Medical & Biological Engineering & Computing

https://doi.org/10.1007/s11517-020-02240-7

ORIGINAL ARTICLE

Differential diagnosis of asthma and restrictive respiratory diseases

by combining forced oscillation measurements, machine learning
and neuro-fuzzy classifiers
Jorge L. M. Amaral 1 & Alexandre G. Sancho 2 & Alvaro C. D. Faria 2 & Agnaldo J. Lopes 3 & Pedro L. Melo 2

Received: 24 January 2020 / Accepted: 26 July 2020

# International Federation for Medical and Biological Engineering 2020

Abstract
To design machine learning classifiers to facilitate the clinical use and increase the accuracy of the forced oscillation technique (FOT) in
the differential diagnosis of patients with asthma and restrictive respiratory diseases. FOT and spirometric exams were performed in 97
individuals, including controls (n = 20), asthmatic patients (n = 38), and restrictive (n = 39) patients. The first experiment of this study
showed that the best FOT parameter was the resonance frequency, providing moderate accuracy (AUC = 0.87). In the second exper-
iment, a neuro-fuzzy classifier and different supervised machine learning techniques were investigated, including k-nearest neighbors,
random forests, AdaBoost with decision trees, and support vector machines with a radial basis kernel. All classifiers achieved high
accuracy (AUC ≥ 0.9) in the differentiation between patient groups. In the third and fourth experiments, the use of different feature
selection techniques allowed us to achieve high accuracy with only three FOT parameters. In addition, the neuro-fuzzy classifier also
provided rules to explain the classification. Neuro-fuzzy and machine learning classifiers can aid in the differential diagnosis of patients
with asthma and restrictive respiratory diseases. They can assist clinicians as a support system providing accurate diagnostic options.

Keywords Clinical decision support system . Forced oscillation technique . Diagnostic of respiratory diseases . Respiratory
oscillometry . Differential diagnosis

Abbreviations estimators. The final output is a weighted com-

ADAB AdaBoost classifier with decision trees. It is a
ML algorithm that employs an ensemble strat-
egy called boosting. Each base estimator (deci-
sion tree) is designed to correctly classify the
instances misclassified by previous base
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11517-020-02240-7) contains supplementary
material, which is available to authorized users.
* Pedro L. Melo
plopes@uerj.br
1
Department of Electronics and Telecommunications Engineering,
State University of Rio de Janeiro, Rio de Janeiro, Brazil
2
Biomedical Instrumentation Laboratory, Institute of Biology Roberto
Alcantara Gomes and Laboratory of Clinical and Experimental
Research in Vascular Biology, State University of Rio de Janeiro,
Rio de Janeiro, Brazil
3
Pulmonary Function Laboratory, Pedro Ernesto University Hospital,
State University of Rio de Janeiro, Rio de Janeiro, Brazil
bination of all base estimators (decision trees)
Aij The fuzzy set of the jth feature in the ith rule
AUC Area under the receiver operating characteristic
curve
BFP Best FOT parameter, the most accurate parameter
obtained using only the FOT method
c Number of classes
C Regularization parameter in SVM
Cdyn Dynamic compliance, reflecting the total compli-
ance of the respiratory system, also being related
to the respiratory homogeneity, expressed as mL/
cmH2O
CdynA Fuzzy set (Gaussian membership function) related
to dynamic compliance Cdyn for Asthma class
CdynR Fuzzy Set (Gaussian membership function) related
to dynamic compliance Cdyn for Restrictive class
CG Control group, a group of healthy subjects used as a
reference for comparisons with the studied diseased
groups
Ck the kth label of class

