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Early detection of lung cancer

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# Early detection of lung cancer through Deep Learning
#### by Gabrielle Gantos, Xiaoxia Lin, Ekaterina Putintseva

## 1. Introduction

With recent advances in deep learning, research has made a significant leap to help identify, classify,
and quantify patterns in medical images. Particularly, improvements in computer vision inspired its
use in medical image analysis such as image segmentation, image registration, image fusion, image
annotation, computer-aided diagnosis and prognosis, lesion/landmark detection, and microscopic
imaging analysis, to name a few. For instance, 2-D skin cancer images were successfully classified
by a single CNN architecture in Novoa RA et al, Nature 2017.

In this same vein, Kaggle selected the topic for the 2017 Data Science Bowl competition in order
to focus teams of data scientists on improving lung health through early lung cancer detection. In
recent months, sophisticated attempts to solve this problem have been released. Beginning with
AlexNet and continuing with the model described by one of the winners of the Kaggle Data Science
Bowl competition as a foundational framework, we propose a simple and elegant approach to the
challenge.

## 2. Methods

### 2.1. Data Cleaning and Preprocessing

Two datasets were used to explore early lung cancer detection: Kaggle Data Science Bowl CT
scans and LUng Nodule Analysis 2016 challenge (LUNA16) CT scans. Both CT scan datasets
are high resolution, represent a patient’s lung tissue at a single point in time, and are representative of
a heterogeneous range of scanner models and technical parameters. Kaggle data were provided by
the National Cancer Institute while LUNA16 data are a subset of the publicly available LIDC/IDRI
dataset.

Each patient in the Kaggle competition is represented by a single, 3-D CT scan without diagnostic
metadata such as age, weight, or sex. Cancer and no-cancer labels were confirmed by pathology
diagnosis and provided for most patients. CT scans range in resolution from 0:49 mm - 0:98 mm per
pixel and have inter-slice spacing ranging from 0:625 mm - 3:0 mm.

LUNA16 patients are represented by a 3-D CT scan and a file of 1; 172 nodule locations annotated
with likelihood of malignancy, spiculation, lobulation, and diameter (mm). Likelihood of malignancy
represents an estimation of malignancy under the assumption that the patient is a 60-year-old
smoker. Lobulation and spicualtion characterize nodule shape and all three estimates are classed by
independent radiologists on a range from 1 to 5.

It should be noted that the nodules represented in both datasets differ meaningfully in size and
location. Generally, annotated LUNA nodules are smaller than those in the Kaggle dataset.

#### 2.1.1. Whole Image Preprocessing

Kaggle data were initially preprocessed in order to load whole 3-D patient scans as inputs to a CNN
architecture. Various resolutions and image spacings were standardization through the following:
* Conversion of original scan intensity scale to Hounsfield Units (HU)
* Lung segmentation and masking
* Resampling such that each pixel is representative of 3mm3

#### 2.1.2. Patch Preprocessing

For nodule analysis and cancer prediction through image patches, Kaggle scans were augmented
by annotated LUNA scans. Kaggle preprocessing for patch extraction resembles whole image
preprocessing and is summarized as follows:
* Conversion of original scan intensity scale to Hounsfield Units (HU)
* Resample such that each pixel represents 1mm3
* Extract lung tissue mask without segmenting the image
* For patches containing lung tissue, extract via sliding window
Each LUNA16 patient is represented in the training set by nodule-centered voxels, random, nonnodule-
centered voxels, and false positive candidate-centered voxels. If the patient does
not have a nodule or false positive candidate then the patient is included only by random, non-nodulecentered
voxels. LUNA data have already been scaled to HU, so extracted patches are only resampled
such that each pixel represents 1mm3 before CNN training.

### 2.2. CNN architectures

Three fundamentally different CNN architectures were constructed in order to predict whether or not
a patient will be diagnosed with cancer within one year.

