# Should We Embed in Chemistry? A Comparison of Unsupervised Transfer Learning with PCA, UMAP, and VAE on Molecular Fingerprints

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## Abstract

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## 1. Introduction

## 2. Results and Discussion

#### 2.1. Setting the Baseline

#### 2.2. Embedding Chemical Spaces

#### 2.3. Impact of Embedding Size and Information Content

#### 2.4. Internal versus External Knowledge

#### 2.5. Should We Embed? Does Embedding Win over Baseline?

#### 2.6. Insights into Latent Representations

## 3. Materials and Methods

#### 3.1. Data

#### 3.2. Machine Learning Methods

#### 3.3. Transfer Learning with Embeddings

#### 3.3.1. Principal Component Analysis (PCA)

**X**~(n,p)) are represented by the product of two matrices, namely the scores (

**T**~(n,k)) and the loadings (

**P**~(p,k)), Equation (3):

**E**~(n,p) is the residual matrix and n, p, and k are the number of samples, variables, and components, respectively. The parameters are estimated to capture as much of the variance in the original data in a least squares sense, and further to be orthogonal matrices, i.e.,

**T**and

**P**are referred to as principal components, and used in various ways in, e.g., exploratory data analysis to map the multivariate sample distribution as well as interrogating feature2feature correlation structure, as well as—like in this work—to represent the data in a few meaningful features used for further analysis. A rewrite of Equation (4) above shows that the score space (

**T**) is a linear mapping by the orthogonal basis represented by

**P**:

**T**=

**XP**, and hence a rotation of the coordinate system as depicted in Figure 7.

#### 3.3.2. Uniform Manifold Approximation and Projection (UMAP)

#### 3.3.3. Variational Autoencoders (VAE)

#### 3.3.4. Embedder Training

#### 3.3.5. Modeling

**(1)**data for CS1 and CS2 are loaded, where CS2 involves the Tox21 modeling data (fingerprints—FPs, labels/endpoints) and CS2 fingerprints;

**(2)**FPs columns for both CS1 and CS2 below 5% variance are removed;

**(3)**removal of structures from CS2 which appear in CS1;

**(4)**train and apply embedders; and

**(5)**optimize classification models and apply them on embedded data, as shown in Table 6.

## 4. Limitations and Future Outlook

## 5. Conclusions

## Author Contributions

## Funding

## Institutional Review Board Statement

## Informed Consent Statement

## Data Availability Statement

## Acknowledgments

## Conflicts of Interest

## References

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**Figure 1.**Exemplary visualization of CS1 (red) and CS2 (blue) show in 2D embedded space generated from molecular fingerprints by means of (

**a**) principal component analysis (PCA), (

**b**) uniform manifold approximation and projection (UMAP), and (

**c**) variational autoencoders (VAEs).

**Figure 2.**Dependence of classification results or transferred embeddings of CS2 by means of Matthews correlation coefficient (MCC) on the log-size of CS1 and dimensions of the PCA embeddings. The three figures represent three classifying algorithms, namely, (

**a**) RFC, (

**b**) KNN, and (

**c**) LR.

**Figure 3.**Dependence of classification results or transferred embeddings of CS2 by means of MCC on the log-size of CS1 and dimensions of the UMAP embeddings. The three figures represent three classifying algorithms, namely, (

**a**) RFC, (

**b**) KNN, and (

**c**) LR.

**Figure 4.**Dependence of classification results or transferred embeddings of CS2 by means of MCC on the log-size of CS1 and dimensions of the VAE embeddings. The three figures represent three classifying algorithms, namely, (

**a**) RFC, (

**b**) KNN, and (

**c**) LR.

**Figure 5.**Comparison of machine learning classifications mean + error bar across all feature sets: FPR-BL = fingerprint baseline, PCA = principal component analysis (EX = external, IN = internal), UMP = uniform manifold approximation and projection, VAE = variational autoencoders. Each bar present nine runs (three classifiers × three random states).

