Invest Clin 63(1): 19 - 31, 2022
Corresponding author. Aline Siteneski. Instituto de Investigación y Facultad de Ciencias de la Salud, Carrera de
Medicina. Universidad Técnica de Manabí, Portoviejo, Ecuador. Phone: (593) 99129 2040 .
E-mail address:
Clinical related factors to neuroendocrine
tumors in Ecuadorian patients: a logistic
biplot approach.
Karime Montes Escobar 1,2, José Luis Vicente Villardón2, Daniel Fabricio Alarcón Cano3
and Aline Siteneski4,5
1Departmento de Matemática y Estadística. Instituto de Ciencias Básicas.
Universidad Técnica de Manabí, Portoviejo, Ecuador.
2 Departmento de Estadística. Universidad de Salamanca, Salamanca, España.
3 Departamento de Docencia e Investigación. SOLCA, Manabí, Ecuador
4 Instituto de Investigación, Universidad Técnica de Manabí, Portoviejo, Ecuador.
5 Facultad de Ciencias de la Salud, Carrera de Medicina. Universidad Técnica de Manabí,
Portoviejo, Ecuador.
Key words: neuroendocrine tumors; cancer symptoms; statistical method; logistic
Abstract. Neuroendocrine tumors (NETs) are relative rare, affecting neu-
roendocrine cells throughout the body. Most tumors are diagnosed at advanced
stages. NETs prevalence has increased in the last years but there is little data
available in developing countries. The aim of this study was to describe symp-
toms associated with NETs in patients of the Society for the Fight Against Can-
cer (SOLCA) in Ecuador from 2005 to 2020; using logistic biplots, in a hospi-
tal database, generating binary responses (presence/absence) relevant to this
study. The results showed that the mean age was 59 and the study showed no
difference in prevalence between genders. NETs were mainly found in lungs
(19%), followed by stomach (18%) and skin (9%). Most patients had pathologi-
cal diagnosis G2 and G3 (30% and 70%, respectively). Symptoms as cough, dys-
pnea, weight loss, diarrhea, constipation, abdominal pain, dyspepsia, hyperten-
sive crisis, distended abdomen and intestinal obstruction had p values <0.05.
Additionally, the statistical analysis showed that cough and intestinal obstruc-
tion were also common, bearing in mind that patients had most frequent NETs
in the lungs and skin. In summary, our results indicate that symptoms of NETs
patients were positively associated with lung and skin. Further investigation is
needed focusing on the type of NETs and their symptoms in order to establish
an early marker for diagnosis.
20 Montes-Escobar et al.
Investigación Clínica 63(1): 2022
Factores clínicos asociados a tumores neuroendocrinos
en pacientes ecuatorianos: un análisis biplot logístico.
Invest Clin 2022; 63 (1): 19 – 31
Palabras clave: tumores neuroendocrinos; síntomas de cáncer; método estadístico;
biplot logístico.
Resumen. Los tumores neuroendocrinos (TNE) son relativamente raros
y afectan a las células neuroendocrinas de todo el cuerpo. La mayoría de los
tumores se diagnostican en etapas avanzadas. La prevalencia de los TNE ha au-
mentado en los últimos años, pero hay pocos datos en los países en desarrollo.
El objetivo de este estudio fue determinar los síntomas asociados a los TNE en
pacientes de la Sociedad de Lucha contra el Cáncer (SOLCA) en Ecuador entre
2005 y 2020, utilizando biplots logísticos en una base de datos hospitalaria,
generando respuestas binarias (presencia / ausencia) relevantes para este estu-
dio. Los resultados mostraron que la edad promedio era de 59 años y el estudio
no encontró diferencias en la prevalencia entre géneros. Los TNE se encontra-
ron con mayor frecuencia en los pulmones (19%), seguidos del estómago (18%)
y piel (9%). La mayoría de los pacientes tenían diagnóstico patológico G2 y G3
(30% y 70% respectivamente). Los síntomas como tos, disnea, pérdida de peso,
diarrea, estreñimiento, dolor abdominal, dispepsia, crisis hipertensiva, abdo-
men distendido y obstrucción intestinal tuvieron valores de p <0,05. Además,
el análisis estadístico mostró que la tos y la obstrucción intestinal también eran
comunes, teniendo en cuenta que los pacientes tenían TNE más frecuentes en
los pulmones y la piel. En resumen, nuestros resultados indican que los sínto-
mas de los pacientes con TNE se asociaron positivamente con los pulmones y
la piel. Se necesitan más investigaciones que se centren en el tipo de TNE y sus
síntomas a fin de establecer un marcador más temprano para el diagnóstico.