#### 2.2.1. AlexNet

The first model was a replica of the classic AlexNet convolutional neural network model, developed
by Alex Krizhevsky. The inputs to this baseline model were whole 3D CT scans (see Section 2.1)
and outputs were ‘cancer’/‘no-cancer’ patient labels.

A classical AlexNet was constructed with a 3x3x3 convolutional kernel sizes, two convolution/max
pooling blocks, three subsequent convolution blocks and three concluding fully connected layers. To
reduce overfitting, we implement dropout in the dense layers with a 50% rate. Moreover, we introduce an L2-regularization term with a degree of 0:001 to each of the layers. ReLU activation functions
were used at each layer, except for the output layer, where a softmax function was implemented
instead. Since the output of the CNN was 0 or 1 class (‘non-cancer’ or ‘cancer’ label), we used a
categorical cross entropy loss function. Stochastic gradient descent optimizer with the learning rate
0:01 and Nesterov momentum were used as the model’s optimizer function.

#### 2.2.2. Patch-based CNN regressor for nodule analysis

The general framework for the second model was adapted from the paper by Daniel Hammack.
Overall, 16 different models with various hyperparameters are constructed for this part. All the
architectures consist of 5 convolutional blocks, followed by a global max pooling and two dense
layers. Each junction between convolutional blocks is complemented with a parallel stream of average
pooling layers of the intact initial patches, augmenting the information being transferred (see Figure
1).

![ML workflow](https://github.com/katyaputintseva/LungCancer/blob/master/CNN_architecture_horizontal-01.png?raw=true)

<b>Figure 1:</b> Schematic representation of machine learning work flow. (A) Principal deep learning
architecture, (B) Cascading nodule classifier and feature regressor.

#### 2.2.3. Patch-based cascade nodule CNN classifier and feature regressor

In order to separate the process of nodule detection and characterization as well as to facilitate the
latter, our third model includes two parts: a CNN classifier and a CNN regressor. Both of these parts
are trained using the LUNA16 dataset (see Section 2.1).

For the nodule classifier, only the positive and negative subsets were used, as the presence of false
positive samples on this stage introduced inter-subset confusion and increased the loss function. On
the second step, however, the negative subset was composed of false positive samples and negative
samples predicted to be positive by the classifier. A consistent 20% validation set was used across
both cascade stages.

The overall architecture is depicted in Figure 1B with each of the 2 blocks utilizing the same core
architecture as the model described in the previous section. In total, 7 different models with various
hyperparameters were built and analyzed.

The obtained optimized models from Sections 2.2.2 and 2.2.3 were used to predict the corresponding
values of extracted patches from Kaggle patients. Based on the obtained predictions, a classification
model was built for discriminating between no-cancer and cancer patients (see Section 2.3).

### 2.3. Patient-level cancer classification and prediction

#### 2.3.1. Feature selection

The final step in our early lung cancer detection pipeline is to predict diagnosis using predictions of
patch characteristics. Kaggle patches extracted in Section 2.1 utilize the LUNA-trained CNN model
(see Section 2.2.2) to predict malignancy, spiculation, lobulation, and nodule diameter for each patch.
From these predicted attributes, we select 14 relevant features for classification of patients into cancer
and no-cancer:

* Max malignancy, spiculation, lobulation, and diameter for all nodules (4 features)
* Standard deviation of malignancy, spiculation, lobulation, and diameter for all nodules (4
features)
* Location of most malignant nodule (3 features, one for each dimension in the scan)
* Standard deviation of nodule locations in each dimension (3 features)

#### 2.3.2. Cancer Classifiers

The selected 14 features are fed into different classifiers (Logistic regression, Support Vector Machine,
Random Forest, etc.) with different parameter tuning (e.g. class-weight, C, penalty, cv-folds etc) to
predict disease diagnosis. We also iterated through different feature combinations before ultimately
selecting to use all 14 features. We implemented a classifier consisting of an L1-penalized logistic
regression model followed by an Extremely Random Trees regressor fit on the residuals from the
linear model.

