Received: 15 June 2023 Revised: 13 July 2023 Accepted: 19 July 2023

DOI: 10.1002/ajmg.c.32057

REVIEW ARTICLE

Applications of artificial intelligence in clinical laboratory

genomics

Swaroop Aradhya 1,2 | Flavia M. Facio 1 | Hillery Metz 1 | Toby Manders 1 |

1 1 1
Alexandre Colavin | Yuya Kobayashi | Keith Nykamp |
Britt Johnson 1 | Robert L. Nussbaum 1,3

1
Invitae Corporation, San Francisco,
California, USA
2
Adjunct Clinical Faculty, Department of
Pathology, Stanford University School of
Medicine, Stanford, California, USA
3
Volunteer Faculty, School of Medicine,
University of California San Francisco, San
Francisco, California, USA
Correspondence
Swaroop Aradhya, Invitae Corporation, San
Francisco, California, USA.
Email: swaroop.aradhya@invitae.com
Abstract
The transition from analog to digital technologies in clinical laboratory genomics is
ushering in an era of “big data” in ways that will exceed human capacity to rapidly
and reproducibly analyze those data using conventional approaches. Accurately eval-
uating complex molecular data to facilitate timely diagnosis and management of
genomic disorders will require supportive artificial intelligence methods. These are
already being introduced into clinical laboratory genomics to identify variants in DNA
sequencing data, predict the effects of DNA variants on protein structure and func-
tion to inform clinical interpretation of pathogenicity, link phenotype ontologies to
genetic variants identified through exome or genome sequencing to help clinicians
reach diagnostic answers faster, correlate genomic data with tumor staging and treat-
ment approaches, utilize natural language processing to identify critical published
medical literature during analysis of genomic data, and use interactive chatbots to
identify individuals who qualify for genetic testing or to provide pre-test and post-
test education. With careful and ethical development and validation of artificial intel-
ligence for clinical laboratory genomics, these advances are expected to significantly
enhance the abilities of geneticists to translate complex data into clearly synthesized
information for clinicians to use in managing the care of their patients at scale.

KEYWORDS
deep learning, germline genetic testing, in silico prediction algorithms, machine learning,
precision medicine, variant classification

1 | N E C E S S I T Y OF A R T I F I C I A L generation sequencing (NGS). Exome and genome sequencing—even

INTELLIGENCE IN GENOMICS
Constrained over the past 50 years to the realms of microscopes, gel
electrophoresis, and radiographs, clinical laboratory genomics is now
dominated by digital data due to the rapid adoption of next-
multigene panels and chromosomal microarrays—have already been
performed for tens of millions of individuals around the world, and
vast amounts of digitized data from millions of these individuals are
available to those interested in mining the data for discoveries or for
insights that can improve standards of practice in clinical laboratory

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
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© 2023 Invitae Corporation. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.

Am J Med Genet. 2023;193C:e32057. wileyonlinelibrary.com/journal/ajmgc 1 of 15

https://doi.org/10.1002/ajmg.c.32057

2 of 15
genomics. These genomic data are essential in precision medicine,
where a variety of complex molecular data are combined with clinical
information to diagnose and treat individuals with disease (Rajpurkar
et al., 2022; Yu et al., 2018). However, even the amount of extractable
data in a single genome—with millions of sequence variants, many
copy number variants, somatic mosaicism, and variable expression of
transcript isoforms—exceeds the capacity of human beings alone to
identify answers to specific questions about health and traits. One
solution is to incorporate advanced artificial intelligence (AI) into
genomic analysis (Diao et al., 2018).
Following the completion of the Human Genome Project,
genomes from multiple human populations and diverse primate and
non-primate species have been sequenced and deposited in public
databases (e.g., gnomAD), enabling important discoveries through
DNA sequence comparisons and assessments of allele frequencies in
different populations (Karczewski et al., 2020; Margulies &
Birney, 2008). Alongside such advances in understanding DNA
sequence variation (genomics) over the past two decades, consider-
able progress has been made in characterizing protein sequence varia-
tion and function (proteomics) and RNA transcript isoforms and their
expression patterns (transcriptomics) (GTEx Consortium, 2015;
Jumper et al., 2021). Furthermore, the ClinVar database at the
National Institutes of Health (www.ncbi.nlm.nih.gov/clinvar/) has
amassed more than two million DNA variants observed in individuals
undergoing genetic testing for a broad variety of hereditary diseases,
providing a rich dataset that has been used to improve and standard-
ize clinical variant classification (Harrison et al., 2016). Collectively,
these data are an enormous resource that can inform many aspects of
biology and precision medicine, from discovery of gene-disease asso-
ciations to insight into how variants in a given gene affect molecular
mechanisms of disease. These data are also useful in virtually every
step of the clinical genetic testing workflow, including effectively cap-
turing relevant target DNA from a patient sample, aligning NGS reads,
training and evaluating complex machine learning (ML) tools that can
analyze genomic variation, and providing evidence to support catego-
rization of individual DNA variants as disease-causing or benign.
2 | ARTIFICIAL INTELLIGENCE METHODS
I N L A B O R A T O R Y G E NO M I C S
Paralleling the dramatic evolution in scale and speed of DNA sequenc-
ing methods, AI has rapidly advanced since the term was coined and
the field born at the Dartmouth Summer Research Project on Artificial
Intelligence in 1956 (Artificial Intelligence (AI) Coined at Dartmouth, n.
d.). Broadly, AI encompasses the theory and development of intelli-
gent systems—systems that act rationally in response to their inputs
(Russell & Norvig, 2021). Decades of nearly exponential growth in
computing power (Moore's law) and the commensurate increase
in data availability have enabled both theoretical and applied achieve-
ments in a variety of AI disciplines, including ML, natural language
processing (NLP), and computer vision. As described in the next sec-
tions, ML and NLP have particularly powerful applications in clinical
laboratory genomics.
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ARADHYA ET AL.
AI
Artificial intelligence
ML
Machine learning
NLP
Deep
learning
F I G U R E 1 Branches of artificial intelligence. Machine learning
(ML) gives computers the ability to learn from examples without being
explicitly programmed. Deep learning is a subset of ML that uses
artificial neural networks and builds a hierarchy of data
representations. Natural language processing (NLP) refers to a range
of computing techniques for interpreting and generating human
language.
ML is an AI discipline that involves applying statistical models and
algorithms to analyze and draw inferences from data (Figure 1).
Within clinical laboratory genomics, ML techniques can be applied to
tasks as diverse as predicting the effect of an altered amino acid resi-
due in a protein or identifying phenotypically similar groups of
patients. In simple terms, an ML-based computer algorithm is trained
using a dataset with well-characterized examples, such as known
pathogenic or benign DNA variants, to recognize specific patterns in
those examples. A trained ML system can then be used to predict pat-
terns from new data (e.g., quantitatively determining if a novel DNA
variant appears to be more like a pathogenic variant or more like a
benign one). Broadly, ML techniques cover a spectrum that spans
from supervised methods—in which a true value or label, such as a
variant's pathogenicity, is known for each example used for training—
to unsupervised methods, in which no such labels are used. The ML
toolkit comprises a wide range of statistical and algorithmic
approaches, each with its own tradeoffs with respect to model com-
plexity, interpretability, computational and data requirements, and
ease of use. Classical techniques (e.g., logistic regression, linear regres-
sion, K-nearest neighbors, random forests, programmed decision
trees), neural networks (i.e., deep learning), and Bayesian methods
(e.g., Gaussian processes, multilevel models) all have suitable applica-
tions in clinical laboratory genomics.
NLP is the branch of AI that involves the application of computers
to understanding, interpreting, and generating human language, often
with deep learning (Figure 1). NLP methods have been used to
develop a variety of tools ranging from machine translation
(e.g., Google Translate) to voice assistants (e.g., Amazon Alexa) to large
language models and chatbots (e.g., GPT-4, ChatGPT) (Box 1).
Large language models represent some of the largest and most com-
plex ML models ever developed, with hundreds of billions of trainable
parameters and trillions of examples used for training. These types of