Received: 13-08-2021 Accepted: 03-09-2021
Neuroendocrine tumors (NETs) are a
group of malignant tumors appearing from
neuroendocrine cells throughout the body
that are defined as epithelial neoplasms
with predominantly neuroendocrine differ-
entiation 1. NETs are commonly located in
the pancreas, digestive tract, and the lungs
although they can appear in any organ 2.
NETs grading is probably the most useful
instrument for providing prognostic infor-
mation for clinicians 3. Currently, the clas-
sification recognizes that neuroendocrine
cancer at any anatomical site is either well-
differentiated defined as NETs, and poorly
differentiated defined as neuroendocrine
carcinoma 3. Severity may be evaluated by
grading the tumor between 1 and 3 and per
proliferation fraction as measured by mitot-
ic count by the Ki67-positive percentage 4,5.
Approximately one-third of the high-grade
group are the most aggressive NETs frac-
tion, predicting either a worst event-free
Clinical related factors to neuroendocrine tumors in Ecuadorian patients 21
Vol. 63(1): 19 - 31, 2022
survival or overall survival compared with
grade 2 NETs 6. Unfortunately, most pa-
tients are diagnosed in late stage of NETs 7.
NETs symptoms vary depending on bio-
logical aggressiveness and the anatomical lo-
cation of the tumor 8. Vague and nonspecific
symptoms may cause considerable delay and
difficulty in diagnosis 9. The clinical presenta-
tion of NETs is generally related to the secre-
tion of hormones that may indicate carcinoid
syndrome or hormonal symptoms 10. Carcinoid
syndrome commonly cause diarrhea, flushing,
fatigue 9, abdominal pain and intermitted bow-
el obstruction 11. It is worth mentioning that
the number of bowel movements and flushing
episodes significantly affect the quality of life of
NETs patients 10. The intensity of these symp-
toms can vary widely, depending primarily on
the site of disease and grade of tumor. More
studies are necessary for clinicians to become
familiar with the natural history and patterns
of disease progression, which are characteristic
of NETs 7. Therefore, the precocious diagnosis
of tumor may increase survival and improve
NETs patient’s quality of life.
In Ecuador, the Cancer Fighting Soci-
ety (SOLCA) Quito Nucleus and National Tu-
mor Registry exists since 1984 (Minist Salud
Pública) and cares for approximately 31% of
the oncological cases of the country 12. In
Ecuador, the clinical management of NETs
is significantly lower, compared to that of
the United States and Europe and there are
few specialized centers managing a multidis-
ciplinary environment 13. Despite the high
prevalence and severity of NETs, this tumor
has not been previously studied in people
from Ecuador to the best of our knowledge.
Consequently, the aim of this research was
to investigate the presence of NETs patients
in the hospital database over fifteen years.
Based on the above, a logistic biplot is pro-
posed as an alternative to identify the most
frequent symptoms in patients with NET us-
ing binary variables (presence / absence)
with binomial distribution 14. This analysis
allows us to obtain a graphic representation
of the NETs types and the main associated
symptoms. In this sense, the approach that
provides a better interpretation to relate
the type of tumor with its symptoms, taking
into account the comparison with the clas-
sic classification / ordering techniques, is
provided by the biplot methods 15, 16, where a
simultaneous graph represents the columns
(variables) and the rows (individuals) of the
given data matrix.
Collected database
The study was done using the hospital
database of SOLCA Portoviejo, in the Prov-
ince of Manabí, Ecuador, analyzing patients
with NETs diagnosis between 2005 and 2020.
Statistical analysis
The main problem with our data is the
very limited number of patients and the high
number of variables (symptoms, types of tu-
mor, locations, etc…) that prevents from us-
ing standard methods as logistic regression.
An exploratory multivariate technique would
be more adequate to explore possible pat-
terns before trying to apply a more formal
model using a relevant subset of symptoms
obtained from it. This kind of techniques
have also the advantage of showing the in-
terrelations among all the variables.
