biological interpretation of deepomicsae output using metaboanalyst

深層学習によるアルツハイマー病におけるシグナル伝達モジュールの解析

An increasingly large proportion of the population is aging and the burden of age-related diseases, such as neurodegeneration, is expected to sharply increase in the coming decades1. Alzheimer&#39;s disease is the most common type of neurodegenerative disease2. Progress in finding a treatment has been slow given our poor understanding of the fundamental&#160;molecular mechanisms driving the onset and progress of the disease. The majority of information on Alzheimer&#39;s disease is gained postmortem from the examination of brain tissue, which has made distinguishing causes and consequences a difficult task3. The Religious Orders Study/Memory and Aging Project (ROSMAP) is an ambitious effort to gain a broader understanding of neurodegeneration, which involves the study of thousands of individuals who have committed to undergo medical and psychological examinations yearly and to contribute their brains for research after their demise4. The study focuses on the transition from the normal functioning of the brain to Alzheimer&#39;s disease2. Within the project, postmortem brain samples&#160;were analyzed with a plethora of omics approaches, including genomics, epigenomics, transcriptomics, proteomics5, and metabolomics.
Omics technologies that offer functional readouts of cellular states (i.e., proteomics and metabolomics)6,7 are key to interpreting disease8,9,10,11,12, due to the direct relationship between protein and metabolite abundance and cellular activities. Proteins are the primary executors of cellular processes, while metabolites are the substrates and products for biochemical reactions. Multi-omics data analysis offers the possibility to understand the complex relationships between proteomics and metabolomics data instead of appreciating them in isolation. Multi-omics is a discipline that studies multiple layers of high-dimensional biological data, including molecular data (genome sequence and mutations, transcriptome, proteome, metabolome), clinical imaging data, and clinical features. Particularly, multi-omics data analysis aims to integrate such layers of biological data, understand their reciprocal regulation and interaction dynamics, and deliver a holistic understanding of disease onset and progression. However, methods to integrate multi-omics data remain in the early stages of development13.
Autoencoders, a type of unsupervised neural network14, are a powerful tool for multi-omics data integration. Unlike supervised neural networks, autoencoders do not map samples to specific target values (such as healthy or diseased), nor are they used to predict outcomes. One of their primary applications&#160;lies in dimensionality reduction. However, autoencoders offer several advantages over simpler dimensionality reduction methods such as principal component analysis (PCA), t-distributed stochastic neighbor embedding (tSNE), or uniform manifold approximation and projection (UMAP). Unlike PCA, autoencoders can capture non-linear relationships within the data. Unlike tSNE and UMAP, they can detect hierarchical and multi-modal relationships within the data since they rely on multiple layers of computational units each containing non linear activation functions. Therefore, they represent attractive models to capture the complexity of multi-omics data. Finally, while the primary application of PCA, tSNE, and UMAP is that of clustering the data, autoencoders compress the input data into extracted features that are well-suited for downstream predictive tasks15,16.
Briefly, neural networks comprise several layers, each containing multiple computational units or &#34;neurons.&#34; The first and last layers are referred to as the input and output layers, respectively. Autoencoders are neural networks with an hourglass structure, consisting of an input layer, followed by one to three hidden layers and a small &#34;latent&#34; layer typically containing between two and six neurons. This structure&#39;s first half is known as the encoder and is combined with a decoder mirroring the encoder. The decoder ends with an output layer containing the same number of neurons as the input layer. Autoencoders take the input through the bottleneck and reconstruct it in the output layer, with the goal of generating an output that mirrors the original information as closely as possible. This is achieved by mathematically minimizing a parameter termed &#34;reconstruction loss.&#34; The input consists of a set of features, which in the application showcased herein will be protein and metabolite abundances, and clinical characteristics (i.e., sex, education, and age at death). The latent layer contains a compressed and information-rich representation of the input, which can be used for subsequent applications such as predictive models17,18.
This protocol presents a workflow, DeepOmicsAE, which involves: 1) preprocessing of proteomics, metabolomics, and clinical data (i.e., normalization, scaling, outlier removal) to obtain data with a consistent scale for machine learning analysis; 2) selecting appropriate autoencoder input features, since feature overload may obscure relevant disease patterns; 3) optimizing and training the autoencoder, including determining the optimal number of proteins and metabolites to select, and of neurons for the latent layer; 4) extracting features from the latent layer; and 5) utilizing the extracted features for biological interpretation by identifying molecular signaling modules and their relationship with clinical features.
This protocol aims to be simple and applicable by&#160;biologists with limited computational experience who have a basic understanding of programming with Python. The protocol focuses on analyzing multi-omics data, including proteomics, metabolomics, and clinical features, but its use can be extended to other types of molecular expression data, including transcriptomics. One important novel application introduced by this protocol is mapping the importance scores of original features onto individual neurons in the latent layer. As a result, each neuron in the latent layer represents a signaling module, detailing the interactions between specific molecular alterations and the patients&#39; clinical characteristics. Biological interpretation of the molecular signaling modules is obtained by using MetaboAnalyst, a publicly available tool that integrates gene/protein and metabolite data to derive enriched metabolic and cell signaling pathways17.