COPD Chronic obstructive pulmonary disease, a lung dis-
ease characterized by chronic obstruction of lung
airflow that interferes with normal breathing
FOT Forced oscillation technique, a method to evaluate
respiratory mechanics using sinusoidal system iden-
tification techniques
frA Fuzzy set (Gaussian membership function) related
to resonant frequency fr for Asthma class
FEV1 The forced expiratory volume in the first second,
obtained from a maximal expiratory effort maneu-
ver, expressed in L
FVC Forced vital capacity, the total amount of air ex-
haled during the espirometric exams, expressed in L
fr Resonant frequency, the frequency at which Xrs
becomes zero, associated with respiratory inhomo-
geneity and expressed as Hz
frR Fuzzy set (Gaussian membership function) related
to resonant frequency fr for Restrictive class
K Number of nearest neighbor
k Number of folds in k-fold validation procedure
KNN K-nearest neighbor. It is a ML algorithm. When it is
used for classification, the class of the query is de-
termined by the majority vote among the class K-
nearest neighbors found in the training set
KS Kyphoscoliosis, an abnormal curvature of the spine
in both a coronal and sagittal plane. It is a combina-
tion of kyphosis and scoliosis
m Number of rules
ML Machine learning, field of artificial intelligence
whose scope is the investigation of algorithms that
can recognize patterns and learn different relation-
ships present in a set of data
n Number of features (variables)
NFC Neuro-fuzzy classifier. It is a fuzzy rule-based sys-
tem, which is encoded as a neural network. Hence,
it is possible to apply neural network learning algo-
rithms to determine the parameters of the fuzzy sys-
tems, such as the fuzzy rules and fuzzy membership
functions
r Standard deviation of the radial basis function
R0 Intercept resistance, obtained using linear regres-
sion in the 4–16 Hz range, a representative of the
resistance in the low-frequency spectra, expressed
as cmH2O/L/s
R0A Fuzzy set (Gaussian membership function) related
to intercept resistance R0 for Asthma class
R0R Fuzzy set (Gaussian membership function) related
to intercept resistance R0 for Restrictive class
R4 Respiratory resistance in 4 Hz, expressed as
cmH2O/L/s
RF Random forests. It is a ML algorithm that employs
an ensemble of decision trees. In classification prob-
lems, the final output class is obtained by the
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majority of the class’s output by the individual de-
cision trees
Rm Mean resistance in the 4–16 Hz range, reflecting
mid-frequency spectra, that is related to the resis-
tance in the central airways, expressed as cmH2O/
L/s
ROC Receiver operating characteristic curve
Rrs Respiratory resistance, including airways, lung, and
thoracic wall resistance, expressed as cmH2O/L/s
S Angular coefficient of resistance, the resistance
change with frequency in the 4–16 Hz range, which
is associated with respiratory nonhomogeneities,
expressed as cmH2O/L/s2
Se Sensitivity, proportion of actual positives that are
correctly identified as such
Sm Width matrix of the Gaussian membership
functions
Sp Specificity, proportion of actual negatives that are
correctly identified as such
SSCG Speeding up Scaled Conjugate Gradient
SVM Support vector machines. It is a ML algorithm that
uses support vectors to determine a decision bound-
ary that is a hyperplane with optimal geometric mar-
gin from the classes, which, in turn, presents the
highest generalization capacity
SVMR support vector machines with radial basis function
kernel. It is a SVM that employs the “kernel trick”
to allow SVM to be employed in nonlinear separa-
ble problems. The “kernel trick” transforms the data
in a new high-dimensional space where it is easier to
separate the classes
U Center matrix of the Gaussian membership
functions
W The weight matrix among the rules and the classes
X4 Respiratory reactance at 4 Hz, expressed as cmH2O/
L/s
Xm Mean reactance evaluated considering the 4 to
32 Hz frequency range, associated with respiratory
inhomogeneity and expressed as cmH2O/L/s
Xrs Respiratory reactance, including airways, lung, and
thoracic wall, expressed as cmH2O/L/s
xj jth input variable in the fuzzy classifier
Z4 Impedance module in 4 Hz, The total mechanical
load including resistance and elastic effects,
expressed as cmH2O/L/s
1 Introduction
Reduction of the maximum air flow of the lungs is understood
as an obstructive disease [37]. Asthma is a particular case of
obstructive disease, a global health problem affecting 1–18%
of the population in different countries [95]. Restrictive
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disease is defined by the restriction of lung expansion due to
parenchymal, pleural, chest wall, or neuromuscular apparatus
changes. These disorders are characterized by a reduced vital
capacity and lung volume at rest, but with normal resistance.
Although asthma and restrictive diseases present similar clin-
ical implications, including shortness of breath, severe cough,
and chest pain, they have different treatments for each condi-
tion, requiring a special differential analysis [85].
Airway obstruction and lung expansion properties are usu-
ally indirectly evaluated by measuring the maximum expired
airflow and volume using spirometry. Whole body plethys-
mography is another useful technique to measure airway ob-
struction and lung restriction. Despite long-term clinical suc-
cess, these methods have a number of problems in use. They
require a high degree of collaboration and maximal effort, and
thus, these measurements may be unreliable and variable if
suboptimal maneuvers are performed. Furthermore, forced
maneuvers may alter the bronchial tone and modify the airway
patency, rendering the obtained indices hardly physiologic.
Accordingly, the literature has emphasized that investigation
on new methods to improve the noninvasive tests of pulmo-
nary function should be considered a great preeminence [13,
22, 30].
The forced oscillation technique (FOT) is a noninva-
sive method that was introduced in the 1950s by Dubois
et al. [31] to evaluate lung function. The method evaluates
respiratory impedance and its associated elements: respi-
ratory resistance and reactance [55]. Owing to a number
of recent technological improvements, this method nowa-
days represents the state of the art in lung function eval-
uation [11]. Several authors have argued that it has the
potential to improve diagnosis and monitor the treatment
of respiratory diseases and that further studies are needed
in this area [16, 63]. Previous studies conducted by our
group suggest that this technique can contribute to the
detection of obstructive respiratory changes in patients
with asthma [18], and restrictive abnormalities in sarcoid-
osis [34], silicosis [25], rheumatoid arthritis [33], and sys-
temic sclerosis [71].
Information obtained from FOT provided a detailed evalu-
ation of the respiratory abnormalities in asthma [18] and re-
strictive disease [34]. Therefore, this method may contribute
to the differential diagnosis of the respiratory abnormalities in
asthma and restrictive diseases. It was pointed out previously,
however, that identification of specific characteristics of re-
strictive diseases by FOT analysis has not yet been fully pre-
sented [58], and only two recent studies have suggested that
FOT may be useful in the differential diagnosis between re-
strictive and obstructive respiratory abnormalities [48, 90].
Initial results obtained in our group provided additional evi-
dence in favor of this hypothesis [86]. However, FOT was
able to provide adequate clinical diagnosis only between
groups presenting diseases in latter stages.
FOT is rapidly becoming a key instrument in pulmonary
function analysis. However, despite the advantages of FOT in
terms of its noninvasiveness and lack of dependence on pa-
tient cooperation, the clinical use of this method is limited
because, in the context of a diagnostic framework, the inter-
pretation of resistance and reactance parameters demands
training and experience, and it is not a simple task for the
untrained pulmonary specialist. To contribute to minimizing
this limitation, prior studies from our laboratory have provided
clear evidence that machine learning (ML) methods may sim-
plify the routine assessment of lung function by FOT. Another
important characteristic that emerged from these studies was a
significant improvement in the diagnostic accuracy of FOT in
several important clinical respiratory conditions [6–8, 68, 69].
In line with these observations, other methods of lung function
analysis were also improved by the use of ML techniques [9].
Although previous studies have shown that these methods
could help the clinical use of the FOT, simplifying test inter-
pretation and increasing accuracy, there are no previous stud-
ies using FOT combined with ML algorithms to improve the
differential diagnoses of asthma and restrictive diseases.
Therefore, we have explored the hypothesis that the appli-
cation of ML algorithms combined with FOT analysis would
improve the differential diagnosis of asthma and restrictive
respiratory diseases. In this context, the specific goals of this
study were (1) to evaluate the ability of FOT parameters alone
to correctly diagnose differences between patient groups
(asthma and restrictive); (2) to evaluate several ML methods
to help in the differential diagnosis of these respiratory dis-
eases; and (3) to explore whether a fuzzy classifier could aid in
the differential diagnosis and provide a useful explanation
concerning how the classification is performed.
2 Methods
2.1 Ethical issues, studied subjects, and inclusion and
exclusion criteria
This research was approved by the research ethics board of the
State University of Rio de Janeiro, and the post-informed con-
sent of all volunteers was obtained before inclusion in the
study. The study was conducted in accordance with the
Declaration of Helsinki. Anthropometric information was ob-
tained from the volunteers before the beginning of the
procedures.
Ninety-seven volunteers were selected for the study, in-
cluding 38 diagnosed with asthma and 39 with restrictive re-
spiratory disease. Among asthmatics, eighteen had severe ob-
struction and twenty moderate obstruction. The group with
restrictive disease was composed of patients with sarcoidosis,
scleroderma, idiopathic pulmonary fibrosis, asbestosis, and
silicosis, of whom twenty patients presented severe restriction

