPTION: Each of the four images above is a visualization of actual sequencer reads aligned to a reference genome. A key question is how to use the reads to determine whether there is a variant on both chromosomes, on just one chromosome, or on neither chromosome. There is more than one type of variant, with SNPs and insertions/deletions being the most common. A: a true SNP on one chromosome pair, B: a deletion on one chromosome, C: a deletion on both chromosomes, D: a false variant caused by errors. It's easy to see that these look quite distinct when visualized in this manner.

We started with GIAB reference genomes, for which there is high-quality ground truth (or the closest approximation currently possible). Using multiple replicates of these genomes, we produced tens of millions of training examples in the form of multi-channel tensors encoding the HTS instrument data, and then trained a TensorFlow-based image classification model to identify the true genome sequence from the experimental data produced by the instruments. Although the resulting deep learning model, DeepVariant, had no specialized knowledge about genomics or HTS, within a year it had won the the highest SNP accuracy award at the precisionFDA Truth Challenge, outperforming state-of-the-art methods. Since then, we've further reduced the error rate by more than 50%.


DeepVariant is being released as open source software to encourage collaboration and to accelerate the use of this technology to solve real world problems. To further this goal, we partnered with Google Cloud Platform (GCP) to deploy DeepVariant workflows on GCP, available today, in configurations optimized for low-cost and fast turnarounds using scalable GCP technologies like the Pipelines API. This paired set of releases provides a smooth ramp for users to explore and evaluate the capabilities of DeepVariant in their current compute environment while providing a scalable, cloud-based solution to satisfy the needs of even the largest genomics datasets.

DeepVariant is the first of what we hope will be many contributions that leverage Google's computing infrastructure and ML expertise to both better understand the genome and to provide deep learning-based genomics tools to the community. This is all part of a broader goal to apply Google technologies to healthcare and other scientific applications, and to make the results of these efforts broadly accessible.

By Mark DePristo and Ryan Poplin, Google Brain Team

DeepVariant: Highly Accurate Genomes With Deep Neural Networks

Crossposted on the Google Research Blog

Across many scientific disciplines, but in particular in the field of genomics, major breakthroughs have often resulted from new technologies. From Sanger sequencing, which made it possible to sequence the human genome, to the microarray technologies that enabled the first large-scale genome-wide experiments, new instruments and tools have allowed us to look ever more deeply into the genome and apply the results broadly to health, agriculture and ecology.

One of the most transformative new technologies in genomics was high-throughput sequencing (HTS), which first became commercially available in the early 2000s. HTS allowed scientists and clinicians to produce sequencing data quickly, cheaply, and at scale. However, the output of HTS instruments is not the genome sequence for the individual being analyzed — for humans this is 3 billion paired bases (guanine, cytosine, adenine and thymine) organized into 23 pairs of chromosomes. Instead, these instruments generate ~1 billion short sequences, known as reads. Each read represents just 100 of the 3 billion bases, and per-base error rates range from 0.1-10%. Processing the HTS output into a single, accurate and complete genome sequence is a major outstanding challenge. The importance of this problem, for biomedical applications in particular, has motivated efforts such as the Genome in a Bottle Consortium (GIAB), which produces high confidence human reference genomes that can be used for validation and benchmarking, as well as the precisionFDA community challenges, which are designed to foster innovation that will improve the quality and accuracy of HTS-based genomic tests.

CAPTION: For any given location in the genome, there are multiple reads among the ~1 billion that include a base at that position. Each read is aligned to a reference, and then each of the bases in the read is compared to the base of the reference at that location. When a read includes a base that differs from the reference, it may indicate a variant (a difference in the true sequence), or it may be an error.

Today, we announce the open source release of DeepVariant, a deep learning technology to reconstruct the true genome sequence from HTS sequencer data with significantly greater accuracy than previous classical methods. This work is the product of more than two years of research by the Google Brain team, in collaboration with Verily Life Sciences. DeepVariant transforms the task of variant calling, as this reconstruction problem is known in genomics, into an image classification problem well-suited to Google's existing technology and expertise.

CAPTION: Each of the four images above is a visualization of actual sequencer reads aligned to a reference genome. A key question is how to use the reads to determine whether there is a variant on both chromosomes, on just one chromosome, or on neither chromosome. There is more than one type of variant, with SNPs and insertions/deletions being the most common. A: a true SNP on one chromosome pair, B: a deletion on one chromosome, C: a deletion on both chromosomes, D: a false variant caused by errors. It's easy to see that these look quite distinct when visualized in this manner.

We started with GIAB reference genomes, for which there is high-quality ground truth (or the closest approximation currently possible). Using multiple replicates of these genomes, we produced tens of millions of training examples in the form of multi-channel tensors encoding the HTS instrument data, and then trained a TensorFlow-based image classification model to identify the true genome sequence from the experimental data produced by the instruments. Although the resulting deep learning model, DeepVariant, had no specialized knowledge about genomics or HTS, within a year it had won the the highest SNP accuracy award at the precisionFDA Truth Challenge, outperforming state-of-the-art methods. Since then, we've further reduced the error rate by more than 50%.