We adjust for very unbalanced data (363 cancer patients versus 1071 no-cancer patients) using
class-weights for all classifiers. Furthermore we used Stratified K-Folds cross-validator to preserve
the percentage of samples for each class and all training and test data were standardized before fitting
into classifiers.

#### 2.3.3. Evaluation Metrics

In the Kaggle competition, the aim is to predict the likelihood that a patient will be diagnosed with
lung cancer a year from when the scan was taken. Log loss is used to evaluate the prediction result.

We decide to use the same loss function in order to compare the results with the participants in the
competition. We have to mention that this comparison is not 100% fair, since the second stage label
is not available, our loss is computed only based on stage1 data using cross validation.

Furthermore, we compute the confusion matrix of the classification result that enable us to define
other important metrics such as recall. In cancer detection because the cost of missing one patient in
a trial is very large, we want the predictor to have very large recall (we do not accept false negatives)
even when this means accepting more false positives. These false positives can be discarded in
subsequent tests.

## 3. Experimental Results

We divide all the experimental results into three major subsections according to the different deep
learning architectures implemented.

### 3.1. AlexNet

The first explored approach was constructing a model using AlexNet CNN architecture. Whole 3D
CT patient scans are fed into the CNN to predict whether or not a certain patient is likely to develop
cancer within a year. While trying to optimize this architecture, GPU memory constraints were
encountered. Attempting to reduce scan resolution and batch sizes did not mitigate this limitation so
we were unable to generate appropriate model results. In any case, when taking into account the ratio
between a lung CT scan (~30cm3) and a small nodule (~1cm3), there was not much room for scan
resolution reduction without dramatically affecting the chances of cancer prediction.

### 3.2. Patch-based CNN regressor

#### 3.2.1. Nodule Analysis

To overcome the memory limitations, we use a similar dataset (LUNA16), in which malignant nodules
are identified and annotated (see Section 2.1.2). The training dataset contains 50% nodule and 50%
non-nodule patches. In the process of training, for some models, the non-nodule set of patches
includes 50% false positive candidate patches. This was done in order to increase the sensitivity and
the predictive power of the model.

The predicted features were: malignancy, spiculation, lobulation, and diameter. The convolutional
part of the architecture (Figure 1) was shared across all the four feature models. Then, the CNN
branched out to optimize and predict all the different features. The branching point was optimized
and chosen to be on the level before the fifth convolutional block, since there is no overfitting. In
general, overfitting was the major problem. In order to control for it, a 20% portion of
the dataset was used as a validation set. A number of parameters was tuned in order to eliminate
overfitting:

1. Dropout. Across different models, the dropout rate was increased from 0 to 20% in the
dense layers of the architecture and set to 0% in the convolutional blocks.
2. Regularization. L2 regularization term was introduced on all the levels of the neural network
with a maximum of 0:001 degree.
3. Parameters reduction. The number of neurons in the first dense layer was reduced from 100
to 32. The number of filters, corresponding to different convolutional blocks, was reduced
from 8-24-64-72-72 to 8-24-48-64-64.
4. Data augmentation. Since the amount of patches containing malignant nodules was less
than benign ones, for the former type of patches we used data augmentation. It included
jittering around nodules (see Section 2.1.2) and flips over random axes.
5. Early stopping. Early stopping was implemented with patience of 4 epochs and validation
data loss change of 0.001.
6. The right choice of an optimizer. Although the training loss was much lower with Nadam
optimizer, for instance, the validation loss started to increase steadily already after several
epochs. The optimizer used in the final model was stochastic gradient descent with Nesterov
momentum.
7. Learning rate scheduler. For the final model, the following scheduler was used (<2 : 0.01,
<5 : 0.001, <10 : 0.0005, else : 0.00005).

It is interesting to note that predicted features had different levels of overfitting. The most susceptible
feature of all was malignancy, while all the others looked comparatively stable across a large variety
of different hyperparameters.

Among other parameters, different activation functions were tested. In the final model, a Leaky ReLU
was used as an activation function for convolutional blocks and a softmax was implemented in the
output dense layer.