and eighteen presented moderate restriction. The inclusion
criteria were as follows: age over 18 years; the clinical diag-
nosis of the respective diseases for patients with asthma and
restrictive abnormalities; exclusion of history of smoking and
other cardiovascular or respiratory diseases. Volunteers with
asthma during a crisis period were not included in the study.
Although the objective of this study was to evaluate the
potential of FOT in the differential diagnosis of asthma and
restrictive respiratory diseases, a control group (CG) was also
included to allow a deeper comprehension of the biomechan-
ical abnormalities in asthma and restrictive diseases, as well as
the changes with the progression of these diseases. This group
was composed of 20 healthy subjects with FOT values within
normal limits, with no history of tobacco use, as well as car-
diac or pulmonary disease.
2.2 Pulmonary function
FOT exams were conducted using an instrument developed in
our laboratory [24] that follows international standards [56].
The measurements were conducted during spontaneous
breathing using small peak-to-peak pressure oscillations
(2 cmH2O) generated by a speaker, which were applied at
the entrance of the individual’s airway through the oral cavity.
The nostrils of the volunteers were occluded with a nose clip.
To minimize the shunt effect of the upper airways [8], the
volunteer firmly held their cheeks and chin with their hands.
Three tests of 16 s were performed, and the result adopted was
the mean score. This measurement duration is an appropriate
compromise, achieving clinically acceptable statistical vari-
ability and a comfortable examination time for the patient.
The test was considerable acceptable if the volunteers present-
ed stable tidal volumes and rate and free of pauses. Common
artifacts such as swallows, coughs, and leaks were identified
by the evaluation of flow and pressure signals, and the acqui-
sition was repeated until three stable and free of artifact mea-
surements were obtained. Frequencies between 4 and 32 Hz
were used in these exams. To reduce the influence of the
spontaneous breathing, only exams with coherence function
≥ 0.9 in the whole frequency range studied were accepted. To
exclude outlying values, the coefficient of variation of respi-
ratory resistance (Rrs) at the lowest oscillation frequency
(4 Hz) for the 3 measurements was ≤ 10%. The analyses were
performed using an instrument developed at our laboratory
and described previously [24].
The resistance results were interpreted using linear regres-
sion in the 4–16 Hz range, which allowed us to obtain the
intercept resistance (R0). This is a representative of the resis-
tance in the low-frequency spectra, describing Newtonian re-
sistance of the respiratory system, as well as the effect of
pendelluft (gas redistribution) [60]. The regression also pro-
vided the angular coefficient of resistance (S), which depicts
the resistance change with frequency, which is associated with
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respiratory nonhomogeneities [15]. The mean resistance (Rm)
was calculated in the 4–16 Hz range and reflects mid-
frequency spectra, which is related to the resistance in the
central airways [64].
Three parameters were used to describe the results related
to reactance: resonant frequency (fr), mean reactance (Xm),
and dynamic compliance (Cdyn). Resonant frequency is the
frequency, at which Xrs becomes zero [18], obtained by the
interpolation of respiratory reactance (Xrs) values adjacent to
the ones at which this variable changes from negative to pos-
itive values. Mean reactance is associated with respiratory
inhomogeneity and was evaluated considering the 4 to
32 Hz frequency range. Dynamic compliance, which was ob-
tained using the reactance at 4 Hz (Cdyn = 1/2πfX4), reflects
the total compliance of the respiratory system, also being re-
lated to the respiratory homogeneity [64]. The total mechani-
cal load, including resistance and elastic effects, was also in-
vestigated using the 4 Hz impedance module (Z4) [74].
Spirometric exams were performed after FOT, following
local [54] and international [70] recommendations. The clas-
sifications of airway obstruction and pulmonary restriction
were also performed following these guidelines, using spiro-
metric exams as a gold standard. The analyzed indexes were
forced expiratory volume in the first second (FEV1), forced
vital capacity (FVC), and FEV1/FVC ratio, which were
expressed as absolute values and as percentages of predicted
values [79]. The GINA guidelines [95] were used to define
asthma.
2.3 Presentation of results and statistical analysis
The results are presented as the means ± standard deviations.
Statistical analysis was performed using the ORIGIN 8.0 pro-
gram (Microcal Software Inc., Northampton, MA, USA). The
characteristics of the sample’s distribution were initially eval-
uated (Shapiro-Wilk test). Then, a parametric test (indepen-
dent t test) was used when the data exhibited a normal distri-
bution, and a nonparametric test (Mann-Whitney) was used
when the data do not presented a normal distribution. A p
value of less than 0.05 was considered significant for the re-
sults of all statistical analysis.
Receiver operating characteristic (ROC) curves were plot-
ted to analyze the clinical use and cutoff points of various FOT
parameters in the discrimination between asthma and restric-
tive respiratory abnormalities. Diagnostic accuracy was
assessed calculating the area under the curve (AUC).
Previous studies suggested that ROC curves with an AUC
between 0.80 and 0.90 are adequate for clinical use, while a
high diagnostic accuracy is observed in conditions of AUCs ≥
0.90 [41, 91]. This accuracy allows the clinicians to easily
balance the values of sensitivity and specificity to the specific
local conditions of use and needs. Diagnostic accuracy
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analyses were performed using MedCalc 12 (MedCalc
Software, Mariakerke, Belgium).
2.4 Datasets
In the present work, experiments were performed in a dataset,
which included 7 input features (FOT indexes) from 241
exams. It included 114 measurements taken from volunteers
with asthma: 60 with moderate asthma and 54 with severe
asthma. It also has 117 measurements taken from patients with
restrictive diseases: 60 with severe and 57 with moderate re-
strictive diseases.
2.5 Machine learning algorithms
Machine learning is the field of artificial intelligence whose
scope is the investigation of algorithms that can recognize
patterns and learn different relationships present in a set of
data [94]. In our previous studies [5, 7, 8], we have appraised
a wide variety of models including logistic linear classifier,
decision trees, neural networks, k-nearest neighbors, support
vector machines (SVMs), and ensemble strategies such as
random forests. It was noted that the AdaBoost classifier, k-
nearest neighbor, random forest classifier, and SVM with ra-
dial basis kernel had presented outstanding performance. Our
incipient exploratory experiments confirm this fact; based on
these observations, we concluded that we conserve only k-
nearest neighbor, AdaBoost, SVM with radial basis kernel,
and the random forest classifier. However, these models only
address accuracy, which is the capability of the model to rep-
licate the real system’s results. It should be more significant as
there is higher conformity between the responses of the real
system and the model [39]. However, when one wishes to
understand how the induced model can distinguish between
different classes or represent relations existing in the data in a
comprehensible way, more symbolic approaches, such as
rule-based systems, become more attractive. In addition to
the ability to express knowledge in a comprehensible way,
they enable the introduction of the specialist’s knowledge.
The fuzzy set theory [96] is one of the most important para-
digms of computational intelligence that explores aspects of
inference and knowledge representation. The greatest motiva-
tion for using the fuzzy set theory was to establish an interface
between quantitative patterns and qualitative knowledge
structures that represent vague and imprecise information for-
mulated in natural language. This feature allows the represen-
tation of the knowledge extracted from the database in linguis-
tic form, generating greater interpretability [47].
The most recurrent application of fuzzy set theory is the
synthesis or inference of fuzzy rule-based systems (FRBS),
where several strategies have been developed to induce
rules-based fuzzy models [21]. It is remarkably vital in the
field of learning fuzzy rules, the hybrid methods that join the
theory of fuzzy systems with computational intelligence tech-
niques such as neural networks and evolutionary algorithms.
In the neuro-fuzzy methods [2, 52, 75], one possible strategy
is to code the fuzzy system as a neural network and to apply
established methods of training, such as backpropagation [46].
When the strategy employs evolutionary algorithms, then the
genetic algorithms are the most used. They provide a way of
codifying and evolving the following fuzzy blocks: member-
ship functions, aggregation operators, different rules compo-
sitions, and defuzzification operators.
To further explore other ML methods, we also selected the
fuzzy classifier because we also wanted to address the inter-
pretability, which is the ability to express the behavior of the
real system in a compressive manner. It is an individual prop-
erty and is usually associated with several factors related to the
structure of the model, such as the number of input variables,
number of rules, number of linguistic terms, and others [39].
Therefore, we would like to answer the following inquiry: Is it
possible to develop a classifier that presents interpretability
and, at the same time, also have a satisfactory accuracy?
As a result, in the present work, the chosen classification
methods were analyzed:
& K-nearest neighbor [45, 57];
& Ensemble strategies (AdaBoost classifier with decision
trees [38, 87] and random forest (RF) [14, 88]);
& SVM with radial basis functions [1, 44];
& Neuro-fuzzy classifier [20, 47, 52].
A description of the ML techniques previously used in
pulmonary function exams was presented elsewhere [9]. The
studied methods will be succinctly presented here, and a thor-
ough description is available in the References.
KNN is a lazy learner because, in the training stage, it does
not learn the relationships between the data in the training set,
it merely stores the training set (a set of labeled instances).
When a new query must be classified, the class of the query is
obtained by using majority vote among the class of the K
objects. Random forest (RF) is an ensemble strategy that as-
sembles and compounds several base decision trees [14]. It
employs the bootstrap aggregation (bagging) which helps to
improve accuracy and control the overfitting [45]. AdaBoost
employs a distinct ensemble strategy, called boosting, where
the user can join several “weak classifiers” (base estimators)
together to form a single “strong classifier” [87]. Each base
estimator (decision tree) is designed to classify the instances
misclassified by previous base estimators correctly. Once the
training process is terminated, the algorithm associated with
each base estimator, a weight related to its accuracy. The final
output is a weighted combination of all base estimators (deci-
sion trees).
The basic principles from which support vector machines
(SVMs) were conceived were established by statistical