著者スポットライト:アルツハイマー病研究の推進 – 早期発見とマルチオミクスアプローチの探求

DeepOmicsAE:プロテオミクス、メタボロミクス、臨床データの深層学習解析によるアルツハイマー病のシグナル伝達モジュールの表現

Alzheimer's disease is thought to initiate decades before symptoms emerge. Recent studies suggest that phenotypic traits such as obesity and hypertension, but also the level of education and social engagement can act as risk factors. Our goal is to become able to decipher their contributions and their relation to molecular drivers of disease to learn how to intervene early and in a personalized manner.Multi-omic data analysis can be used for integrating various layers of biological data such as proteomics, transcriptomics, metabolomics, and phenotypic traits to comprehensively understand a disease state. Autoencoder models use deep learning to reduce the dimensionality of multi-omics datasets, effectively summarizing the crucial information, However, it is challenging to interpret how important are individual features in the original data with respect to the summarized output. In Deep-omics AE, we built in an algorithm that derives the importance of individual multi-omics features relative to the learn reduced dimensionality representation.With this approach, we can identify molecularly similar modules and their association with patient's phenotypic traits. Deep-omics AE helps putting in relation patient's phenotypic traits with the molecular makeup of disease. For example, you can use it to ask, what are the molecular pathways that are most implicated in Alzheimer's disease in older patients, and what are those that are most implicated in younger patients?What are those implicated in developing the disease in less educated patients versus more educated patients?

MetaboAnalystを用いたDeepOmicsAE出力の生物学的解釈

まず、Web ブラウザーを開き、MetaboAnalyst Web サイトの Joint Pathway Analysis 機能にアクセスするためのリンクに移動します。DeepOmicsAE実装の出力ファイルが保存されているフォルダにアクセスし、生成された各シグナリングモジュールのmodule_n. txtという名前のテキストファイルを開きます。テキストファイルから、タンパク質のリストを見つけてコピーします。MetaboAnalystのWebページで、コピーしたタンパク質のリストを遺伝子のタンパク質に貼り付け、オプションのフォールド変更ウィンドウを表示します。代謝物について繰り返し、同じウェブページのオプションの折り目変更ウィンドウで化合物リストに貼り付けます。関連する生物と ID タイプを選択します。次に、ページ下部の [送信] をクリックして情報を送信します。次のページで、ID マッピングを確認して識別子が正しく認識されていることを確認し、[続行] をクリックします。[パラメーター設定]ページで、[代謝経路の統合]または[すべての経路の統合]を選択して、代謝経路またはすべてのシグナル伝達経路への入力の寄与を視覚化します。[アルゴリズムの選択] パネルで、[エンリッチメント分析]、[超幾何学的検定] の順に選択します。トポロジー測定、次数中心性。積分法、p値の結合経路レベル。ページ下部の [送信] をクリックします。最後のページである [結果ビュー] には、エンリッチメント解析の結果が表示されます。これには、その影響と重要性に基づくエンリッチメントされた経路のプロットと、経路の表形式リストが含まれます。健常者またはアルツハイマー病患者の脳サンプルからのデータセットでDeepOmicsAEで得られたシグナル伝達モジュールをMetaboAnalystが解釈したところ、シグナル伝達モジュールごとに、異なる代謝経路とシグナル伝達経路が濃縮されていることが明らかになりました。さらに、臨床的特徴とシグナル伝達モジュールの間に発生する相互作用の特徴付けは、アルツハイマー病患者のグリセロ脂質代謝の変化が性別と死亡時年齢に関連していることを示しました。逆に、シナプスと軸索機能の変化は、性別、教育レベル、寿命に関係なく、アルツハイマー病患者全体で発生する傾向があります。

Research

JoVE Journal

Biology

Biological Interpretation of DeepOmicsAE Output Using MetaboAnalyst

DeepOmicsAE: Representing Signaling Modules in Alzheimer's Disease with Deep Learning Analysis of Proteomics, Metabolomics, and Clinical Data

Large omics datasets are becoming increasingly available for research into human health. This paper presents DeepOmicsAE, a workflow optimized for the ...

生物学

Data Preprocessing for DeepOmicsAE Workflow

DeepOmicsAEワークフローのためのデータ前処理

Optimizing Model Parameters and Implementing DeepOmicsAE Workflow

モデル パラメーターの最適化と DeepOmicsAE ワークフローの実装