ARADHYA ET AL.
B O X 1 ChatGPT on use of AI in genetic medicine. Interacted
February 20, 2023.
Question posed: “How can AI improve genetic testing?”
ChatGPT response:
“Artificial intelligence (AI) has the potential to improve genetic testing in
several ways. Here are a few examples:
Developing more accurate algorithms for interpreting genetic data: AI can
be used to develop sophisticated algorithms that can accurately
interpret genetic data. These algorithms can help identify genetic
variants associated with diseases, assess an individual's risk of
developing a disease, and provide personalized recommendations for
treatment or preventive measures.
Identifying novel genetic variants: AI can be used to identify previously
unknown genetic variants that are associated with diseases. This can
be achieved by analyzing large datasets of genetic information using
machine learning techniques.
Streamlining genetic testing workflows: AI can be used to automate many
of the steps involved in genetic testing, from sample preparation to
data analysis. This can help reduce the turnaround time for test results
and increase the efficiency of the testing process.
Enhancing genetic counseling: AI can be used to analyze a patient's
genetic information and provide personalized counseling based on their
individual risk factors. This can help patients make informed decisions
about their health and well-being.
Facilitating the integration of genetic data into electronic health records
(EHRs): AI can be used to help integrate genetic data into EHRs,
making it easier for healthcare providers to access and utilize this
information in patient care.
Overall, AI has the potential to revolutionize genetic testing and improve
our ability to diagnose and treat diseases. However, it is important to
ensure that AI-based solutions are developed and implemented in a
responsible and ethical manner, with appropriate safeguards in place to
protect patient privacy and ensure the accuracy and reliability of test
results.”
models have important uses in clinical genomics, such as in text min-
ing and simple chatbots, and are expected to expand rapidly in scope
and utility.
Compared to the use of traditional methods, the application of AI
technologies represents a critical opportunity for dramatically improv-
ing the scalability, accuracy, and utility of clinical genomics. Diverse AI
approaches are already being applied in this realm (Ledgister
Hanchard et al., 2022)—to support the identification of rare diseases
through analysis of facial gestalt in the clinic (Gurovich et al., 2019;
Hsieh et al., 2022; Myers et al., 2020; Porras et al., 2021), to non-
invasively select embryos for preimplantation genetic testing or direct
uterine transfer (Barnes et al., 2023; Dimitriadis et al., 2022), and to
provide information to individuals with genetic health concerns
(Schmidlen et al., 2022; Smith et al., 2023).
Several publications have described the use of AI in genomics in
general, and mostly within the context of basic research (Diao
et al., 2018; Ledgister Hanchard et al., 2022; Libbrecht & Noble, 2015),
but an article specifically on the applications of AI in clinical laboratory
genomics has become both timely and necessary. Here we discuss new
applications of AI within clinical laboratory genomics (Figure 2) and pro-
vide real-world data to illustrate their use and value. To preserve clarity
in describing the various applications, we discuss use cases for AI rather
than the technical details of each AI method.
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3 of 15
3 | SEQUENCING AND BIOINFORMATICS
The types and scale of sequencing data have dramatically changed
over the past decade, owing to rapid improvements in NGS chemistry
and throughput. The massive outputs from NGS demand large com-
puting power to process the data into readable formats for down-
stream analyses. As an example, the predominant DNA sequencing
equipment vendor, Illumina, uses the DRAGEN™ Pipeline to acceler-
ate data processing, relying in part on AI (DRAGEN Sets New Stan-
dard for Data Accuracy in PrecisionFDA Benchmark Data, n.d.). Once
primary NGS data have been assessed for quality and completion,
GATK HaplotypeCaller has been the benchmark tool for calling vari-
ants from aligned sequence reads (DePristo et al., 2011). The critical
step of accurately identifying variants is being further improved
through newer algorithms, some based on AI methods (Alharbi &
Rashid, 2022; Olson et al., 2023; Poplin et al., 2018). For instance, a
deep learning method (DeepVariant-AF) developed recently by Goo-
gle Health considers population allele frequencies from the 1000
Genomes Project and appears to call variants more accurately than
prior methods (Chen, Kolesnikov, et al., 2023).
We and others have also developed methods for detecting copy
number variants from NGS, by applying logistic regression on data
from known copy number samples to generate a mean model that
provides a baseline for calling actual copy number events in clinically
tested samples (Hill & Unckless, 2019; Lincoln et al., 2021; Özden
et al., 2022; Truty et al., 2019; Välipakka et al., 2020). Similarly, we
use an AI approach to identify which variants from primary sequenc-
ing analysis need confirmation through orthogonal methods (Lincoln
et al., 2019; unpublished data). In sum, AI is being used both to accel-
erate data processing and to improve the accuracy of variant calling,
including for variant types that have historically been difficult to
detect from NGS data (e.g., copy number variants).
4 | CLINICAL CLASSIFICATION OF
SEQUENCE VARIANTS
The significance of DNA variants observed in individuals undergoing
clinical genetic testing for hereditary disease is determined through a
variant classification process based on guidelines prescribed by the
American College of Medical Genetics and Genomics (ACMG)
(Richards et al., 2015). This process uses a standardized approach for
collating diverse types of evidence to classify variants into one of five
tiers: pathogenic, likely pathogenic, variant of uncertain significance
(VUS), likely benign, or benign. Types of evidence include the nature
of the DNA sequence variant and its intragenic location, evolutionary
conservation at the variant position, prevalence of the variant in a
general population cohort, predicted effect of the variant on the
downstream transcribed mRNA or translated protein, presence of pro-
tein functional domains at or near the variant position, clinical pheno-
type of the individual undergoing genetic testing, published reports of
that variant or other variants at the same position or nearby positions,
and family history. How these types of evidence are interpreted and
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4 of 15 ARADHYA ET AL.

