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S. B. Khan et al.
The discriminative ability of the models was further assessed using ROC curves.
As illustrated in the ROC curve comparison in Fig.17, the proposed ResNeXt
model exhibits a higher area under the curve (AUC) than the traditional CNN model.
The higher AUC value signies that the ResNeXt model can better differentiate
between positive and negative classes, reinforcing its superior performance.
Apart from quantitative metrics, interpretability is a crucial aspect of medical
applications. The proposed ResNeXt model excels in this regard, thanks to applying
XAI techniques, particularly Grad-CAM.The Grad-CAM visualizations for both
models were generated, and the results differed. The Grad-CAM heatmap for the
proposed ResNeXt model highlighted specic regions within the kidney CT scan
images that inuenced its predictions. In contrast, the traditional CNN needed more
harvestability, making it challenging for medical professionals to understand the
reasoning behind its decisions.
Our suggested ResNeXt model has been found to be superior to conventional
CNN methods, as demonstrated through statistical evaluations, ROC curve analyses, and Grad-CAM visual representations. This framework not only achieves
higher accuracy, precision, recall, and F1 score metrics, but also has advanced capability in diagnosing kidney irregularities. In addition, XAI techniques have been
integrated into our approach to enhance its interpretability, providing medical practitioners with a clearer understanding of the model’s reasoning. Our methodology is
Fig. 17 ROC curve for proposed and CNN model comparison

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at the forefront of solutions in diagnosing and treating kidney anomalies, offering
heightened diagnostic precision and clarity in decision-making. This ResNeXt
model is poised to make groundbreaking strides in kidney care, elevating patient
outcomes. Furthermore, its efcacy on the IoMT platform signies the potential of
delivering top-tier diagnostic solutions to areas with constrained resources, thus
democratizing access to quality healthcare worldwide.
5 Conclusion
In this chapter, our research endeavors are centered around enhancing the interpretability of deep learning models, often characterized as “black boxes,” particularly in
detecting kidney-related abnormalities. Our efforts have yielded substantial
advancements by integrating AI Shapley values and Grad-CAM for visualization,
coupled with the ResNeXt and XAI models, aimed at identifying kidney cysts,
stones, and tumors. By harnessing AI Shapley values, we have bestowed the model
newfound transparency, enabling healthcare professionals to delve deeper into the
factors underpinning its predictions. This level of transparency not only bolsters the
model’s reliability but also furnishes clinicians with invaluable insights that can
signicantly enhance patient care. Notably, our proposed framework has demonstrated an exceptional level of accuracy, achieving an impressive rate of 99.52%
through the utilization of K= tenfold stratied sampling. This amalgamation of
heightened accuracy and transparency stands poised to revolutionize the eld of
kidney abnormality diagnosis, ultimately translating into improved patient outcomes. With a transparent model, healthcare practitioners can make more informed
decisions, leading to heightened diagnostic precision and increased condence in
administering treatments.
Our research is an example of the successful integration of ResNeXt and XAI
models in medical informatics contexts, paving the way for further development
and expansion of deep learning methodologies in the medical domain. Additionally,
the framework’s prociency when applied on an IoMT platform shows its feasibility in resource-constrained regions, making sophisticated diagnostic tools more
accessible to a broader audience and democratizing access to state-of-the-art
healthcare.
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Explainable AI forColorectal Cancer
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Classication
MwengeMulenga, ManjeevanSeera, SameemAbdulKareem,
andAznulQalidMdSabri
Abstract Colorectal cancer (CRC) ranks second highest in global mortality among
nonsex-related cancers. Conventional machine learning (ML) algorithms applied to
microbiome-based CRC detection often yield suboptimal accuracy. Conversely,
deep neural network (DNN)-based methods encounter limitations due to scarce
labeled samples, data imbalance, and dominant features. The lack of interpretability
in articial intelligence models further hinders their adoption in healthcare. This
chapter proposes an explainable DNN model for improved CRC detection utilizing
stool-based microbiome data. The model employs a square root-based normalization method and a feature extension approach, incorporating customized normalization techniques to enhance prediction performance. These methods effectively
address outliers, dominant features, and dimensionality challenges. The square
root-based method mitigates the effect of outliers and feature dominance, while the
feature extension technique expands the dataset’s feature space, potentially improving feature relevance across samples. Leveraging automatic feature selection by the
DNN algorithm, the model performs classication using a subset of available features. Evaluation on publicly available datasets demonstrates the efcacy of the
proposed methods, with the square root-based method achieving area under the
curve scores of 91.3% and 75.8% on datasets 1 and 2, respectively. The feature
extension-based method achieves AUC scores of 90.2% and 74% on the respective
datasets.