#### 3.2.2. Cancer Prediction

In order to get an intuition of how well the model was predicting, we analyzed paired box plots and
a scatter plot of the feature matrix for cancer and non-cancer patients and the feature importance histogram. To our surprise, the features for both cancer and non-cancer patients are extremely similar,
and all the features seem to have almost equal importance.

We suspect that it would be very challenging for our classifiers to distinguish two classes that are so
similar. Our suspicion is confirmed in the result.

We want to analyze and understand the possible causes of the poor prediction. As already mentioned
in section 2.1, LUNA has some very small annotated nodules, which may be less relevant to cancer
prediction. In our model, we do not exclude these nodules and so we suspect these small nodules
may cause noise. The other significant difference between LUNA nodules and Kaggle nodules as
seen in 1 indicates that a network trained on LUNA alone will struggle to adequately learn to detect
large nodules with such different characteristics.

As a positive control, we used LUNA patients to validate that the trained CNN model performs well
on LUNA patches. Therefore we followed the same methodology as for Kaggle1 to classify and
predict cancer and no-cancer in LUNA patients. Ideally, we would split LUNA data into training and
test sets. However, due to the limited number of nodules and patients on which to predict, the same
patients used to train were used to validate our model’s predictive capabilities and estimate training
error.

For each LUNA patient and annotated nodule, we generated predictions using patches extracted
using randomness different from the randomness used to generate patches for the training dataset.
We predict on these patches and build a feature matrix similar to that of Kaggle1 except for that we
exclude patch location. And we plotted the feature importance histogram, a paired box plot and a
scatter plot from 30 cancer and 30 no-cancer patients to compare features relevancy. We see that the
max malignancy, spiculation, lobulation, and diameter appear to be the most important important in
early cancer prediction. Also, the max malignancy, spiculation, lobulation, and diameter are higher in
cancer patients than the no-cancer patients.

### 3.3. Patch-based cascade nodule CNN classifier and feature regressor

#### 3.3.1. Nodule Analysis

to discriminate between patches containing malignant nodules from the patches that do not contain
malignant nodule tissue. The second CNN uses the predicted malignant patches to predict four
features of interest mentioned above: malignancy, lobulation, spiculation and diameter.

Both parts of the model were optimized sequentially. For the nodule classifier, 7 models with different
hyperparameters were built. By decreasing the number of neurons in the dense layer to 10, increasing
the droupout rate, tuning kernel initializer, loss function and optimizer, we successfully reduced the
level of overfitting and managed to obtain a comparatively accurate nodule classifier.

After tuning a number of different parameters, the second part of the cascade ended up being a close
replica of the model implemented in Section 3.2. The higher dropout rate (0.3) and a 0.3:0.7 ratio
between negative and positive samples, correspondingly, substantially improved our results.

#### 3.3.2. Cancer Prediction

We used the constructed models in the same pipeline as described in Section 3.2.2 to predict whether
a patient will develop cancer within the next year. To our surprise, although the loss function in the
course of training the regressor was lower than the one of model 2, the prediction accuracy was
not improved. We believe that this is due to the data inconsistency problem presented in Section
3.2.

As a point of reference, we would like to highlight that the winning team achieved a log-loss score of
0.39975 in the Kaggle competition (the lower the score the better).

# 4. Conclusion and Future Work

Medical image recognition for diagnostic prediction is difficult due to computation resources required,
non-standardized data collection practices, and potential for signal minimization due to human-tohuman
variational noise. We proposed three CNN architectures for early cancer detection using
patient CT scans. Although our model was not able to significantly predict cancer in Kaggle patients,
the positive control test performed on LUNA patients demonstrated learning for nodules of that
dataset’s size and our Log-Loss places us in the top quartile of competitors in the Kaggle DSB. There
is a lot of work that can be done to improve our model such as thresholding nodule diameter in training, extended data augmentation, ensemble learning, and further exploration of the feature space
and CNN architectures.

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