Clinical genomics
Examples of supporting AI methods
testing process

Gia and other AI chatbots

Pre-test education and information gathering
Pre-test Collecting additional clinical information through NLP
Decision trees to identify individuals eligible for genetic testing

ACACCG Illumina DRAGEN pipeline

CGATGGC
GGCTTTA NGS Primary data processing to ensure that raw sequence data
GCACTAC
meet set parameters

< <
Custom lab-developed algorithms
</>
Lab-specifc Assess sequencing quality and identify variants
bioinformatics Detect specific classes of variants, e.g., indels, CNVs, expansions
Select specific variants for orthogonal confirmation

Invitae Apollo, Fabric GEM, and Illumina Emedgene

A Variant
C Mine published literature to support variant interpretation via NLP
A Invitae Moon: find links between clinical phenotypes and variants
C interpretation
Invitae EMP: use ML to evaluate evidence-generating models

Human-aided automated reporting to clinicians

Reporting Programmed decision trees for automated inclusion of variant details
and clinical summaries

Gia and other AI chatbots

Post-test Post-test education and information sharing
Collecting additional clinical information through NLP

F I G U R E 2 Points in clinical laboratory genomics where artificial intelligence methods can be applied. Examples of publicly available as well as
proprietary methods are listed. Gia, Apollo, Moon, and Invitae EMP are trademarks of Invitae; Fabric GEM is a trademark of Fabric Genomics;
DRAGEN and Emedgene are trademarks of Illumina. AI, artificial intelligence; CNV, copy number variant; EMP, evidence modeling platform; ML,
machine learning; NGS, next-generation sequencing; NLP, natural language processing.

weighed relative to each other determines the final clinical classifica-
tion of the observed variant.
The types of evidence used for variant classification fall into two
highly correlated but conceptually distinct classes: evidence demon-
strating a deleterious effect of a DNA variant on gene function and evi-
dence demonstrating a detrimental effect of the variant on the health
and well-being of an individual carrying that variant. Examples of a vari-
ant's deleterious effect on protein function include its impact on pro-
tein structure and stability or on enzymatic, receptor, or channel
activity as demonstrated through in silico, in vivo, or cellular models. In
contrast, examples of a variant's detrimental health effects include clini-
cal observations, such as segregation of a variant with disease in fami-
lies or presence of the variant in affected patients in different families,
as well as population effects over time such as degree of evolutionary
conservation of a residue in orthologous proteins among different spe-
cies or allele frequencies of the variant in various human populations.
The greatest source of uncertainty in clinical genetic testing for
hereditary disease today stems from our limited ability to accurately
predict the functional consequences of protein sequence changes that
result from missense DNA variants. This class of variants makes up
the largest proportion of those clinically classified as VUSs. We con-
ducted a study of the full spectrum of variants observed in clinical
genetic testing and found that 87% of VUSs were missense variants
(submitted manuscript), underscoring the urgent need to improve
functional prediction methods for this class of variants encountered in
clinical laboratory genomics. A smaller proportion of VUSs comprise
variants that might have possible effects on splicing, protein synthesis,
or gene expression (Figure 3).
4.1 | Predicting the effects of DNA variants on
protein structure and function
Clinical laboratories typically use a suite of in silico models designed
to predict the consequences of DNA sequence variants, and these
predictions represent evidence that contributes to classifying variants.

