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\documentclass[slidestop]{beamer}
\author{Jeroen F.J. Laros}
\title{Artificial Intelligence in Genetics}
\providecommand{\mySubTitle}{Requirements and examples}
\providecommand{\myConference}{ML/AI meeting LUMC - LIACS}
\providecommand{\myDate}{27-06-2018}
\providecommand{\myGroup}{Research Software Engineering}
\providecommand{\myDepartment}{Department of Human Genetics}
\providecommand{\myCenter}{Center for Human and Clinical Genetics}
\usetheme{lumc}
\usepackage{fancyvrb}
\begin{document}
% This disables the \pause command, handy in the editing phase.
%\renewcommand{\pause}{}
% Make the title slide.
\makeTitleSlide{\includegraphics[height=2.7cm]{sanger_trace}}
% First page of the presentation.
\section{Introduction}
\makeTableOfContents
\section{Sequencing}
\subsection{From DNA to sequences}
\begin{pframe}
\begin{minipage}[t]{0.47\textwidth}\begin{figure}[]
\begin{center}
\includegraphics[width=\textwidth]{NovaSeq6000}
\end{center}
\caption{Illumina NovaSeq 6000.}
\end{figure}
\end{minipage}
\hfill
\begin{minipage}[t]{0.47\textwidth}
\begin{Verbatim}[fontsize=\tiny]
@K0187:120:GFLBXX:1:1101:2950:1191 1:N:0:CTTGAG
TTAGGAAATAATAAATTGTAGTTTTTTTTATGATTTGGTTGAATTGATT
+
AAAFFJJJJJJ-AJFFFJ-FF<F<JJJAFJFFFJAFJJ<-FFFA<FFAA
@K0187:120:GFLBXX:1:1101:7710:1209 1:N:0:CTTGAG
GTCCACTAGAACTTGTAGAGCTGGAACCAACTGATTTGCAAAAGCAAAA
+
AA-FFFJAAAF-FFAJJJFJJJ--AFFJJFFJJFAFA-FJJJJFJJJJF
@K0187:120:GFLBXX:1:1101:17269:1209 1:N:0:CTTGAG
GTACTTGATGAATATTTACTAAAGAATGGAAGGAAAAAAGAAAGAAGGA
+
AAFFFJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJ
@K0187:120:GFLBXX:1:1101:28067:1209 1:N:0:CTTGAG
TGGGTGTGTTAAGAATGACATTCAACGCAGTCTCTTTACCACCTCCCCA
+
AAA-FJFJFJFAJJJJFFJFAFJJJJFFJFAJJJJFFJJJAAJ7FFJJA
@K0187:120:GFLBXX:1:1101:1367:1226 1:N:0:CTTGAG
NTAGGTGTAAAAACATGATCATCGAAGAGACAAGAAATAGAACGTATTT
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#AAFFFJFJJJJJJJJJJJJJJJJFJFJFAFJJJJJJJJJJJJJJJAFF
@K0187:120:GFLBXX:1:1101:8410:1226 1:N:0:CTTGAG
AGTGAGACCCTCTCTCTAAAAAGAAAAAAGAAAAAAAATTATGATGTTT
+
AAFAFFJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJ
\end{Verbatim}
\end{minipage}
\end{pframe}
\section{Background}
\subsection{Current status and requirements}
\begin{pframe}
We work a lot with \emph{sequences} (over an alphabet of four letters).
\begin{itemize}
\item Alignment / variant calling.
\item \textit{De novo} assembly / gene prediction.
\item $k$-mer profiling.
\end{itemize}
\bigskip
For most of these problems, there are efficient deterministic algorithms
available, with the exception of \textit{de novo} assembly.
\bigskip
\pause
We have a strong need for being able to \emph{explain} results.
\begin{itemize}
\item Techniques like decision trees.
\item Optimisation of procedures, which are in the end very clear.
\end{itemize}
\end{pframe}
\section{Farmacogenetics}
\subsection{Personalised Medicine}
\begin{pframe}
Predict drug response from patient genetics.
\begin{itemize}
\item The current gold standard $r^2 \approx 0.55$.
\end{itemize}
\bigskip
Over the years, we have collected quite some data.
\begin{itemize}
\item High quality genotypes from sequencing.
\item $550$ \textit{in vivo} metabolite measurements.
\end{itemize}
\bigskip
\pause
The approach, a neural network with:
\begin{itemize}
\item Binary vectors indicating presence/absence of genetic features (two
sets of inputs due to ploidy) as input.
\item Predicted metabolite measurement (scalar) as output.