learning theory [93]. SVMs were employed in a myriad of
problems with the state-of-the-art performance [62, 65, 66].
Considering a binary, linearly separable classification prob-
lem, SVM provides a decision boundary that is hyperplane
with optimal geometric margin from the classes, which in turn
presents the highest generalization capacity. This conception
can be extended to a nonlinear separable problem by applying
an artifice called a “kernel trick.” This scheme transforms the
data into a new high-dimensional space, where one expects
the classes to be effortlessly separable [45].
Fuzzy classification is the procedure of segmenting feature
spaces into fuzzy classes. It assumes the frontier between two
neighbor classes as a continuous, super-imposed area within
an object has partial membership in each class. A fuzzy clas-
sifier can be characterized as a set of fuzzy classification rules
Ri which depicts the relation between the input feature space
and the classes, which can be expressed as follows:
Ri : If x1 is Ai1 and…and xj is Aij and…and xn is Ain
Then class is C k
where xj stands for the jth feature or input variable; Ck
represents the kth label of class; n represents the number of
features; and Aij indicates the fuzzy set of the jth feature in the
ith rule and is depicted by the pertinent membership function
[51]. The fuzzy classifier employed in this work is like Jang’s
classifier and it is displayed in Fig. 1.
The feature space in Fig. 1 has two features {x1, x2}, and
the classifier discriminates them into two classes {C1, C2}.
The network structure of the fuzzy classifier is similar to the
one presented in the study by Jan and his collaborators [51].
However, every feature is expressed with two fuzzy sets. As a
result, there are four fuzzy rules.
The parameters of the fuzzy classifier θ = {Umxn Smxn Wmxn}
can be fit by supervised training algorithms, where U and S are
the center and the width matrices of the Gaussian membership
functions, respectively; W represents the weight matrix among
the rules and the classes; and m, n, and c are the number of rules,
features, and classes, respectively. The adaptive neuro-fuzzy net-
works have also been trained using different optimization
methods, such as the Kalman filter [50], gradient descent [52],
Fig. 1 Neuro-fuzzy classifier
used in the present work
Med Biol Eng Comput
and second-order methods as Levenberg–Marquardt [51]. In this
work, we chose the approach described in [20], which employs a
Speeding up Scaled Conjugate Gradient (SSCG) to optimize the
parameters of the neuro-fuzzy classifier. The SSCG is a variation
of the Scaled Conjugate Gradient, which shortens the optimiza-
tion time without compromising the convergence rate.
2.6 Performance analysis
Generalization is a very important characteristic of a classifier
[72]. It is the faculty of the classifier to encounter a suitable
class estimate for new and unseen data; that is, data was not
used to the training procedure. One key issue to carry out the
assessment of the generalization ability is the election of prop-
er evaluation criteria [3, 94]. Since our research deals with the
medical diagnosis, we opt to embrace sensitivity (Se), speci-
ficity (Sp), and the area under the receiver operating charac-
teristic (ROC) curve (AUC) [43]. Additionally, this choice
grants permission to contrast and correlate our findings with
other previous studies carried out by our group [5, 7, 8, 69].
After the selection of the performance assessment criteria, it
was needed to design a proper evaluation structure to measure
the performance of the trained model based on unseen exam-
ples to infer its generalization ability. Since the dataset has a
modest size, k-fold validation procedure [53] is a more suit-
able choice because it allows the valuation of the generaliza-
tion capability in the whole dataset. We subdivided the dataset
into k equal (or approximately equal) data subsets or folders,
ensuring the same class proportional to each folder. Each sub-
set is utilized for testing, and the training of the classifier
model employs the remaining k − 1 subsets. The performance
of each algorithm on each folder can be calculated. Upon the
end of the k-fold validation, k outcomes of the performance
metric are available, and they can be aggregated to produce a
final estimation of the generalization capability of the model.
This aggregation in the k-fold validation is an essential feature
because it circumvents the reporting of an idealist result
achieved from a single, particular division of the dataset in
the training and test sets, as it could occur in holdout proce-
dures. Furthermore, it is also possible to use these outcomes to
contrast various ML methods using statistical hypothesis
Med Biol Eng Comput
testing, which is a vital element to compare two or more ML
algorithms. McNemar’s test and Wilcoxon’s signed-rank test
are endorsed by Dietrich [29], Demsar [28], and Japkowicz
and Shah [53]. Another methodology commonly employed is
the comparison of AUCs, which was performed as described
in Delong et al. [27].
2.7 Experimental analysis
Four experiments were conducted. Firstly, we figured out the
ability of each one of the FOT indexes alone to accurately set
apart patients with asthma and with restrictive respiratory dis-
eases (experiment 1).
Secondly, ML algorithms were exploited to determine
whether a boost in performance could be accomplished. We
did not carry out any feature selection; hence, all the original
FOT indexes were used. K-nearest neighbors, AdaBoost, ran-
dom forests, and SVMs classifiers were implemented with a
Python machine learning library Scikit-learn [78]. This library
allows the user to tune several classifiers’ hyperparameters.
Here, AdaBoost employed the decision tree as its base estima-
tor (“weak classifier”), and the adjusted parameters were the
number of base estimators (50, 100, 150, 300) and the max
depth of the base estimator (4, 5, 6, 7, 8). In the KNN, K (3, 5,
7) was the tuned hyperparameter. In the RF method, the
hyperparameters were the number of base estimators (50,
100) and the max depth of the base estimator (4, 5, 6, 7).
The SVM with an RBF kernel had two hyperparameters, the
regularization parameter C (1, 10, 100, 1000) and the standard
deviation of the radial basis function r (0.001, 0.0001). The
investigation for the best hyperparameters was executed in the
training routine for each classifier. Because of the use of 10-
fold cross-validation, the training was reiterated ten times;
each training routine selects one fold as a test set and the
remaining ones as a training set. A second 10-fold cross-val-
idation (also called inner, or nested), which employed only the
training set, was carried to completion to spot suitable
hyperparameters for each classifier. The performance metric
was average AUC.
We also implemented in MATLAB a neuro-fuzzy classifi-
er based on the source code provided by Cetişli and Barkana
[20]. It has, as its main hyperparameter, the number of clusters
per class, which is used by K-means [49, 51] to obtain the
initial parameters (centers and widths of the Gaussian mem-
bership functions) and to formulate the fuzzy rules. Later,
those parameters are optimized by a modified version of the
scaled conjugate gradient algorithm [73]. Also, we add an
early stopping procedure, which is known to reduce
overfitting and improve generalization [81].
Overfitting can be responsible for poor predictive perfor-
mance in unseen data when a model has not acquired the ability
to generalize. Therefore, to circumvent overfitting, we thorough-
ly manage the classifier complexity and model. AdaBoost is
known to be unsusceptible to overfitting [87]. Schapire argues
that the increase in confidence of the predictions with additional
cycles of boosting is responsible for achieving improved gener-
alization. Besides, the max depth of the base estimators was
controlled to avoid the overfitting of the base estimators. In the
k-nearest neighbor classifier, the number of neighbors was al-
ways chosen to be higher than 1; as a result, the classification
is based on a set of nearest neighbors, which turns the classifier
more resistant to outliers. The RF is an ensemble strategy that
aggregates the outcomes of several trees, which tends to mitigate
overfitting errors; also, similarly to AdaBoost, the max depth of
the base estimator was also controlled, diminishing the possibil-
ity of overfitting. The SVMR is built to obtain the optimal deci-
sion frontier between classes to ensure a higher generalization
ability. The fuzzy partition applied in the neuro-fuzzy classifier
turns it resistant to small fluctuations in training, which could
lead to variance errors. The training procedures can also adopt
the same strategies employed to avoid overfitting in neural net-
works, such as early stopping [10].
Also, the use of nested cross-validation procedure [19] was
enforced to find the best classifier hyperparameters and to
provide extra protection against overfitting.
The third experiment followed the same methodology of
experiment 2, but in the processing pipeline, a feature selec-
tion procedure was included. The utility of the input feature
selection is to encounter the smallest number of pertinent and
informative features that can result in adequate performance.
Our primary motivation to perform feature selection is to al-
low data visualization (2D or 3D) [42]. The chosen feature
selection method was the recursive feature elimination, which
is a backward search [42], which recursively removes attri-
butes and builds a model on those features that remain. The
chosen model was a linear support vector machine. It is a low
complexity model (linear) with the ability to produce the hy-
perplane to maximize the margin and, as a result, to provide
better generalization. Also, the low complexity model pro-
vides protection against overfitting in the choice of the feature,
which may happen if a high complexity model was applied.
The fourth experiment also employed feature selection, but
it used a method stability selection [76]. It is a relatively new
method for feature selection, where the basic idea is to apply a
feature selection algorithm on distinct subsets of data and with
diverse subsets of features. Once the process is rerun numer-
ous times, the selection results can be accounted for, for ex-
ample, by checking how many times a feature was elected as
necessary when it was in a scrutinized feature subset.
Therefore, strong features would have scores close to 100%
(since they would always be selected when possible), weaker,
but somewhat essential features would have non-zero scores,
and irrelevant features would have a score close to 0.
For all experiments in the study, the ROC curve, obtained
using only the best individual FOT parameter (BFP) as an input
feature, was used to confront the performance of the classifiers.
 Med Biol Eng Comput