ARADHYA ET AL.
>1.6 million patients Unique VUSs
Missense
Missense
VUS 87%
87%
Other
only
68%
32% 1% CNV
4% other
6% non-coding
2% splicing/truncating
F I G U R E 3 Variant types observed in a large clinical cohort
referred for genetic testing. Among 1,689,845 individuals tested using
a diagnostic multi-gene panel for a variety of hereditary disorders,
692,227 (41%) had at least one VUS, and 535,385 (31.7%) had VUS-
only findings. Across all patients there were 475,284 unique VUSs,
87% of which were missense variants and 2% of which affected
splicing.
Our group uses a collection of these evidence-generating models, all
of which are trained using ML and validated in ways that ensure high
positive predictive values. Predictions from these models are incorpo-
rated into variant classification only when a high performance (accu-
racy) threshold is met. These models together comprise Invitae's
Evidence Modeling Platform (EMP) (Figure 4).
In silico algorithms have long been available for predicting the
effects of missense changes, including some that leverage ML
(e.g., PolyPhen-2, MutationTaster, CADD) (Garcia et al., 2022). How-
ever, when these in silico algorithms are applied broadly (i.e., to predict
the effects of variants in all coding genes in the genome), their accuracy
tends to be inconsistent. Factors contributing to this inconsistency
include the relative paucity of definitively classified variants in some
genes, inadequate consideration of gene-specific molecular mechanisms
of disease, and challenges in ruling out circularity or double counting of
redundant data during AI training and evaluation (Ghosh et al., 2017;
Grimm et al., 2015). As a result, the ACMG guidelines award little weight
to outputs from each of the algorithms when used by itself, and instead
recommend the use of multiple algorithms to obtain consensus scores
(Richards et al., 2015; Variant Effect Predictors, n.d.).
Recent improvements in algorithms designed to predict the
effects of missense variants, especially those developed as ensemble
predictors (e.g., REVEL), have overall led to higher accuracy (Pejaver
et al., 2022). However, their accuracy is still diminished in certain
types of genes because they extrapolate from a limited training data-
set to score variants in diverse genes that often do not resemble the
training set. To address this limitation, as part of Invitae's EMP
(Figure 4) we have developed new ML-based algorithms using care-
fully curated training sets of pathogenic or benign variants from select
genes, and these algorithms show high positive predictive values
when applied to evaluating new variants in those same genes (manu-
script in preparation). This gene-by-gene training and implementation
approach achieves both high performance and systematic incorpora-
tion into the overall process of clinical variant classification.
A quantum leap occurred recently when AlphaFold—a deep
learning-based algorithm developed by DeepMind—accurately
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5 of 15
predicted the structures of 100,000 proteins (Jumper et al., 2021).
This and similar advances raise an important question: How can such
technologies be incorporated into clinical variant classification to
accurately indicate the effects of DNA variants on downstream pro-
tein structure and function and, ultimately, on health? Some have
explored whether evidence from the analysis of protein structures can
be used to help classify variants (Caswell et al., 2022). In a more elabo-
rate approach, to support clinical classification of missense variants,
our group has developed methods that use AlphaFold output to pre-
dict the effects of amino acid substitutions on the molecular stability
of resulting proteins (manuscript in preparation). These methods have
been incorporated into Invitae's EMP, where the accuracy of the
molecular instability scores are assessed and, if they meet a strict
quality threshold, are converted into gene-specific calibrated evidence
that is used for classifying missense variants. This process for validat-
ing and integrating AI-based evidence into variant classification is
described in more detail in Figure 4.
Another important piece of evidence that clinical laboratories use
to interpret the significance of a DNA variant within a protein-coding
region is the degree of evolutionary conservation at the affected DNA
sequence and its corresponding amino acid position. A high degree of
conservation at a specific amino acid position across many species, or
even complete conservation between vertebrates and invertebrates,
suggests the necessity of that residue for normal protein structure or
function. Simple sequence alignments that help determine the degree
of conservation among genomic sequences of different species have
been used to predict the consequences (if any) of novel DNA variants.
However, it was not until recently that sophisticated in silico tools
could demonstrate high accuracy in those predictions. Among these
tools, ML-based EVE (evolutionary model of variant effect) in particu-
lar has demonstrated strong performance in predicting the pathoge-
nicity of a DNA variant (Figure 5a), as measured by concordance with
clinical classifications in the ClinVar database (Figure 5b) and
with experimental data (Frazer et al., 2021). Despite its improved
proteome-wide performance, EVE still demonstrates variable accuracy
in predicting the effects of amino acid changes in certain proteins. To
address this limitation, we use Invitae's EMP to systematically evalu-
ate the output from EVE, gene-by-gene, and use it for variant interpre-
tation only when it meets the required quality threshold (Figure 5c).
Newly described in a publication in Science, Primate-AI3D is a
deep learning model that leverages natural variation in primates to
make inferences about the impact of DNA variants in humans (Gao
et al., 2023). Built on the premise that protein-altering variants com-
monly found in any non-human primate have been tolerated by natu-
ral selection—and are thus likely benign in humans—Primate-AI3D
uses deep learning to map genetic variants onto 3D protein structures
partially derived from AlphaFold (Jumper et al., 2021) to make predic-
tions about their pathogenicity. Prior to building Primate-AI3D, the
authors showed that among missense variants that had clinical classi-
fications in the ClinVar database that were concordant between two
or more laboratory submitters and were also common in at least one
non-human primate, 99% were classified as benign, demonstrating
the validity of their model's premise. Notably, sequence data collected
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6 of 15 ARADHYA ET AL.

(a)
Population frequency Biophysical Spatial Molecular & cellular Sequence
(population) (in silico) (indirect) (experimental) (in silico)

Single cells
Pathogenicity

Score
Allele frequency Molecular Residue
G Transcriptome
variants

(b)
Model generation Performance Standardization Clinical variant
and learning evaluation interpretation
Benign VUS Pathogenic

Variants
Input
data

Pathogenicity Score

(c)
Example AI models ACMG variant classification tiers

Benign LB VUS LP Pathogenic

Types of evidence
Population allele frequency models Population data
SpliceAI Variant type
NLP-mined clinical data Clinical observations
Cellular evidence models Experimental studies
EVE, Biophysical and spatial analyses Indirect, computational