For the exploratory analysis of our data,
we used a multivariate technique called
“logistic biplot” 14 that was specifically de-
signed to treat binary data, as well as more
traditional analyses. Although logistic bi-
plots have not been extensively used with
medical data, some authors 17 propose these
kind of multivariate techniques as a mean to
perform an exploratory analysis previous to
a more formal analysis. Other authors 18 also
propose the technique as an analysis of the
residuals of a model, to check for the good-
ness of fit or the violation of some previous
hypothesis about the data.
Because logistic biplots are less known,
we include here a brief description. A bip-
lot is a graphical representation of a data
22 Montes-Escobar et al.
Investigación Clínica 63(1): 2022
matrix, containing the measures subjects
on numerical variables 15, that jointly rep-
resents subjects and variables on the same
plot. We have patients with different NETs
and related symptoms (presence or absence)
organized in a binary data matrix (0 for pres-
ence, 1 for absence).
The adequate method for binary data is
the logistic biplot, originally proposed by Vi-
cente-Villardón et al 14 and later extended by
Demey et al 19 to binary matrices where the
number of variables is high compared to the
number of individuals. This extension was
applied to the investigation of the single nu-
cleotide polymorphisms related to different
racial groups of people with data from the
HAPMAP project 20. The method has been ap-
plied in different fields as sustainability 21,
dermatology 22 and lately it has also been ex-
tended to deal with nominal data 23.
Logistic biplots represent individuals as
points on a Euclidean map (scattergram) and
variables as directions (arrows) on the same
map. Patients with similar combinations of
symptoms tend to group together while dis-
tinct individuals tend to pull apart. The vec-
tors for the variables on the plot are the direc-
tions more correlated to the presence of the
symptom, so we can infer which symptoms are
responsible for the grouping of the patients.
To interpret the symptoms associated to the
grouping of patients we project the points onto
the direction of the vectors - the further (in the
direction of the arrow) the point is projected,
the higher is the probability of the symptom.
The origin of the vector is the point predicting
probability 0.5 and the arrow indicates the di-
rection of increasing probabilities.
Angles among vectors can help with the
identification of the relationships among the
symptoms: small acute angles mean strong
positive relations; plane angles (Formed by
two right angles 180°), negative relations;
and straight angles (formed by two perpen-
dicular lines 90°), are not related. The posi-
tion of the vectors can also help identifying
the main gradients (or latent traits) sum-
marizing the variation of the symptoms and
its relation to the different locations of the
cancer. It is called logistic biplot because
the relation of the symptoms and the traits
(dimensions) is logistic, it is like a Principal
Component Analysis (or biplot) for binary
data in which the relation to the components
is logistic rather than linear. When data are
binary, like those obtained in the analysis
of neuroendocrine tumors, Classical Linear
Biplots and Principal Components Analysis
(PCA) are not suitable because the response
along the dimensions is linear. This is the
same reason why linear regression is not ap-
propriate for binary or categorical data 14, 21.
The MULTBIPLOT 24 and MultBiplotR25
packages were used to perform the calcula-
tions and obtain the graphical representa-
tions. For this study, we first performed a
Principal Coordinates Analysis (Classical
Multidimensional Scaling), with the simple
matching coefficient, and then fitting sepa-
rated logistic regressions to represent the di-
rections on the Euclidean map 19. The inter-
pretation of the relevance of the symptoms
to classify the patients was evaluated by tra-
ditional indicators for logistic regressions as
Wald tests, pseudo R-squared coefficients or
percentages of accurate classification.
Population characteristics and NETs
A total of 94 adult patients (aged 19 to
95 years-old) were diagnosed with NETs be-
tween 2005 and 2020 and included in our
research. The most frequent primary loca-
tion was the lungs (19%), followed by stom-
ach (18%), rectum (8%) and skin (8%). Un-
known primary location represents 8% of the
tumors studied. The set symptoms present
in our patients with different types of NETs
are shown in Table 1.
Table 2 represent sociodemographic
characteristic, mortality, primary site and
histologic grade of NETs patients. The mean
age in this study was 59 years-old and the
prevalence was higher in men (57% versus
Clinical related factors to neuroendocrine tumors in Ecuadorian patients 23
Vol. 63(1): 19 - 31, 2022
43%). The most prevalent stage in NETs pa-
tients was G3 (70%) while G1 and G2 repre-
sent 30% of the patients.