M. Mulenga
Business Studies Division, National Institute of Public Administration, Lusaka, Zambia
M. Seera (*)
School of Business, Monash University Malaysia, Selangor, Malaysia
e-mail: manjeevansingh.seera@monash.edu
S. A. Kareem · A. Q. M. Sabri
Faculty of Computer Science and Information Technology, University of Malaya,
Kuala Lumpur, Malaysia
Ltd. 2024
R. Aluvalu et al. (eds.), Explainable AI in Health Informatics, Computational
Intelligence Methods and Applications,
https://doi.org/10.1007/978-981-97-3705-5_10
203© The Author(s), under exclusive license to Springer Nature Singapore Pte

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Keywords Colorectal cancer · Microbiome data · Deep neural networks ·
Normalization techniques · Feature dominance
M. Mulenga et al.
1 Introduction
Colorectal cancer (CRC) ranks second highest among nonsex-related cancers
worldwide in terms of mortality rate [1]. Early detection of CRC can reduce the
death rate by approximately 90% [2]. The analysis of the microbiome in stool samples has gained signicant interest as a noninvasive method for CRC detection [3,
4]. The advent of Next Generation Sequencing technologies has resulted in the gen-
eration of massive, high-dimensional, and heterogeneous omics data [5]. However,
analyzing such complex microbiome data using statistical methods poses signicant challenges. Traditional machine learning (ML) algorithms have limitations in
selecting relevant features from a large number of microbial taxa [6]. Although
recent works have explored deep neural network (DNN)-based methods to handle
high-dimensional features, they are prone to overtting [7]. Research indicates that
the use of DNNs does not provide signicant performance improvements over traditional ML methods [1, 8]. Nevertheless, other studies have achieved impressive
results in DNN-based classication of microbiota [9–11].
The classication performance of ML algorithms on microbiome data is negatively affected by its sparsity, dominant features, and skewed nature [12–14].
Consequently, preprocessing techniques such as data normalization play a vital role
in microbiome data classication. However, the normalization of microbiome data
remains a challenge [15] and represents an ongoing area of research. Conventional
data normalization methods such as minimum–maximum (min–max), Z-score normalization (ZSN), and median and median absolute deviation normalization
(MMADN) are considered unsuitable for normalizing gene sequence-based data
[16]. This is because gene sequence-based data, such as microbiome data, exhibit
compositional characteristics, with a constant sum and restricted to nonnegative
values [17]. To address this limitation, normalization methods specically tailored
to gene sequence-based data have been developed, including trimmed mean of
M-values (TMM), relative log expression (RLE), and rarefying, aiming to enhance
data classication [18]. However, these methods also have limitations, such as the
inability to handle the excessive number of zeros commonly found in sequence
data [13].
A study conducted by Pereira etal. [16] evaluated the performance of nine gene
sequence-based data normalization methods in identifying differentially abundant
genes in microbiome data. The study found that TMM and RLE yielded the best
performance, exhibiting high true positive rates (TPR), low false positive rates
(FPR), and low false discovery rates. However, these methods may not perform
optimally on noncompositional data, which arises when demographic data is combined with operational taxonomic units (OTUs) to create a single dataset. In such
cases, conventional data normalization methods appear to be more appropriate.

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Furthermore, while recently Singh and Singh [19] demonstrated that no single
method surpasses others across all datasets, Mulenga etal. [20] showed that extending the feature space of a dataset using conventional normalization methods
enhances the performance of a DNN model by adjusting feature importance
throughout the dataset.
Moreover, the lack of interpretability or explainability in articial intelligence
(AI) models poses a signicant challenge in healthcare applications [21]. In the
context of cancer detection, interpretability is crucial for understanding the reasoning behind an AI model’s decision-making process and building trust in its accuracy
[22]. While AI models have demonstrated high accuracy rates, their lack of interpretability raises concerns regarding their reliability and safety in healthcare applications. To tackle this issue, researchers have begun exploring the use of explainable
AI (XAI) methods in cancer detection, aiming to provide insights into the decisionmaking process of AI models.