F I G U R E 4 Evidence modeling platform (EMP). Invitae's EMP system is composed of validated machine learning models that evaluate data
and make predictions to support variant classification. Machine learning represents a subset of AI. (a) A suite of models assesses unique attributes
of a DNA variant and its downstream amino acid change. Each model predicts the pathogenicity or benignity of the variant, and this prediction is
included as evidence during variant classification. (b) A standardized process is applied to train the models on known gene-specific input data
(e.g., labels such as pathogenic or benign variants). Each model is validated by measuring its performance on a new set of known labels, and only
models that reach a high accuracy threshold—area under the receiver operating characteristic (AUROC) ≥0.80—are included within EMP to
generate predictions for novel variants. (c) A model's prediction serves as evidence that contributes, alongside other types of evidence, toward
the final variant classification. Each type of evidence provides different information about a variant's likelihood of being pathogenic or benign.
The shaded bars illustrate the degree to which data from each type of evidence are useful for classification. For example, population allele
frequency can rule out the possibility of a variant causing disease (e.g., if that allele is found at high frequency in the general population), but on its
own cannot indicate pathogenicity. ACMG, American College of Medical Genetics and Genomics; AI, artificial intelligence; EVE, evolutionary
model of variant effect; LB, likely benign; LP, likely pathogenic; NLP, natural language processing; VUS, variant of uncertain significance.

from just 809 individual non-human primates (233 species, some criti-
cally endangered) contained 20% more exome variants than all
human data currently in gnomAD, illustrating the value of this biodi-
versity. The authors then used this wealth of primate data and
Primate-AI3D to predict the pathogenicity of all possible human mis-
sense variants (>70 million variants). In validation tests, Primate-AI3D
performed strongly at separating pathogenic and benign ClinVar-
classified variants. Thus, while EVE leverages evolutionary conserva-
tion broadly across diverse animals, Primate-AI3D may be more pow-
erful in part because it focuses on the taxa most closely related to
us—though both methods illustrate the promise of applying AI-based
methods to sequence data from diverse species.
Another valuable source of evidence totally distinct from in silico
models comes from experimental assessments of the impact of
variants on cellular function in vitro. Over the past decade, high-
throughput cellular assays, collectively termed multiplex assays of var-
iant effect (MAVEs), have been developed to systematically
characterize—on a very large scale—the impact of DNA variants on a
wide array of molecular functions, including protein–protein interac-
tions (Araya et al., 2012), enzymatic activity (Romero et al., 2015),
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ARADHYA ET AL. 7 of 15

(a) within a single experiment. As a result, MAVEs present a useful oppor-

Multiple seq. Predicted pathogenicity tunity to incorporate new, highly informative functional data into vari-

alignment of missense variants ant classification during clinical genetic testing for hereditary disease
(Esposito et al., 2019). Notwithstanding the importance and richness

EVE model Benign of this resource, it remains imperative that MAVE outputs are care-
Pathogenic fully evaluated gene-by-gene and experiment-by-experiment to
ensure that the data are suitable for variant classification. To that end,
again using Invitae's EMP, we examined 49 MAVE datasets from
22 publications and discovered that 42 were relatively poor at dis-
criminating between benign and pathogenic DNA variants (i.e., the
AUROC was <0.80). In contrast, MAVE data related to BRCA1, TP53,
(b) and several other genes were extremely useful for variant classifica-
ClinVar
(likely) pathogenic tion, because those data faithfully represented the effects of DNA
EVE Score

(likely) benign variants on gene function in ways that correlated strongly with patho-
genicity in individuals diagnosed with cancer (Findlay et al., 2018;
ClinVar VUS Giacomelli et al., 2018). These results underscore the need to consider
EVE pathogenic deleterious effects of variants on protein structure and function as
EVE benign contributing to, and not unilaterally, determining whether a variant is
EVE VUS
clinically pathogenic.
Position

(c)
4.2 | Predicting the effects of variants on gene
Number of genes

120
100 Genes with
80 low performance
60
40
20
0
0.2 0.4 0.6 0.8 1.0
AUROC
F I G U R E 5 Using EVE (evolutionary model of variant effect) to
predict functional effects of DNA variants within coding regions of
genes. (a) The EVE algorithm considers evolutionary conservation of
DNA sequences across diverse organisms and a deep learning model
to determine the strength of evolutionary constraint at positions
within coding regions of genes. Using this measure, it then predicts
whether protein sequence changes caused by specific missense
variants would be tolerated (“benign”) or not tolerated (“pathogenic”).
(b) EVE produces continuous scores that are strongly concordant with
clinical classifications in the ClinVar database. As a result, these scores
may be useful for reclassifying variants of unknown significance
(VUSs) into benign or pathogenic tiers. (c) The accuracy of EVE
predictions of variant pathogenicity varies among genes offered for
clinical genetic testing. The level of accuracy, assessed through
Invitae's Evidence Modeling Platform, is measured for each gene
individually. EVE predictions are used for variant classification in
certain genes only when those predictions meet a high accuracy
threshold, defined as an area under the receiver operating
characteristic (AUROC) score of ≥0.80. In the example shown here of
EVE predictions of pathogenicity for variants in 495 genes,
performance exceeded the required threshold for a majority of genes.
regulatory control (Kwasnieski et al., 2012), and protein stability
(Hasle et al., 2019). Unlike previous approaches for determining vari-
ant effects, MAVEs enable the characterization of many DNA variants
splicing
In addition to methods that enhance our ability to interpret the clinical
significance of amino acid changes in protein sequences, other newly
developed methods have become useful for predicting the effect of
DNA variants on RNA splicing. Although variants that may alter RNA
splicing account for a small proportion of VUSs (Figure 3), these vari-
ants are nevertheless responsible for a broad variety of hereditary dis-
eases and must be carefully evaluated during clinical genetic testing
(Kamps-Hughes et al., 2023; Karam et al., 2019). RNA sequencing is
increasingly used alongside DNA sequencing to identify splice alter-
ations directly; however, transcripts for some genes are poorly
expressed in available biological specimens and are therefore not
amenable to this parallel testing approach. It is therefore critical that
laboratory geneticists have access to robust algorithms that can pre-
dict the effects of DNA variants on splicing.
Algorithms to identify splice sites were developed years ago, and
some were co-opted to predict how specific novel DNA variants might
impact splicing. Examples of these algorithms include MaxEntScan,
NNSplice, and GENSCAN. Similar to algorithms designed to predict the
effects of missense variants, most splice-predicting algorithms have
shown moderate positive predictive values because they were trained
on limited datasets but then used to predict the potential splicing
effects of variants in all genes (Jian et al., 2014; Ohno et al., 2018).
However, deep learning-based algorithms with superior performance,
such as SpliceAI, are now available (Jaganathan et al., 2019). More
recently, the Pangolin deep learning model has been developed,
leveraging splicing data from closely related species to improve upon
results from SpliceAI (Zeng & Li, 2022). We and others are working on
using Pangolin to annotate exome and genome sequences in the next
version of the gnomAD database (Karczewski et al., 2020).
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8 of 15 ARADHYA ET AL.