Logistic Biplot in types of NETs and our
symptoms in patients of SOLCA
Fig. 1 shows the result of applying the lo-
gistic biplot to the binary matrix of 94 patients
and 37 symptoms. Each patient (points) has
been labeled using the primary location of its
tumor and each symptom (arrow) using the
name of the symptom. Only the symptoms
significantly related to the patient’s configu-
ration were retained on the plot (See Table
3). We observe that most patients having
lungs as the primary location are on the top
of the plot, while tumors related to the diges-
tive system (rectum, stomach, right colon,
ileum and pancreas) are on the bottom part
and well separated from the “lung” group, so
we can conclude that the analysis has some
power to classify the tumors.
When projecting the patients’ points
onto the directions for the symptoms, we
obtain the expected probability that the
patient has the symptom. In order to pre-
dict the expected presence when the ex-
pected probability is higher than 0.5. For
each arrow, we only represent the point
predicting 0.5 and the direction of increas-
ing probabilities. Thus, we can correctly
predict 95.75% of the presences and ab-
sences. All the individual symptoms have
percentages of correct predictions over
94%. The associated R-squared values are
all over 70% and the information of each
variable can be accurately interpreted. We
can conclude that the representation is a
good picture of our data matrix and can be
used for exploration.
To search for the symptoms that char-
acterize each group, we can look at the di-
Table 1
Represent total symptoms found in NETs
patients among eleven years in SOLCA, Manabí.
Primary location Patient Porcentage
LUNG 18 19%
STOMACH 17 18%
SKIN 8 9%
LIVER 4 4%
COLON 2 2%
ILEUM 1 1%
TOTAL 94 100%
Table 2
Represent sociodemographic characteristic,
mortality, primary site and histologic grade
of NETs patients.
Variable Parameters No. Patients
<40 11 12%
40-54 22 23%
55-70 30 32%
> 70 31 33%
Sex Man 54 57%
Woman 40 43%
Mortality Alive 38 40%
Dead 56 60%
Type 1 y 2 28 30%
Type 3 66 70%
24 Montes-Escobar et al.
Investigación Clínica 63(1): 2022
rection they point. For example, Dyspnea
and Cough are present in patients for which
the primary location is lungs, while Diar-
rhea, Stomach pains, Distended abdomen,
Hypertensive Crisis and Intestinal obstruc-
tion point to the direction of the tumors
related to the digestive system. Both sets
of symptoms point in opposite direction
meaning that they are inversely related,
that is, the symptoms present in one group
are absent in the other. Together, they de-
fine the gradient that separate both types
of tumors. Dyspnea and Cough point to
the same direction, meaning that they are
highly positively correlated and appear to-
gether in some patients. Weight Loss has a
very good fit but is not clearly character-
ized in any of the groups. The same is true
to Dyspepsia and Constipation. The three
are closely related to the first dimension,
but they are less important to separate be-
tween groups of tumors.
Fig. 1. Biplot representation of the relations among the type of disease and the symptom that determine the
groups structure in the simulation. Small acute angles mean strong positive relations; plane angles
(Formed by two right angles 180º), negative relations; and straight angles (Formed by two perpen-
dicular lines 90º), are not related. Sign (+) represents each of the individuals. Segments (lines) re-
present each of the variables (symptoms). Point represents the value of 0.05. Direction of the vector
predicts the increase in the probability. The colors: red, brown, green, purple represents group the
variables with respect to the individuals.
Clinical related factors to neuroendocrine tumors in Ecuadorian patients 25
Vol. 63(1): 19 - 31, 2022
Neuroendocrine cells have endocrine
and neural properties and are widely distrib-
uted in the body 3. Many organs contain this
cell phenotype and may be affected by NETs.
The tumor has a particular morphofunctional
characteristic, such as the hormones produc-
tion, and the immunohistochemical features
staining pattern with chromogranin, synapto-
physin, and neuron-specific enolase 26. More-
over, the World Health Organization (WHO)
advices characterizing NETs by proliferation
fraction as measured by either mitotic count
or (more easily) by the Ki67-positive percent-
age (Ki67 index) 6. It is worth mentioning
that, epidemiological studies indicate that
the most frequent source of metastasis in
NETs are the small intestine, lungs and co-
lon 27. In the present retrospective databased
study, we found lungs and stomach as more
frequent NETs followed by rectum, and skin.
Here, the diagnosis was through synapto-
physin, chromagranin or Ki67 by biopsy, and
most patients had several pathological diag-
nostics. Despite the malignancies of the tu-
mor, to the best of our knowledge, this is the
first evidence about NETs in patients from the
Ecuadorian coast.