The option of single-feature classification based on the BFP was a

6.0
inspired by the present clinical scenario, where only one param- 5.5 Control
eter is assessed to categorize the severity of respiratory diseases. 5.0 Asthma
Restrictive
4.5
Airway obstruction severity, for example, is grounded only on

Resistance (hPa.s.l )
-1
4.0
FEV1 [70]. For these experiments, the comparative analysis be- 3.5
tween the classifiers was executed using MedCalc 8.2 (Medicalc 3.0
Software, Mariakerke, Belgium) [27]. 2.5
2.0
1.5
1.0
0.5
3 Results 0.0
4 8 12 16 20 24 28 32
Regarding the biometric characteristics of the studied individ- Frequency (Hz)
uals (Table 1), no significant differences were observed in
b
terms of weight and height among groups (p > 0.05). The 2
control group produced higher FEV1 and FVC values (within
normal limits). As expected, the spirometric parameters were
0
reduced in the patient groups and FVC was reduced in patients

Reactance (hPa.s.l )
-1
with restrictive diseases in comparison with the asthma group,
while FEV1/FVC were higher in patients with restrictive dis- -2

eases in comparison with patients with asthma.

-4 Control
Asthma
3.1 Forced oscillation Restrictive
-6
4 8 12 16 20 24 28 32
Values of resistance and reactance as a function of frequency
Frequency (Hz)
for the investigated groups are described in Fig. 2, while Fig. 3
shows the effects of asthma and restriction on the resistive and Fig. 2 Mean respiratory resistance (a) and reactance (b) curves in
controls and patients with asthma and restrictive diseases
reactive properties of the respiratory system.
All of the evaluated parameters presented significant
Considering the reactive parameters, Xm was more nega-
changes in the comparison between the control group and
tive in asthma than in restrictive subjects (Fig. 3d; p < 0.001),
the restrictive group, as well as comparing the control group
whereas Fig. 3e shows that a significantly higher fr occurred
with asthmatic patients (p < 0.05). The R0 values (Fig. 3a) in
in asthma in comparison with restrictive subjects (p < 0.001).
individuals with asthma were significantly higher than those
Visually, individuals with restrictive abnormalities presented
observed in the restrictive individuals (p < 0.001). Figure 3b
lower Cdyn than patients with asthma (Fig. 3f). Statistical
shows a similar observation in Rm (p < 0.001). The S of indi-
comparisons, however, do not evidenced significant changes.
viduals with asthma was significantly more negative in com-
Figure 3g displays the experimental data on Zrs. Significantly
parison with those in the restrictive group (p < 0.001).
higher values were observed in asthma in comparison with the
restrictive group (p < 0.01).
Table 1 Demographic and spirometric characteristics of study groups

Control (n = 20) Asthma (n = 38) Restrictive (n = 39)

3.2 First step: Diagnostic accuracy of FOT parameters
Age 53.1 ± 11.8 46.8 ± 17.8 57.5 ± 16.0* to discriminate the different conditions
Weight 65.6 ± 10.3 67.5 ± 14.0 63.0 ± 14.8
Height 162.2 ± 6.6 159.0 ± 10.1 157.4 ± 8.0 Figure 4 includes the ROC curves for each FOT parameter.
Male/female 5/15 15/23 12/27 The associated areas under the curve (AUCs), standard errors,
FEV1 (%) 107.9 ± 18.3 49.1 ± 16.1 55.3 ± 8.7
and 95% confidence intervals are displayed in Table 2.
FVC (%) 104.4 ± 19.6 77.4 ± 19.3 50.3 ± 8.1**
FEV1/FVC 85.1 ± 6.7 52.7 ± 9.2 98.7 ± 15.9**
Fig. 3 FOT parameters obtained in the control group and groups of„
patients with restrictive diseases and asthma. Extrapolated Newtonian
FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEV1/
resistance in 0 Hz (R0; a), mean resistance (Rm; b), slope of the
FVC, Tiffeneau index; (%), percentage of the predicted value
resistance values (S; c), mean reactance (Xm; d), resonance frequency
*p < 0.05 comparing with the asthma group; (Fr; e), dynamic compliance (Cdyn; f), and impedance modulus in 4 Hz
**p < 0.001 comparing with the asthma group (Z4; g)
Med Biol Eng Comput

a b
18 18
p<0.001
15 15

p<0.001
12 12

Rm (hPa.s.l )
R0 (hPa.s.l )

-1
-1

9 * 9

6 6 *
*
*
3 3

0 0
Control Restrictive Asthma Control Restrictive Asthma

c d
200 2

* * 0 * *
0

Xm (cmH2O/L/s)
S (hPa.s .l )
2 -1

-200 -2

-400 -4

-600 -6
p<0.001
p<0.001
-800 -8
Control Restrictive Asthma Control Restrictive Asthma

e 60
f
0.18

50 0.15
p<0.001

40 ns
0.12
*
Cdyn (l/hPa)
fr (Hz)