This chapter extends the method proposed in the aforementioned study [20] and
demonstrates that customized normalization methods can be employed for feature
extension to enhance the classication performance of a DNN model. Customized
normalization methods play a signicant role in the implementation of dynamic
data normalization, overcoming the limitations of static normalization, which
exhibits poor generalization performance due to its dependence on underlying data
properties [19]. The contributions of this chapter are as follows:
• A method called square root-sum (sqrt-sum) that transforms a dataset by com-
puting the sum of each data entry and the standard deviation of the dataset, fol-
lowed by taking the square root of the sum.
• A method that utilizes custom normalization methods to convert a two-
dimensional (2D) dataset into a three-dimensional (3D) dataset by representing
each scalar data point as a vector.
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The chapter is organized as follows: Sect. 2 provides a review of related works,
followed by the description of the proposed method in Sect. 3. Results are presented
in Sect. 4, and subsequent discussions are provided in Sect. 4. Finally, Sect. 5 concludes the chapter and outlines potential future research directions.
2 Related Works
Data imbalance in microbiome samples is an active research area. Knights etal. [23]
conducted a study to identify microorganism groups that change with respect to
variations in the host’s physiology or disease. They found out that replicating training data by adding noise can lead to improvements in the predictive power of models. Although the use of data augmentation on the training set helped to reduce
overtting and consequently improved the models’ prediction accuracy, the decrease
in error was not very signicant. Lo and Marculescu [24] proposed a method that
uses neural networks (NN) to classify phenotypes of a host based on metagenomic

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M. Mulenga et al.
data. To address overtting, they used a new data augmentation technique and a
dropout technique. The proposed model had a comparatively high classication
accuracy on both synthetic and real data. However, the method was not tested on
pooled datasets, and hence did not address the issue of variability across CRC
datasets.
Another signicant area of microbiome samples classication is data normalization, a preprocessing technique that identies and removes systematic variability
[16]. While the effectiveness of a normalization method depends on the characteristics of the target dataset, datasets used in ML tasks differ in terms of underlying
features. Therefore, there has been a substantial amount of research on the application of data normalization methods on various types of datasets. Manor and
Borenstein [15] proposed a normalization method that applied ML methods on
single-copy genes to correct marked biases within and across human microbiomebased samples, and to obtain measures that have biological meanings, which are
also accurate. Though the method corrects spurious variations across samples and
produces accurate downstream comparative analysis with meaningful abundance
measures, it is limited to identifying bacterial and archaeal organisms only and does
not cover fungal and viral organisms. Gloor etal. [17] demonstrated that current
methods for compositional data-based analysis can be easily adopted for analysis of
high throughput sequence data. Their method produced good results because it
accounted for the compositional nature of microbiome data. However, the study was
only based on 16S rRNA data and did not consider shotgun sequence data. Kaul
etal. [25] conducted a study that addresses the challenges associated with sparsity
in microbiome data. They proposed a method that identies three types of zero values found in microbiome data and conducted hypothesis testing on relative taxa
abundance in more than one experimental group. Although the method was able to
improve the false positive discovery rate, experiments were based on simulated data
that may not reproduce the same level of performance on real data.
Peng etal. [12] proposed a zero-inated beta regression method for the identication of features that are differentially abundant for multiple phenotype classication. The method used cumulative sum normalization and outperformed other
methods with signicantly higher area under the curve (AUC) scores on simulation
data. Though the method accounted for the sparse and compositional nature of
metagenomic data that improved its performance, comparisons were based on simulated data that may limit the method’s ability to generalize when using real data.
Similarly, Douglas etal. [26] conducted a study to determine if multi-omics can
differentially classify the state of Crohn’s disease (CD) and its treatment outcome.
The method controlled for inter-sample variation due to microbiome genome size
by normalizing Kyoto Encyclopedia of Genes and Genomes (KEGG) abundances
within each sample using universal single-copy gene abundance. However, model
generalization was not attained in the study owing to technical limitations encountered across individual studies.
Zyprych-Walczak etal. [27] proposed a method for selecting optimal normalization procedure for any dataset by computing bias and variance values of control
genes, specicity and sensitivity of a method, classication errors, and diagnostic

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plots. Though automation of data normalization selection process is important,
datasets used in the study were not sufcient to conclusively establish an optimum
procedure for automatic selection of normalization methods. Pereira etal. [16] compared nine normalization methods for analyzing metagenomic data and associated
high performance to trimmed mean m-value (TMM) and relative log expression
(RLE). Though the study used a data-driven method for the evaluation of metagenomic data, it did not consider phonotype classication, which is an important area
in metagenomic based studies.