DeepVariant is being released as open source software to encourage collaboration and to accelerate the use of this technology to solve real world problems. To further this goal, we partnered with Google Cloud Platform (GCP) to deploy DeepVariant workflows on GCP, available today, in configurations optimized for low-cost and fast turnarounds using scalable GCP technologies like the Pipelines API. This paired set of releases provides a smooth ramp for users to explore and evaluate the capabilities of DeepVariant in their current compute environment while providing a scalable, cloud-based solution to satisfy the needs of even the largest genomics datasets.

DeepVariant is the first of what we hope will be many contributions that leverage Google's computing infrastructure and ML expertise to both better understand the genome and to provide deep learning-based genomics tools to the community. This is all part of a broader goal to apply Google technologies to healthcare and other scientific applications, and to make the results of these efforts broadly accessible.

By Mark DePristo and Ryan Poplin, Google Brain Team

DeepVariant: Highly Accurate Genomes With Deep Neural Networks

Crossposted on the Google Research Blog

Across many scientific disciplines, but in particular in the field of genomics, major breakthroughs have often resulted from new technologies. From Sanger sequencing, which made it possible to sequence the human genome, to the microarray technologies that enabled the first large-scale genome-wide experiments, new instruments and tools have allowed us to look ever more deeply into the genome and apply the results broadly to health, agriculture and ecology.

One of the most transformative new technologies in genomics was high-throughput sequencing (HTS), which first became commercially available in the early 2000s. HTS allowed scientists and clinicians to produce sequencing data quickly, cheaply, and at scale. However, the output of HTS instruments is not the genome sequence for the individual being analyzed — for humans this is 3 billion paired bases (guanine, cytosine, adenine and thymine) organized into 23 pairs of chromosomes. Instead, these instruments generate ~1 billion short sequences, known as reads. Each read represents just 100 of the 3 billion bases, and per-base error rates range from 0.1-10%. Processing the HTS output into a single, accurate and complete genome sequence is a major outstanding challenge. The importance of this problem, for biomedical applications in particular, has motivated efforts such as the Genome in a Bottle Consortium (GIAB), which produces high confidence human reference genomes that can be used for validation and benchmarking, as well as the precisionFDA community challenges, which are designed to foster innovation that will improve the quality and accuracy of HTS-based genomic tests.

CAPTION: For any given location in the genome, there are multiple reads among the ~1 billion that include a base at that position. Each read is aligned to a reference, and then each of the bases in the read is compared to the base of the reference at that location. When a read includes a base that differs from the reference, it may indicate a variant (a difference in the true sequence), or it may be an error.

Today, we announce the open source release of DeepVariant, a deep learning technology to reconstruct the true genome sequence from HTS sequencer data with significantly greater accuracy than previous classical methods. This work is the product of more than two years of research by the Google Brain team, in collaboration with Verily Life Sciences. DeepVariant transforms the task of variant calling, as this reconstruction problem is known in genomics, into an image classification problem well-suited to Google's existing technology and expertise.

CAPTION: Each of the four images above is a visualization of actual sequencer reads aligned to a reference genome. A key question is how to use the reads to determine whether there is a variant on both chromosomes, on just one chromosome, or on neither chromosome. There is more than one type of variant, with SNPs and insertions/deletions being the most common. A: a true SNP on one chromosome pair, B: a deletion on one chromosome, C: a deletion on both chromosomes, D: a false variant caused by errors. It's easy to see that these look quite distinct when visualized in this manner.

We started with GIAB reference genomes, for which there is high-quality ground truth (or the closest approximation currently possible). Using multiple replicates of these genomes, we produced tens of millions of training examples in the form of multi-channel tensors encoding the HTS instrument data, and then trained a TensorFlow-based image classification model to identify the true genome sequence from the experimental data produced by the instruments. Although the resulting deep learning model, DeepVariant, had no specialized knowledge about genomics or HTS, within a year it had won the the highest SNP accuracy award at the precisionFDA Truth Challenge, outperforming state-of-the-art methods. Since then, we've further reduced the error rate by more than 50%.


DeepVariant is being released as open source software to encourage collaboration and to accelerate the use of this technology to solve real world problems. To further this goal, we partnered with Google Cloud Platform (GCP) to deploy DeepVariant workflows on GCP, available today, in configurations optimized for low-cost and fast turnarounds using scalable GCP technologies like the Pipelines API. This paired set of releases provides a smooth ramp for users to explore and evaluate the capabilities of DeepVariant in their current compute environment while providing a scalable, cloud-based solution to satisfy the needs of even the largest genomics datasets.

DeepVariant is the first of what we hope will be many contributions that leverage Google's computing infrastructure and ML expertise to both better understand the genome and to provide deep learning-based genomics tools to the community. This is all part of a broader goal to apply Google technologies to healthcare and other scientific applications, and to make the results of these efforts broadly accessible.

By Mark DePristo and Ryan Poplin, Google Brain Team