30 0.09
*
20 0.06
*
10 0.03
*
0 0.00
Control Restrictive Obstructive Control Restrictive Asthma

g
24

p<0.01
20

16
Z4 (hPa.s.l )
-1

12 *

8
*

0
Control Restrictive Asthma
 Med Biol Eng Comput

The resonance frequency (fr) was the best FOT parameter Table 2 Results of experiment 1. The area under the ROC curve
(AUC), the standard error (SE), and the 95% confidence interval (95%
and it provided moderate accuracy diagnoses (0.7 ≤ AUC <
CI) of each FOT parameter
0.9).
AUC SE 95% CI

fr (Hz) 0.87 0.02 0.82–0.92

3.3 Second step: Diagnostic accuracy of FOT
Xm (cmH2O/L/s) 0.71 0.03 0.64–0.77
parameters associated with machine learning
R0 (cmH2O/L/s) 0.70 0.03 0.64–0.77
algorithms and with the neuro-fuzzy classifiers
S (cmH2O/L/s2) 0.73 0.03 0.66–0.79
Rm (cmH2O/L/s) 0.70 0.03 0.63–0.77
Figure 5 presents the ROC curves of the BFP, the ML algo-
Zrs4Hz (cmH2O/L/s) 0.62 0.04 0.54–0.69
rithms and the neuro-fuzzy classifiers. Table 3 presents a sum-
mary of experiment 2. One can see that the AUC was greatly Cdyn,rs (L/cmH2O) 0.45 0.04 0.37–0.53
improved and that the ML and neuro-fuzzy (NFC) classifiers fr, resonance frequency; Xm, mean respiratory reactance; R0, respiratory
achieved a high diagnostic accuracy (AUC ≥ 0.9). resistance extrapolated at 0 Hz; S, slope of the linear relationship of
Table 4 compares the AUCs acquired with the BFP and resistance versus frequency; Rm, mean respiratory resistance; Zrs4Hz,
each studied classifier using the method introduced by Delong absolute value of respiratory impedance in 4 Hz; Cdyn,rs, respiratory
system dynamic compliance
et al. [27]. All the ML algorithms presented a statistically
significant difference in relation to the BFP.
3.5 Fourth experiment: Diagnostic accuracy of FOT
parameters in association with machine learning
3.4 Third experiment: Diagnostic accuracy of FOT algorithms and with the neuro-fuzzy classifiers with
parameters in association with machine learning stability feature selection
algorithms and with the neuro-fuzzy classifiers with
recursive feature elimination Figure 7 presents the ROC analysis of the BFP, the ML algo-
rithms, and the neuro-fuzzy classifiers. Table 7 presents a
Figure 6 presents the ROC curves of the BFP, the ML algo- summary of experiment 4. One can see that the AUC was
rithms, and the neuro-fuzzy classifiers. Table 5 presents a greatly improved and that the ML and neuro-fuzzy (NFC)
summary of experiment 3. One can see that the AUC was classifiers achieved a high diagnostic accuracy (AUC ≥ 0.9).
greatly improved and that the ML classifiers achieved a high Table 8 includes the difference between AUCs obtained
diagnostic accuracy (AUC ≥ 0.9). considering the BFP and each studied classifier [27].
Table 6 includes a comparative analysis among the AUCs AdaBoost, K-nearest neighbor, and random forests showed a
(i.e., the difference between AUCs) obtained with the BFP statistically significant difference in relation to the BFP.
and each investigated classifier [27]. AdaBoost, K-nearest The results of experiments 2, 3, and 4 are summarized in
neighbor and random forests showed a statistically significant Fig. 8. A more detailed analysis is described in Fig. 9a and b,
difference in relation to the BFP.

Fig. 5 ROC curves of the best FOT parameter (BFP), and the FOT
Fig. 4 ROC curves for the first experiment, describing the diagnostic parameters associated with the ML algorithms and the neuro-fuzzy clas-
performance of each FOT parameter sifier (NFC)
Med Biol Eng Comput

Table 3 Results of
experiment 2. Best Se Sp AUC
studied classifiers with (%) (%)
the original FOT
parameters as inputs. The BFP 89.7 77.2 0.87
95% confidence interval ADAB 87.2 96.5 0.97
is shown in parenthesis
below each performance KNN 92.3 90.4 0.95
metric. The AUC RF 92.3 89.5 0.97
standard error is also SVMR 99.1 80.7 0.94
shown in parenthesis
NFC 88.9 78.1 0.90

BFP, best FOT parameter (obtained with-

out the use of classifiers); ADAB,
AdaBoost with decision tree classifiers;
KNN, K-nearest neighbor (K = 1); RF, ran-
dom forests; SVMR, support vector ma-
chines with radial basis kernel; NFC,
neuro-fuzzy classifier Fig. 6 ROC curves for experiment 3

accuracy. In addition, the neuro-fuzzy classifier also provided

which show the Se obtained at a Sp of 90% and at a Sp of
75%, respectively. In general, the use of ML methods and the
NFC classifier resulted in increased values of Se in both stud-
ied conditions.
Figure 10 describes the visualization of the three selected
features in experiment 3 (fr, R0, and Cdyn), which allow us to
evaluate if it is possible to discriminate asthma from restrictive
diseases only using FOT parameters.
4 Discussion
In this study, we developed and examined a neuro-fuzzy and a
number of ML algorithms to design an automatic classifier to
support the differential diagnosis of patients with asthma and
restrictive diseases using forced oscillation exams. It was
showed that such a clinical decision support system, based
on the use of neuro-fuzzy, AdaBoost with decision trees,
KNN, random forests, and support vector machines with ra-
dial basis kernel, is able to increment the accuracy of the FOT
in differential diagnosis, allowing for a high diagnostic
rules to explain the classification.
There is a controversy in the literature about the use of FOT
in the differential diagnosis of obstructive and restrictive dis-
eases. This may be because, despite the importance of this
topic, there remains a paucity of well-controlled studies in this
area. Lappas et al. suggested that impedance indices’ modifi-
cations are of no specificity for restrictive syndrome [58].
Investigating patients with interstitial lung disease (ILD), asth-
ma, and chronic obstructive pulmonary disease (COPD),
Sugiyama et al. suggested that changes in reactance are dif-
ferent in ILD in comparison with asthma and COPD [90].
Recent previous research using FOT parameters associated
with multidimensional scaling analysis in COPD and
kyphoscoliosis (KS) provided evidence that this combination
is able to distinguish between obstructive (COPD) and restric-
tive (KS) diseases [48]. The present research is the first spe-
cifically designed to explore this hypothesis.
Initially, we can observe that the changes in the FOT curves
and parameters obtained in the asthmatic and restrictive
groups (Figs. 2 and 3) were in close agreement with the in-
volved pathophysiology [95]. It was interesting to note that

Table 4 Comparison of AUCs in experiment 2

ADAB KNN RF SVMR NFC

BFP 0.103 ± 0.027** 0.083 ± 0.028** 0.095 ± 0.027** 0.067 ± 0.029* 0.025 ± 0.026
ADAB - 0.020 ± 0.009* 0.008 ± 0.008 0.035 ± 0.016* 0.078 ± 0.022**
KNN - - 0.012 ± 0.010 0.016 ± 0.016 0.058 ± 0.025*
RF - - - 0.028 ± 0.013* 0.070 ± 0.023**
SVMR - - - - 0.042 ± 0.028

BFP, best FOT parameter (obtained without the use of classifiers); ADAB, AdaBoost with decision tree classifiers; KNN, K-nearest neighbor (K = 1); RF,
random forests; SVMR, support vector machines with radial basis kernel; NFC, neuro-fuzzy classifier
*p < 0.05 (Delong et al. [25])
**p < 0.01 (Delong et al. [25])
 Med Biol Eng Comput

Table 5 Results of
experiment 3. Best Se Sp AUC
studied classifiers with (%) (%)
the original FOT
parameters as inputs. The BFP 89.7 77.2 0.87
95% confidence interval ADAB 92.3 91.2 0.96
is shown in parenthesis
below each performance KNN 93.2 82.5 0.94
metric. The AUC RF 95.7 84.2 0.96
standard error is also SVMR 99.1 82.5 0.93
shown in parenthesis
NFC 89.7 79.8 0.89