>1 P/LP pediatric disorders. These structural variants can be detected using
~3,500 individuals G-banded karyotyping, the mainstay of constitutional cytogenetic
(1%) testing for nearly three decades, or high-resolution chromosomal
microarrays, which became the standard about a decade ago (Miller
et al., 2010). Because AI methods have been developed for visual pat-
VUS tern recognition in X-rays, computed tomography scans, and stained
~70,500 tissue slices, one might predict that these methods could also be
individuals
applied to the analysis of chromosomal karyotypes for constitutional
Individuals Individuals (20%)
rearrangements or to the analysis of tumor tissue for chromosomal
without ML with ML
rearrangements. To date, little to no AI appears to be used to rou-
evidence evidence >1 B/LB
tinely analyze chromosomal karyotypes for constitutional rearrange-
applied applied ~85,000
ments (Tseng et al., 2023), although various efforts have been used to
individuals
~192,000 ~159,000 (24%) decipher chromosomal rearrangements in cancer specimens, such as
(55%) (45%) from karyotyped hematologic malignancies (Bokhari et al., 2022; Cox
et al., 2022; Vajen et al., 2022; Walter et al., 2021). As genomic analy-
sis increasingly shifts toward molecular approaches, even for chromo-
Both P/LP & B/LB somal disorders, AI methods are being developed to identify
~340 individuals (<0.5%) chromosomal deletions, duplications, and other types of rearrange-
ments from NGS data directly (Lin et al., 2022; Popic et al., 2023).
F I G U R E 6 Machine learning-based evidence-generating models
contribute to reducing variants of uncertain significance in an
appreciable fraction of individuals undergoing genetic testing. B/LB,
benign/likely benign; ML, machine learning; P/LP, pathogenic/likely 6 | M I N I N G P U B L I S H E D LI T E R A T U R E OR
pathogenic; VUS, variant of uncertain significance. ELECTRONIC HEALTH RECORDS

NLP has become ubiquitous in modern society, including in genomic med-

4.3 | Impact of ML-based evidence modeling on
providing definitive clinical results
A genetic testing result of a VUS is not clinically actionable. Although in
silico methods for predicting the effects of DNA sequence variants
have improved, their ability to help laboratory geneticists reduce the
number of VUSs reported and resolve uncertainty for patients has not
been directly assessed. Therefore, to empirically examine the magni-
tude of the impact of Invitae's EMP system (Figure 4) on providing
definitive answers to individuals referred for clinical genetic testing, we
evaluated data from 350,695 patients who underwent diagnostic multi-
gene panel testing over a six-month period for a variety of hereditary
diseases. At least one evidence-generating model was available for
3087 genes, and 159,000 patients (45%) received results that
included EMP evidence for at least one reported variant (Figure 6). The
application of these models contributed to the classification of at least
one B/LB variant in 85,000 individuals (24%), one P/LP variant in
3500 individuals (1%), and both P/LP and B/LB variants in 340 indi-
viduals (0.1%) (Figure 6). Among individuals who had at least one vari-
ant with EMP evidence applied toward its interpretation, more than
50% resulted in definitive (B/LB or P/LP) classifications.
icine (Simmons et al., 2016). Important uses, such as mining published lit-
erature or electronic health records for clinical phenotype information,
are expected to improve genetics research, innovation, and clinical diag-
nostics (Birgmeier et al., 2020; Luo et al., 2021; Son et al., 2018). One
powerful application is within the context of rapid whole genome
sequencing in the neonatal intensive care unit for children with suspected
genetic disease. AI methods, including NLP-based text mining, have facili-
tated rapid identification of the molecular causes of disease in newborns
(Clark et al., 2019; Owen et al., 2022; Peterson et al., 2023), significantly
reducing the time to diagnosis and the associated costs. Because of the
advantages of such AI-based approaches, they could conceivably be
applied to screening of newborns to identify those at risk for severe dis-
ease (Kingsmore et al., 2022). Similarly, AI-based approaches for virtual
screening for cardiovascular conditions, including familial hypercholester-
olemia, have been explored by mining electronic health records for phe-
notypic information suggestive of elevated risk of disease (Pina
et al., 2020; Safarova et al., 2016; Sheth et al., 2021). Finally, clinical labo-
ratories use NLP to rapidly identify relevant evidence (e.g., data on geno-
types or clinical phenotypes) from the published literature that helps to
classify new variants observed in patients or resolve variants of uncertain
significance. A proliferation of such examples of applied NLP in genomic
medicine should be expected in the coming years.