**Figure 6.**Top: Silhouette plots for best (top left) and worst (top right) performing clustering, which are VAE with NR-AR and UMAP with SR-HSE, respectively. The gray and green masses are points in two classes (0 and 1) with their silhouette coefficients, respectively. The dashed red line is the average value of both. The scatter plot visualizes their coordinates in the 2D embedded space. The number is their center points for each class (0 and 1). We notice that, for the best clustering, the silhouette coefficient tends to be higher, and points that belong to NR-AR label visually agglomerate together. Conversely, the silhouette coefficient seems to be negative for the worst clustering, and the points belonging to SR-HSE label are visually indistinguishable from other points. Silhouette coefficients for externally embedded CS2 data (bottom) by means of the three embedders (PCA, UMAP, VAE) calculated per label, which are presented by the color map. We see that VAE gains a higher silhouette coefficient on most tasks than UMAP or PCA, indicating a better separation.

**Figure 7.**An example of dimensionality reduction by means of PCA. Instances/points in a 3D space (original space) are transformed into a 2D space of two latent variables called principal components (PC1 and PC2).

**Figure 8.**Visual explanation of how UMAP works. It first computes a graph representation of the input data, which is then used to learn embeddings that preserve the structure of the graph representation. Figures is redrawn based on ref. [57].

**Figure 9.**Architecture illustration of the variational autoencoder. Encoder compresses the input X into a latent representation Z. VAE is different to a standard autoencoder as it assumes that the input data have an underlying probability distribution (e.g., Gaussian) for which they try to optimize parameters. The decoder then attempts to reconstruct the original input from the representation by minimizing the reconstruction loss.

**Figure 10.**In external transfer learning, an embedder (PCA, UMAP, VAE) is fit on fingerprints on an external set of fingerprints (CS1). The same model (pre-trained embedder) is then utilized to encode fingerprints from CS2. In internal transfer learning, the embedder is fit on the pre-split train set of CS2 and used to encode the test set of CS2. The embeddings of CS2 were utilized for training predictive classification tasks.

**Figure 11.**Schematics of chemical space transformation from fingerprint through a pre-trained embedder model. The transformation can either be conducted from an external data set to the data set of interest or within the data set of interest, but split into the train and test set.

**Table 1.**A comparison of our baseline results trained on fingerprints to a similar study from Zhang et al. [37]. The results from Zhang are denoted with a “Z“, while the respective classifiers are as follows: L—lightGBM, R—random forests, S—support vector machines, X—XGBM, D—deep neural networks. The classifiers from this work are k-nearest neighbor classifier (KNN), logistic regression (LR), and random forests classifier (RFC), which are represented by their mean values per classifier, respectively. Additionally, the mean and max of all classifiers in this work are compared. The best baseline models in our work are marked with an superscript “a“, while the best models from Zhang are marked with an superscript “b“.

Label (endpoint) | Mean (all) | Max (all) | KNN | LR | RFC | Z-L | Z-R | Z-S | Z-X | Z-D |
---|---|---|---|---|---|---|---|---|---|---|

NR-AR | 0.52 | 0.62 | ^{a}0.59 | 0.4 | 0.56 | 0.50 | 0.62 | 0.43 | 0.60 | ^{b}0.68 |

NR-AR-LBD | 0.57 | 0.63 | 0.61 | 0.48 | ^{a}0.62 | 0.60 | 0.71 | 0.60 | ^{b}0.73 | 0.72 |

NR-AhR | 0.44 | 0.47 | ^{a}0.45 | 0.44 | 0.43 | 0.52 | ^{b}0.61 | 0.47 | 0.54 | 0.59 |

NR-Aromatase | 0.29 | 0.35 | ^{a}0.32 | 0.25 | 0.29 | 0.28 | ^{b}0.52 | 0.32 | 0.50 | 0.48 |

NR-ER | 0.29 | 0.34 | ^{a}0.33 | 0.24 | 0.29 | 0.37 | 0.42 | 0.32 | 0.40 | ^{b}0.44 |