BFP, best FOT parameter (obtained with-

out the use of classifiers); ADAB,
AdaBoost with decision tree classifiers;
KNN, K-nearest neighbor (K = 1); RF, ran-
dom forests; SVMR, support vector ma-
chines with radial basis kernel; NFC,
neuro-fuzzy classifier Fig. 7 ROC curves for experiment 4

mean FOT curves in the asthmatic and restrictive groups were
clearly distinct (Fig. 2). The resistance values in the group of
asthmatic patients were higher than those observed in the
groups of restrictive patients, which, in turn, were higher than
those observed in controls (Fig. 2a). Perhaps the most impor-
tant finding was that the reactance values were more influ-
enced by asthma than by restrictive abnormalities (Fig. 2b).
This unanticipated finding may be explained, at least in part,
considering that the effect of the small airway obstruction on
dynamic compliance [26] and inertance [59], which are pres-
ent in obstructive diseases, in the respiratory reactance may be
stronger than the effects of elastic changes, typical in restric-
tive diseases.
Accordingly, FOT parameters were distinct in these groups
(Fig. 3). The current study found that resistive parameters
were higher in asthmatic patients (Fig. 3 a, b, and c), which
is consistent with the characteristics of the studied groups. The
changes observed in Xm (Fig. 3d), fr (Fig. 3e) and Cdyn (Fig.
3f) reflect the changes in the mean reactance curves (Fig. 2b)
and can be explained by the same observations described pre-
viously. Another important finding was that Z4, a parameter
that integrates resistive and elastic effects, presented increased
changes in patients with asthma compared with patients with
restrictive diseases. These results further support two hypoth-
esis: (1) that asthma introduces increased effects in the resis-
tance values in comparison with restrictive diseases and (2)
that the effect of the small airway obstruction on dynamic
compliance [26] may be stronger than the effects of elastic
changes observed in restrictive diseases.
Among the historiography of FOT, several studies have
described that this method may provide a sensitive analysis
for detecting abnormalities in respiratory mechanics [35, 36,
71, 77, 80, 82–84]. The results of this study provide additional
evidence of this hypothesis (Table 2) and extend these finding
to the differential diagnosis of patients with asthma and re-
strictive diseases.
In the first experiment, we investigated the ability of each
of the FOT indexes alone to adequately discern patients with
asthma and restrictive (Table 2). The best FOT index was fr,
which had an AUC equal to 0.87. None of the FOT parameters
alone allowed a highly accurate discrimination among patients
with asthma and restrictive abnormalities.

Table 6 Comparison of AUCs in experiment 3

ADAB KNN RF SVMR NFC

BFP 0.090 ± 0.028** 0.073 ± 0.028* 0.087 ± 0.029** 0.059 ± 0.031 0.023 ± 0.026
ADAB - 0.017 ± 0.009 0.003 ± 0.008 0.031 ± 0.017 0.067 ± 0.026**
KNN - - 0.013 ± 0.010 0.015 ± 0.015 0.050 ± 0.027
RF - - - 0.0280 ± 0.016 0.064 ± 0.027*
SVMR - - - - 0.036 ± 0.027

BFP, best FOT parameter (obtained without the use of classifiers); ADAB, AdaBoost with decision tree classifiers; KNN, K-nearest neighbor (K = 1); RF,
random forests; SVMR, support vector machines with radial basis kernel; NFC, neuro-fuzzy classifier
*p < 0.05 (Delong et al. [25])
**p < 0.01 (Delong et al. [25])
Med Biol Eng Comput

Table 7 Results of In the fourth experiment, the stability feature selection

experiment 4. Best Se Sp AUC
was employed and found that fr, Xm, R0, S, and Cdyn
studied classifiers with (%) (%)
the original FOT were the most important features. When the classifiers
parameters as inputs. The BFP 89.7 77.2 0.87 were trained using only these features, the ML classifiers
95% confidence interval ADAB 90.6 90.4 0.94 presented a small performance decrease (Fig. 7, Table 7).
is shown in parenthesis
KNN 91.5 91.2 0.96 This did not prevent obtaining a high diagnostic accuracy
below each performance
metric. The AUC RF 90.6 87.7 0.95 by all ML algorithms and the neuro-fuzzy classifiers
standard error is also SVMR 95.7 85.1 0.93 (Table 7). Additionally, the use of AdaBoost, KNN,
shown in parenthesis and RF introduced a statistically significant increase in
NFC 88.0 82.5 0.90
diagnostic accuracy in comparison with BFP (Table 8).
BFP, best FOT parameter (obtained with- Figure 8 provides a summary of experiments 2, 3, and 4
out the use of classifiers); ADAB,
describing a comparison of the accuracies of the best
AdaBoost with decision tree classifiers;
KNN, K-nearest neighbor (K = 1); RF, ran- classifiers and the BFP.
dom forests; SVMR, support vector ma- In order to deepen the analysis of the ROC curves,
chines with radial basis kernel; NFC, Fig. 9a and b show, respectively, the Se observed at a
neuro-fuzzy classifier
Sp of 90% and at a Sp of 75% (representing moderate
specificity). The 90% specificity level was included be-
In the second step, we used classifiers to determine if an cause it theoretically forces the cases presumed to be
improvement in accuracy could be obtained. This experiment the most difficult into the correct disease group (asthma
showed that the AdaBoost, KNN, RF, SVM with radial basis, or restrictive) by allowing only 10% false positives [28].
and neuro-fuzzy classifiers could provide a high diagnostic It is also important to point out that the sensitivities at
accuracy (Table 3). The AUC was significantly increased 90% Sp of all the ML and the NFC methods were
from 0.87 (using the FOT parameter fr alone) to 0.97 by always higher than those obtained based on the BFP
AdaBoost and RF (Tables 3 and 4). It is also worth mention- in all three experiments. ML classifiers always had bet-
ing that all the classifiers (ML and neuro-fuzzy) reached an ter results than BFP at 75% Sp. Also, the NFC classi-
AUC ≥ 0.9, reflecting a high accuracy [91] and indicating that fier presents slightly better results than BFP only in
these classifiers are able to provide an adequate differentiation experiments 2 and 3.
among patients with asthma from patients with restrictive lung The additional benefit of the feature selection is that the
diseases. three selected features in experiment 3 can be visualized in
In the third experiment, the recursive feature elimination 3D (Fig. 10). This procedure allows a simple visual analysis,
was applied and found that the fr, R0, and Cdyn were the most which shows that it possible to discriminate asthma from re-
important features. When the classifiers were trained using strictive diseases only using FOT parameters.
only these features, the ML and neuro-fuzzy classifiers pre- We demonstrated that a simple neuro-fuzzy classifier
sented a small performance decrease (Fig. 5, Table 5), but a (NFC) with only three features was able to achieve an
high accuracy was still achieved by all ML algorithms. Even AUC = 0.89, which is very close to high diagnostic ac-
in the presence of this reduction, statistically significant im- curacy (Table 5). In addition, at the same time, it pro-
provement in accuracies between BFP and AdaBoost, KNN, vides an explanation on how the classifier reached the
and RF was observed (Table 6). classification through the obtained rules. As an example,