\end{itemize}
\vfill
\permfoot{Guy Allard}
\end{pframe}
\begin{pframe}
\vspace{-0.5cm}
\begin{figure}[]
\begin{center}
\includegraphics[height=0.8\textheight]{pm_network}
\end{center}
\caption{Model architecture.}
\end{figure}
\end{pframe}
\begin{pframe}
Techniques and libraries:
\begin{itemize}
\item Model constructed and trained using TensorFlow.
\item Allele submodules share the same layers (same model).
\end{itemize}
\begin{figure}[]
\begin{center}
\includegraphics[width=\textwidth]{allele}
\end{center}
\caption{Visualising contribution of features.}
\end{figure}
\vspace{-0.5cm}
Results:
\begin{itemize}
\item $10$-fold cross validation, $r^2 \approx 0.7$.
\item Allele submodule ($p_{a1}$) can be interrogated and the effects of
genetic features explored.
\end{itemize}
\vfill
\permfoot{Guy Allard}
\end{pframe}
%\section{Single cell sequencing}
%\subsection{???}
%\begin{pframe}
% Slides here.
%\end{pframe}
\section{Clinical Genetics}
% Use case 2: Variant classification for the purposes of clinical diagnostics
% in the clinic is currently a tedious manual task. Clinicians have to go
% through lists of dozens of variants, and manually curate them. This task can
% take up to several hours per patient. It would greatly speed up diagnosis if
% the clinical could have an automated ranking, which would select the best
% candidate hit first. As variants are automatically annotated with dozens of
% annotation fields, we reasoned we could very well use some machine learnings
% methods for this purpose. Our first attempt was to use a decision tree, or
% ensemble of decision trees, as this is a white-box model. A confounding
% factor here is that the vast majority of variants (millions) are
% unclassified, with just a few thousand classified variants. This is currently
% an ongoing project in cooperation with the ICT department.
\subsection{Variant classification}
\begin{pframe}
From the tens of thousands of genetic variants, we are only interested in the
one that causes a disease.
\begin{itemize}
\item Filtering strategies narrow it down to a few dozens of variants.
\item Manual curation takes a few hours per patient.
\end{itemize}
\bigskip
Can this be done automatically?
\bigskip
\pause
Challenges:
\begin{itemize}
\item Make the selection explainable (decision trees).
\item Large number of unclassified variants.
\end{itemize}
\vfill
\permfoot{Sander Bollen}
\end{pframe}
% Use case 1: Classifying reads to the lab protocol they were sequenced with.
% Within the department of clinical genetics, several lab protocols are used
% for the generation of Next-Generation Sequencing. Two different capture kits
% are used (WES and IDP), as well as two different sequencers (Hiseq4000 and
% NextSeq500). Downstream analysis can be slightly different for each protocol
% used, which requires run metadata to be correct. Unfortunately, this is not
% always the case, and a way of validating the input metadata is required. We
% have used machine learning to accomplish this task. Briefly, k-mers were
% counted for each NGS read, after which an SVM was trained on the dataset of
% several hundred thousand reads. Nextseq reads separate well from all other
% classes, but both hiseq4000 classes were more difficult to separate. This
% method may also be useful for other purposes where separating reads into
% classes is required, e.g. separating virus from host reads.
\subsection{Detecting lab protocol from raw data}
\begin{pframe}
Differences in preprocessing (lab) steps:
\begin{itemize}
\item Capture kit (selection of part of the genome).
\item Different sequencers.
\end{itemize}
\bigskip
Validation of this metadata is needed because downstream analysis depends on
it.
\bigskip
\pause
Approach:
\begin{itemize}
\item $k$-mer counts of every read.
\item Training on over $100,\!000$ examples:
\begin{itemize}
\item SVM.
\item Random forest.
\end{itemize}
\end{itemize}
\vfill
\permfoot{Sander Bollen}
\end{pframe}
\begin{pframe}
Distinguishing sequencing platform works very well.
\begin{figure}[]
\begin{center}
\includegraphics[width=0.5\textwidth]{svm_error}
\hfill
\includegraphics[width=0.5\textwidth]{random_forest_error}
\end{center}
\caption{Overall error (left: SVM, right: Random forest).}
\end{figure}
Potential applications in contamination and \emph{infection} detection.
\vfill
\permfoot{Sander Bollen}
\end{pframe}
% Make the acknowledgements slide.
\makeAcknowledgementsSlide{
\begin{tabular}{l}
Guy Allard\\
%Peter van 't Hof\\
Sander Bollen\\
Leon Mei\\
\end{tabular}
}
\end{document}
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