5 | DECIPHERING CHROMOSOMAL
STRUCTURAL VARIANTS
Although most DNA changes associated with genetic disease are
sequence variants, large deletions and duplications within chromo-
somes are also frequently pathogenic, particularly in prenatal and
7 | C O R R E LA T I N G G E N O T Y P E S A N D
P H EN O T Y P E S F O R CL I N I C A L D I A G NO S E S
Diagnostic rates in hereditary disease, particularly involving neurode-
velopmental disability, have improved substantially in recent years

ARADHYA ET AL.
thanks to AI-based approaches. Clinical whole exome sequencing
(WES) or whole genome sequencing require robust tools to sift
through the thousands of variants typically found in an individual and
identify the one or few variants responsible for that individual's clini-
cal condition. Roughly a dozen years ago, clinical analysis of WES
relied primarily on manual analysis due to a paucity of powerful soft-
ware tools that could pull together diverse evidence types including
genotype-disease annotations, relevant published medical literature,
genome sequence annotation resources, and predictions from in silico
modeling algorithms. Various sophisticated proprietary software plat-
forms for analyzing WES have since been developed, many of which
incorporate AI (e.g., Invitae's Moon™, Fabric GEM™, Illumina's
Emedgene™, FindZebra) (De La Vega et al., 2021; Dragusin
et al., 2013; Meng et al., 2023; O'Brien et al., 2022; Wright
et al., 2023). These platforms have become faster and more accurate
by incorporating improved genotype–phenotype annotations from
the Human Phenotype Ontology, the Monarch Initiative, DisGeNET,
and other research efforts (Köhler et al., 2021; Pilehvar et al., 2022;
Piñero et al., 2020; Robinson et al., 2008, 2014; Shefchek
et al., 2020); by refining the heuristics used to analyze WES
(by mimicking the analysis processes used by experienced clinical lab-
oratory geneticists); and by deploying NLP to mine published litera-
ture for phenotype and DNA variant information that could be
relevant to identifying the molecular cause of an individual's clinical
condition. In addition, global sharing of clinical WES data among clini-
cal labs, clinicians, and researchers has accelerated the discovery of
disease genes, further fueling improvements in diagnostic rates
of WES (Boycott et al., 2022; Kirkpatrick et al., 2015; Osmond
et al., 2022).
8 | P R E - T E S T A N D P O ST - T E S T
APPLICATIONS
As genomic information becomes more voluminous and complex—
with NGS panels, exome or genome sequencing, family variant testing,
follow-up testing to resolve VUSs, and the need to confirm results in
certain circumstances (e.g., in non-invasive prenatal screening)—it is
imperative that patients and clinicians have access to pre-test and
post-test education and other information resources. A relatively new
type of resource that has demonstrated significant benefits in this
regard is the interactive AI-based chatbot (Nazareth, Hayward,
et al., 2021; Siglen et al., 2022). A chatbot can be built either with sim-
ple rules to respond to expected questions or, on a more sophisticated
level, as a generative large language model that can self-learn and
improve its performance over time.
The arrival of ChatGPT has understandably created widespread
excitement and, at the same time, trepidation for what it may eventu-
ally mean for human participation in different work environments. In
the healthcare context, after more carefully designed trials and valida-
tions are completed, interactive tools like ChatGPT are expected to
become ubiquitous, powerful tools for identifying individuals who
should consider genetic testing due to their elevated risk profiles
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9 of 15
(Heald et al., 2021; Nazareth, Nussbaum, et al., 2021), for exchanging
information during the informed consent process (Schmidlen
et al., 2019), for sharing information between patients and their rela-
tives, healthcare providers, and others (Chavez-Yenter et al., 2021);
and for providing education before and after genetic testing (Chavez-
Yenter et al., 2021). For instance, a recent publication (Kurian
et al., 2023) describes a disappointingly low rate of germline genetic
testing (only 6.8%) among individuals with a cancer diagnosis, despite
existing guidelines that recommend testing for such individuals. The
authors recommend AI-supported chatbots as one approach to
increasing rates of genetic testing in these patients. As chatbots
become more sophisticated and natural (human-like), users may be
unable to distinguish between chatbots and humans. Some have sug-
gested that patients may even prefer chatbots because of their inher-
ent ability to better modulate responses to a wide range of user needs
and personalities, and because of the high quality of their interactions
with users (Ayers et al., 2023). While additional research is still needed
to understand in detail how physicians may benefit from the use of AI
chatbots within their clinical genetics workflows (e.g., Smith
et al., 2023), the breadth of applications for AI chatbots in healthcare
will likely increase overall. As we described recently (Snir et al., 2021),
the successful integration of genomics into all areas of medicine will
in part require the use of chatbots and other software tools, many of
which will be developed using AI.
9 | C O N S I DE R A T I O N S F O R U S E O F A I I N
CLINICAL LABORATORY GENOMICS
The deployment of AI models for clinical laboratory genomics pre-
sents unique opportunities, whether those models are designed for
classification and reporting of sequence variants, chromosomal
changes or, perhaps in the future, other molecular changes
(e.g., transcriptional, epigenetic, or proteome changes). There are sev-
eral pitfalls, however, that need to be recognized. First, incorrect
assumptions or inappropriate training sets used during the develop-
ment or validation of AI models could lead to spurious results (Grimm
et al., 2015). For example, if models that contribute evidence toward
classifying variants rely too heavily on determining whether a variant
is deleterious at the molecular level without having complementary
evidence of pathogenicity (e.g., case reports, population frequency,
evolutionary conservation), and these variants are submitted into Clin-
Var, future researchers may be at risk of using AI-corrupted training
data to develop new AI models. This potential pitfall may be mitigated
by carefully recognizing which classifications in ClinVar are AI-
supported and ensuring the use of only high-quality inter-lab consen-
sus submissions derived from multiple types of evidence.
A second challenge to the adoption of AI models is determining
how much weight should be assigned to evidence generated from dif-
ferent models, and how that evidence should be considered in combi-
nation with other types of evidence during variant classification.
Although some methods are being proposed to calibrate in silico
models and determine the value of their outputs (Pejaver et al., 2022),