Table 8 Comparison of AUCs in experiment 4

ADAB KNN RF SVMR NFC

BFP 0.072 ± 0.030* 0.089 ± 0.027** 0.084 ± 0.027** 0.057 ± 0.031 0.032 ± 0.028
ADAB - 0.016 ± 0.017 0.012 ± 0.016 0.015 ± 0.022 0.040 ± 0.028
KNN - - 0.004 ± 0.011 0.031 ± 0.018 0.056 ± 0.024*
RF - - - 0.027 ± 0.016 0.052 ± 0.026*
SVMR - - - - 0.0250 ± 0.030

BFP, best FOT parameter (obtained without the use of classifiers); ADAB, AdaBoost with decision tree classifiers; KNN, K-nearest neighbor (K = 1); RF,
random forests; SVMR, support vector machines with radial basis kernel; NFC, neuro-fuzzy classifier
*p < 0.05 (Delong et al. [25])
**p < 0.01 (Delong et al. [25])
 Med Biol Eng Comput

Fig. 8 Summary of experiments

2–4 describing comparisons of
the accuracies obtained using the
best FOT parameter (BFP), ML
methods, and the neuro-fuzzy
classifier (NFC). In the ML class,
the figure describes the best clas-
sifier or a list of classifiers with
(AUC ≥ 0.9). Also, “*” indicates
that there a statistically significant
difference in relation to BFP

Fig. 9 Summary of the

experiments describing
comparisons of the sensitivity at
90% Sp (a) and 75% Sp (b)
obtained using the best FOT
parameter (BFP), ML methods,
and the neuro-fuzzy classifier
(NFC). In the ML class, the figure
describes a list of classifiers with
descending order of the sensitivi-
ty. The sensitivity at 90% Sp and
75% Sp presented in the ML class
is that of the best classifier
Med Biol Eng Comput
Fig. 10 Representation of the dataset using three features: fr, R0, and
Cdyn. The restrictive diseases are represented by the red dots and the
blue points represent the asthma
these are the rules for the discrimination between Asthma
(A) and Restrictive (R) patients:
R1: If (fr is frA) and (R0 is R0A) and (Cdyn is CdynA) then
(class is Asthma)
R2: If (fr is frR) and (R0 is R0R) and (Cdyn is CdynR)
then (class is Restrictive)
The membership functions are Gaussians and their names
indicate the FOT parameter and the class. For example, frA is
related to resonance frequency fr for Asthma class. With the
help of the MATLAB’s Fuzzy toolbox, it is possible to use a
graphical interface (Fig. 11) which allows the user to
Fig. 11 Neuro-fuzzy classifier presented in a graphical user interface
experiment with the neuro-fuzzy classifier to get a better un-
derstanding on how it works.
When the user inputs the measured FOT parameters from a
patient, the neuro-fuzzy classifier calculates their membership
degrees that are combined by a conjunctive operator (mini-
mum or product operator) to obtain the firing strength of each
rule regarding the patient to be categorized. Then, we take the
weighted average of the outputs using the firing strengths as
the weights. In Fig. 11, one can see that the firing strength of
the rule R2 is more substantial than that of R1; therefore, the
weighted average favors the class 2 (restrictive). The neuro-
fuzzy classifier looks at the individual contribution of each
FOT parameter and combines them; as a result, it can improve
the obtained results from a single FOT parameter, while it is
still able to explain the classification. From the example pre-
sented in Fig. 11, it possible to see that the FOT parameters of
the presented patient have higher membership degrees to the
rule that classifies it as class 2 (restrictive).
Several previous studies have demonstrated the necessity
of enhancing the noninvasive tests of respiratory function [17,
22, 30] and our understanding of the respiratory system [12].
In the current state of technology, the FOT has been widely
recognized as the state of the art in the analysis of respiratory
mechanics [11], and one of the most promising emerging pul-
monary function methods [16, 63]. However, the interpreta-
tion of the indexes obtained by the FOT requires training and
practice, and it is one of the main aspects that limit its wide
practical application. Besides that, it is important to note that
diagnostic easiness is a fundamental characteristic for occu-
pied non-specialist clinicians [40]. In this context, this study
gives new insights into the differential diagnosis of asthma
and restrictive diseases using FOT. Additionally, it was also
shown that ML algorithms are able to improve the medical

services provided to these patients, making the use of the FOT
simpler and improving the discrimination of the cited
diseases.
This study confirms that the use of ML algorithms is asso-
ciated with a significant improvement in the diagnostic accu-
racy. This is consistent with our earlier observations, which
showed that these algorithms improved the early diagnosis of
the smoking effects [8], COPD identification [4, 6], automatic
analysis of disease severity [5], and respiratory abnormalities
in sickle cell anemia [68, 69]. These results further support
previous works of other researchers describing improvements
in the description of biological systems [32], as well as in the
diagnostic accuracy of respiratory exams based on pulmonary
sounds [89], magnetic resonance imaging [61], and spirome-
try [67, 92]. The interested reader may find in the supplement
(Table S1) a detailed description of the increase in the diag-
nostic accuracy observed in the present study and in previous
studies due to the use of ML methods.
A clear description of the potential limitations of this paper
is necessary. The principal limitation of this study is that we
only studied 77 subjects with asthma and restrictive diseases
and that the precise sensitivity and specificity continues un-
known. More research using a higher number of volunteers is
necessary. However, this preliminary result significantly con-
tributes to elucidate important debates concerning the differ-
ential diagnosis of obstructive and restrictive diseases [48, 58,
90], and the use of ML algorithms in the clinical diagnosis of
respiratory abnormalities [23].
Provided that the work was limited to Brazilian population
at a single practice site, it was not possible to guarantee its
generalizability to a different population. Future works should
include multicenter data to expand the generalizability of the
findings. It is noteworthy that readers can easily assess wheth-
er they are likely to obtain similar results in their own patient
population by examining the inclusion and exclusion criteria
adopted and the biometric features. It is relevant to consider
also that the experimental design of the present work increases
its generalizability. Globally recognized inclusion and exclu-
sion criteria were used, and the work was conducted under
usual clinical procedures in a typical setting.
5 Conclusions
We developed and analyzed the performance of various clas-
sifier algorithms to elaborate a clinical decision support sys-
tem to help in the differential diagnosis of asthma and restric-
tive respiratory diseases. FOT indexes are able only to reach
moderate diagnostic accuracy (0.70–0.90). The introduction
of the neuro-fuzzy and ML classifiers resulted in a significant
improvement in the accuracy, attaining high accuracy in the
differential diagnosis of patients with asthma and restrictive
respiratory diseases. Additionally, the developed system may
Med Biol Eng Comput
be useful for simplifying the use of the FOT in the everyday
evaluation of respiratory function. Particularly, the neuro-
fuzzy classifier provides simple rules to explain the achieved
classification and a graphical interface, which is very easy to
use. These classifiers hold the promise of improving the med-
ical services provided to patients with asthma and restrictive
diseases.
Funding information This study was supported by the Brazilian Council
for Scientific and Technological Development (CNPq) and the Rio de
Janeiro State Research Supporting Foundation (FAPERJ) and in part by
the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -
Brasil (CAPES) - Finance Code 001.
Compliance with ethical standards
This research was approved by the research ethics board of the State
University of Rio de Janeiro, and the post-informed consent of all volun-
teers was obtained before inclusion in the study. The study was conducted
in accordance with the Declaration of Helsinki.
Conflict of interest The authors declare that they have no conflict of
interest.
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Publisher’s note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
JorgeAmaral received his D.Sc.
degree from the Catholic
University of Rio de Janeiroin
2006. He is an Associate
Professor at the State University
of Rio de Janeiro.His main re-
search area is Machine Learning
applied to instrumentation.