NR-ER-LBD | 0.35 | 0.47 | 0.37 | 0.26 | ^{a}0.42 | 0.45 | 0.56 | 0.36 | ^{b}0.59 | 0.58 |

NR-PPAR-gamma | 0.18 | 0.26 | 0.14 | 0.18 | ^{a}0.22 | 0.32 | 0.50 | 0.30 | ^{b}0.52 | 0.47 |

SR-ARE | 0.28 | 0.36 | 0.25 | ^{a}0.31 | 0.29 | 0.46 | 0.49 | 0.36 | 0.46 | 0.48 |

SR-ATAD5 | 0.24 | 0.26 | ^{a}0.25 | 0.22 | 0.24 | 0.37 | ^{b}0.59 | 0.36 | 0.53 | 0.55 |

SR-HSE | 0.18 | 0.25 | 0.15 | 0.18 | ^{a}0.20 | 0.31 | ^{b}0.37 | 0.21 | 0.40 | ^{b}0.37 |

SR-MMP | 0.44 | 0.47 | 0.44 | ^{a}0.47 | 0.43 | 0.63 | ^{b}0.65 | 0.54 | 0.64 | 0.63 |

SR-p53 | 0.22 | 0.26 | 0.21 | ^{a}0.24 | 0.23 | 0.42 | ^{b}0.57 | 0.37 | 0.52 | 0.55 |

**Table 2.**Comparison of external and internal embeddings for PCA, UMAP, and VAE. Each cell represents the mean MCC score across nine different machine learning models (three random states × three classifiers). Values marked with an asterisk (*) highlight cases where, on average, models trained using external knowledge outperformed models trained on internal knowledge. Additionally, results marked with a quotation mark (‘) highlight cases where using external or internal knowledge yielded equal results (when rounded off to two decimal places).

Label | PCA | UMAP | VAE | |||
---|---|---|---|---|---|---|

IN | EX | IN | EX | IN | EX | |

NR-AR | 0.45 | 0.43 | ‘ 0.47 | ‘ 0.47 | 0.45 | 0.44 |

NR-AR-LBD | 0.45 | 0.43 | * 0.45 | * 0.53 | ‘ 0.43 | ‘ 0.43 |

NR-AhR | ‘ 0.33 | ‘ 0.33 | * 0.34 | * 0.35 | ‘ 0.34 | ‘ 0.34 |

NR-Aromatase | 0.22 | 0.18 | 0.18 | 0.15 | ‘ 0.21 | ‘ 0.21 |

NR-ER | 0.22 | 0.21 | ‘ 0.23 | ‘ 0.23 | ‘ 0.27 | 0.24 |

NR-ER-LBD | 0.31 | 0.26 | ‘ 0.26 | ‘ 0.26 | ‘ 0.28 | ‘ 0.28 |

NR-PPAR-gamma | ‘ 0.14 | ‘ 0.14 | * 0.09 | * 0.11 | 0.11 | 0.09 |

SR-ARE | * 0.19 | * 0.21 | * 0.19 | * 0.2 | * 0.19 | * 0.2 |

SR-ATAD5 | 0.16 | 0.13 | * 0.12 | * 0.16 | * 0.14 | * 0.15 |

SR-HSE | * 0.09 | * 0.11 | ‘ 0.08 | ‘ 0.08 | * 0.07 | * 0.1 |

SR-MMP | ‘ 0.36 | ‘ 0.36 | ‘ 0.32 | ‘ 0.32 | * 0.35 | * 0.36 |

SR-p53 | 0.19 | 0.18 | 0.16 | 0.14 | * 0.15 | * 0.17 |

**Table 3.**Classification results across all data sets and labels expressed by maximum values of the MCC. The fingerprint-based model maxima (FPR-BL) were set as 100%, while the embedding models referred to these 100%. Results assigned with an asterisk (*) outperformed baseline.