10 of 15
integrating the full spectrum of evidence generated from increasingly
diverse AI-based models into variant classification will require a sys-
tematic approach. One solution could be to develop a holistic and
quantitative variant classification framework, for example by using
probabilistic Bayesian inference that allows systematic assignment of
weight to each type of evidence and combinations of evidence to out-
put an overall probability of pathogenicity.
A third challenge facing AI approaches to variant classification is
that the use of genomic datasets with underrepresentation of individ-
uals of non-Northern European ancestry could perpetuate inadequa-
cies in the delivery of definitive variant classification for such groups.
For example, it is well documented that individuals with some genetic
ancestries receive more VUSs than others because of a paucity of
population frequency data in public databases such as gnomAD
(Appelbaum et al., 2022; Florentine et al., 2022). Because some
genetic ancestry groups are better represented in public databases,
they are also better represented in the data used for training and vali-
dating AI models for variant interpretation. With the development of
any AI model for clinical laboratory genomics, it is necessary to exer-
cise caution and monitor for potential reinforcement of genetic ances-
try biases in AI-generated evidence. The deployment of AI models
that are informed by biological principles and are agnostic to genetic
ancestry should help to correct such biases and lead to more equity in
variant classification.
1 0 | CO NC L U SIO NS A ND F U T U R E
DIRECTIONS
The number of known monogenic diseases has increased rapidly over
the past decade and is expected to climb further. Importantly, the
number of genetic diseases with available therapies and precision clin-
ical management is also increasing (Bick et al., 2021). AI methods will
continue to improve and be used to rapidly diagnose hereditary dis-
eases, identify those who can benefit from available therapies, recog-
nize those at risk of genetic disease, and fuel further discovery of
novel disease genes.
AI-based resources will also become richer as genomics databases
grow in both volume and quality. Some of this data accumulation will
occur through basic research aimed at further characterizing the
structure of the human genome (Liao et al., 2023), and through
insights into less understood elements such as promoters, enhancers,
alternative transcripts, functional non-coding regions, methylated
sites, and heterochromatin regions. Tens of millions of new exome
and genome sequences are expected to soon be added to public data-
bases through international research efforts (Manolio et al., 2020).
Importantly, these studies are aggregating genomic data from diverse
populations around the world (Wang et al., 2022), thereby improving
the representation of genetic ancestry groups and the accuracy of
studies on genomic contributions to complex diseases and other clini-
cal questions. Complementing this, phenomics research with elec-
tronic health records can reveal important gene–disease associations
that may be translated into useful screening and diagnostic
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ARADHYA ET AL.
approaches to reduce disease burden (Hebbring, 2019; Linder
et al., 2021; Movaghar et al., 2021; Robinson et al., 2018; Yang
et al., 2022). In addition, large-scale population data from genome-
wide association studies are increasingly being leveraged to identify
polygenic risk for disease, and AI-based methods are being used to
conduct these types of studies and develop risk scores (Nicholls
et al., 2020; Steinfeldt et al., 2022). Together, often with the support
of AI methods, these complementary advances in genomics and phe-
nomics are expected to catalyze faster drug discovery for hereditary
diseases (Alves et al., 2022; Boniolo et al., 2021; Visibelli et al., 2023)
and, importantly, extend to groups historically underserved by clinical
genomics.
Although this article has largely focused on AI applications in rela-
tion to hereditary disease, AI approaches for clinical laboratory geno-
mics in relation to precision oncology likely hold equal promise for
improving human health (Stenzinger et al., 2022). This topic is too vast
in scope to be covered here and deserves its own article. However, in
brief, AI may be explored to investigate the complex landscape of
somatic DNA variants detectable in tumors (i.e., through NGS-based
cancer genome profiling). Applying powerful AI methods in this man-
ner promises to uncover relationships between cancer risk or diagno-
sis and multi-omic data derived from DNA sequencing, RNA
sequencing, epigenetic signatures of methylation, histology, radiology,
and clinical observations (Espín-Pérez et al., 2022; Silvestri
et al., 2023; Sun et al., 2023). It also promises to help in monitoring
molecular residual disease at different points in an individual's cancer
treatment journey (Chen, Zhang, et al., 2023) and in identifying novel
biomarkers detectable by liquid biopsy. All of these applications would
represent important advancements that are urgently needed in medi-
cal oncology.
AI methods are becoming increasingly and urgently necessary as
the use of genomic medicine increases rapidly across the world. How-
ever, it is worth emphasizing that AI at present still has limited scope
of use in clinical laboratory genomics due to continuously evolving
genomic databases, a steady pace of discoveries of gene-disease rela-
tionships, and limited deployment for providing education and infor-
mation (Luca et al., 2023). Expert clinicians and laboratory geneticists
will therefore need to carefully oversee the emerging use of AI in
genomic medicine and help other professionals incorporate genomic
information appropriately for clinical management of their patients
(Solomon, 2022). It is also important to note the potential lost oppor-
tunity costs of delaying the use of AI, since that would hinder diagno-
sis and treatment for millions of individuals who need conclusive
genetic testing results, even as the data that could provide answers
are available and waiting to be analyzed. Because the number of AI
models and the areas of their potential use are expected to grow rap-
idly, even exponentially, it is important to standardize how they are
used in healthcare. Key guiding principles for the scientific and clinical
community need to be developed as genomic medicine evolves to
become universal across healthcare specialties (Badal et al., 2023;
Rajpurkar et al., 2022), and as the need for individuals to interact with
their genomic information for different purposes through their life-
spans becomes a reality.

ARADHYA ET AL.
AUTHOR CONTRIBUTIONS
All authors have reviewed, discussed, and agreed to their individual
contributions to this manuscript. All authors contributed to conceptu-
alizing, writing, editing, or reviewing the manuscript.
ACKNOWLEDGEMEN TS
We thank Dr. Elaine Chen of Invitae for analyzing data for figures and
Kerry Aradhya of Invitae for scientific editing.
CONF LICT OF IN TE RE ST ST AT E MENT
All authors are employees and stockholders of Invitae.
DATA AVAI LAB ILITY S TATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
Swaroop Aradhya https://orcid.org/0000-0001-6219-2931
Flavia M. Facio https://orcid.org/0000-0002-7472-471X
Hillery Metz https://orcid.org/0000-0002-8246-3513
Alexandre Colavin https://orcid.org/0000-0002-4996-5378
Yuya Kobayashi https://orcid.org/0000-0002-8202-2101
Keith Nykamp https://orcid.org/0000-0002-1389-5320
Britt Johnson https://orcid.org/0000-0003-1883-5201
Robert L. Nussbaum https://orcid.org/0000-0003-3445-8880
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