McKnight etal. [28] investigated potential problems with normalization methods that are used in gene sequence data and observed that TMM and other similar
transformation methods contrary to rarefying and proportions do not ensure equality in the number of reads across samples. The authors claimed that the methods
used to reduce the effect of dominant features while amplifying rare features could
be misleading in terms of community differences. Though the study considered
variance standardization, differential abundance testing, and investigated abundance
across community levels, it was based on one simulated dataset and a single real
dataset that may not be enough for drawing conclusions about the robustness of
methods. Weiss etal. [29] investigated how challenges associated with microbiome
data affect its normalization procedures and differential abundance testing, and
observed that among normalization techniques, rarefying was the only approach
that was not frequently confounded by library size, which obscures biological interpretation of results. Interpretation of results is as important as accuracy in medical
application of automated detection of diseases [30]. Unlike other studies that were
solely based on simulated data, the method investigated data normalization based on
both real and simulated data. However, rarefying tends to have reduced sensitivity
due to the elimination of part of the dataset.
Metagenomic analysis was used by Guo etal. [31] to investigate the phylogenetic and functional traits of anammox communities in three microbial aggregates,
and ZSN was used to preprocess data to reduce the impact of outliers and dominant
features. ZSN, however, does not take the compositional nature of microbiome data
into account, which may affect classication performance of a ML algorithm.
Korpela etal. [32] investigated the use of gut microbiome signatures of obese individuals to predict their host and microbiome response to dietary interventions. The
study used min–max normalization in addition to log transformation in order to
preprocess input data. Despite the use of log transformation, which is a suitable
technique for skewed datasets such as microbiome data, the use of min–max normalization is not suitable for microbiome-based datasets due to the presence of
dominant features in the data. Singh and Singh [19] investigated how 14 selected
data normalization methods. Which included min–max, ZSN, sigmoid, and
MMADN, impact the classication performance of ML algorithms based on full
feature set, feature selection, and feature weighting methods. The study covered a
wide range of normalization methods and the comparisons performed were quite
elaborate and showed that no single data normalization method is superior to others.
However, the study did not consider metagenomic data, which has slightly different
properties than the ones covered in their study.

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With a few exceptions, most works on microbiome-based data does not apply
conventional data normalization methods since the data is considered to be compositional, rendering conventional methods unsuitable for normalization [17].
Microbiome data consists of operational taxonomic unit (OTU) data and accompanying metadata. OTUs account for the part of the microbiome data that is compositional, while the metadata that have elds such as age, weight, and other demographic
attributes represents the part that has absolute values. Therefore, a study that combines the metadata and the OTU data in an analysis produces a dataset that appears
to be noncompositional, and hence normalization techniques that are normally used
for noncompositional data can be used. The study proposes a method that uses a
dataset and combines two demographic attributes such as age and biomass index
(BMI) with OTU data in order to improve DNN prediction of CRC based on the
microbiome in stool samples.
Furthermore, the researchers are realizing the importance of XAI in CRC detection [21]. For example, Zhang etal. [22] proposed a general method for modifying
conventional convolutional neural networks (CNNs) to improve their interpretability. Although CNN models are associated with very high performance, their use in
microbiome is still limited. Le etal. [10] proposed an interpretable neural networks
algorithm that has both an encoder and decoder for predicting gut metabolites
obtained from the gut microbiome. While the model was highly interpretable, the
dataset was very small. Carrieri etal. [33] used XAI to reveal changes in skin microbiome composition caused by phenotypic differences. Although interpretability is
attained in the model, it lacks details on disease-based classication.
Based on the need to treat a microbiome dataset as noncompositional data and
the limitations discussed in the related methods, our study, while adopting an XAI
approach, proposes the sqrt-sum and a feature extension method to improve the
classication of microbiome data. As a priory, customized normalization methods
such as the sqrt-sum and other related functions are generated based on existing
methods such as Pareto scaling [34]. The new methods are targeted at reducing
feature dominance and outliers by combining a technique that uses standard deviation with the one that computes square roots of nonzero data points in order to
transform a dataset. The customized normalization methods are then used to generate additional features in the dataset and potentially improve the feature importance.
The transformed dataset is then subjected to a DNN for classication, which performs an embedded form of feature selection on the potentially improved feature space.
M. Mulenga et al.
3 Methods
This chapter proposes a square root-based customized normalization method called
sqrt-sum and a feature extension method for microbiome data classication. The
sqrt-sum method transforms samples by adding the standard deviation of the dataset
to nonzero items in that dataset, then computes the square root of the sum. The
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