Label (endpoint) | FPR-BL | PCA-EX | PCA-IN | UMAP-EX | UMAP-IN | VAE-EX | VAE-IN |
---|---|---|---|---|---|---|---|

NR-AR | 100 | 95 | 99 | 96 | 96 | 97 | * 100 |

NR-AR-LBD | 100 | 92 | 98 | * 100 | 97 | 98 | * 102 |

NR-AhR | 100 | 84 | 85 | 90 | 86 | 83 | 85 |

NR-Aromatase | 100 | 65 | 82 | 75 | 74 | 84 | 75 |

NR-ER | 100 | 83 | 85 | 86 | 95 | * 103 | * 101 |

NR-ER-LBD | 100 | 70 | 90 | 79 | 88 | 90 | 83 |

NR-PPAR-gamma | 100 | 81 | 82 | 68 | 81 | 78 | 75 |

SR-ARE | 100 | 74 | 69 | 70 | 69 | 63 | 63 |

SR-ATAD5 | 100 | 63 | 99 | 92 | 84 | 75 | 88 |

SR-HSE | 100 | 82 | 77 | 56 | 90 | 65 | 55 |

SR-MMP | 100 | 92 | 87 | 83 | 83 | 93 | 89 |

SR-p53 | 100 | 99 | 95 | 79 | 87 | 85 | 93 |

**Table 4.**Correlation of average classification results of the embedded classifiers (PCA-EX, UMAP-EX. VAE-EX) with the imbalance ratio (Pos class %) and baseline fingerprints classifiers (FPR-BL) with their respective silhouette coefficients—s(PCA), s(UMAP), and s(VAE).

PCA-EX | UMAP-EX | VAE-EX | |
---|---|---|---|

s(PCA) | 0.74 | ||

s(UMAP) | 0.86 | ||

s(VAE) | 0.85 | ||

Pos class % | 0.11 | 0.02 | 0.13 |

FPR-BL | 0.98 | 0.98 | 0.99 |

**Table 5.**Elements of the confusion matrix that show the possible outcomes when predicting labels in Tox21.

Experimental/Model | Positive (Model) (1) | Negative (Model) (0) |
---|---|---|

Positive (Experimental) (1) | TP (experimentally active and predicted active) | FN (experimentally active, but predicted as inactive) |

Negative (Experimental) (0) | FP (experimentally inactive, but predicted as active) | TN (inactive experimentally and predicted) |

Predictive Variables | Classifier | Seed | Embedder | Emb. Dim. | CS1 Data Size | N Models |
---|---|---|---|---|---|---|

Fingerprints (raw data) | RFC, KNN, LR | 1–3 | N/A | N/A | N/A | 144 |

Internal emb. | RFC, KNN, LR | 1–3 | PCA, UMAP, VAE | 2–15 | N/A | 9072 |

External emb. | RFC, KNN, LR | 1–3 | PCA, UMAP, VAE | 2–15 | 200–30,000 | 9072 |

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Lovrić, M.; Đuričić, T.; Tran, H.T.N.; Hussain, H.; Lacić, E.; Rasmussen, M.A.; Kern, R. Should We Embed in Chemistry? A Comparison of Unsupervised Transfer Learning with PCA, UMAP, and VAE on Molecular Fingerprints. *Pharmaceuticals* **2021**, *14*, 758.
https://doi.org/10.3390/ph14080758

**AMA Style**

Lovrić M, Đuričić T, Tran HTN, Hussain H, Lacić E, Rasmussen MA, Kern R. Should We Embed in Chemistry? A Comparison of Unsupervised Transfer Learning with PCA, UMAP, and VAE on Molecular Fingerprints. *Pharmaceuticals*. 2021; 14(8):758.
https://doi.org/10.3390/ph14080758

**Chicago/Turabian Style**

Lovrić, Mario, Tomislav Đuričić, Han T. N. Tran, Hussain Hussain, Emanuel Lacić, Morten A. Rasmussen, and Roman Kern. 2021. "Should We Embed in Chemistry? A Comparison of Unsupervised Transfer Learning with PCA, UMAP, and VAE on Molecular Fingerprints" *Pharmaceuticals* 14, no. 8: 758.
https://doi.org/10.3390/ph14080758