An approach that facilitates the genetic
interpretation, compared to the classic tech-
niques of classification/ordination, is pro-
vided by the Biplot methods 28, 15, 16, that is,
a simultaneous graphical representation of
the rows (individuals) and the columns (vari-
ables) of a given data matrix. The main uses
are exploratory, although it has also been
used as a graphical representation for more
formal models 29. The biplot can be fitted
by performing alternating regressions and
interpolations 30-32. However, when data are
binary, like those obtained in the analysis
of molecular information, Classical Linear
Biplots and Principal Components Analysis
(PCA) are not suitable because the response
along the dimensions is linear. This is the
same reason why linear regression is not ap-
propriate for binary or categorical data.
There is a significant delay between
the symptoms onset and diagnosis of NETs
and, consequently, most patients are diag-
nosed at a late stage of the disease 7. Our
results demonstrated that most patients
were diagnosed in histologic grade 3, met-
astatic or advanced NETs and do not sur-
vive. Previous works consider NETs as a low-
grade, usually non-functioning, malignant
cancer characterized by long survival of pa-
Table 3
Goodness of adjunct for the main symptoms in NETs patients.
Primary symptom Deviance p-value R2 % Correct
Vomiting 5.326 2,22045E-14 0,9390 100
Dyspepsia 6.467 0 0,8622 91.489
Flushing 4.791 1,78129E-07 0,8474 100
Distended Abdomen 5.922 1,69207E-11 0,8167 97.872
Diarrhea 4.848 0 0,8136 94.681
Weight Loss 6.146 0 0,8129 94.681
Cough 5.591 8,95759E-10 0,7999 97.872
Intestinal Obstruction 4.953 1,40092E-09 0,7847 94.681
Dyspnoea 5.574 6,51029E-11 0,7410 94.681
Acute Abdomen 4.306 1,96949E-07 0,7350 98.936
Constipation 5.730 1,26565E-14 0,7266 92.553
26 Montes-Escobar et al.
Investigación Clínica 63(1): 2022
tients with prognosis depending on grade
and stage 33. In fact, WHO in 2017 classified
NETs with a Ki67 >20% as either grade 3
NET (well-differentiated) or as grade 3 NEC
(poorly differentiated) on the basis of mor-
phological characteristics as necrosis and
differentiation 34. NETs account for about
0.5% of all currently diagnosed malignan-
cies 35. Given this scenario, our work pres-
ents most NETs cases registered in the ad-
vanced stage, which could explain, at least
in part, the death rates from NETs found in
the present data-based study. Furthermore,
the retrospective characteristic of the study
with a duration of fifteen years should be
considered. Indeed, NETs origin and rank-
ing grade can define patient survival if pre-
viously reported 103 months from disease
originating in the small intestine and only
14 months for cancers originating in the
colon 36. A severity nation-wide multi-center
study in Korea reported a high G1 percent-
age of 92.3% 37. However, research in Ken-
tucky found a population with 67% in G3 38.
Reinforcing this notion, our study reports
most patients in G3 - 70%. Nevertheless, of
special importance is that lower grade NETs
do not indicate a better outcome in terms
of survival 38.
Given this background, retrospective
studies in different populations are impor-
tant as an alert for the early diagnosis of
disease. In the present study, we decided
to investigate NETs more frequently and
its associated symptoms. Lungs were the
most frequently NETs reported in our study
and it was associated with the symptoms
of cough and dyspnea. In line with our re-
sults, previous research as a nation-wide
study from the Netherlands and SEER data-
base reported pulmonary NETs as being the
most prevalent 36. The NETs are often mis-
diagnosed before the cause of the patient’s
symptoms is finally diagnosed and managed
appropriately 9.
Our results demonstrated that after lung
and stomach, the most incidence of NETs was
in the rectum and skin. We found a signifi-
cantly positive relationship between the most
frequent symptoms and the NETs found dur-
ing or study. Therefore, symptoms such as
diarrhea, constipation, dyspepsia, and intes-
tinal obstruction in addition to weight loss
were more prevalent. We should note that our
research found that NETs in the stomach and
rectum were associated with syndromes such
as carcinoid syndrome. It has been previously
described that carcinoid syndrome occurs
in 8% to 35% of NETs patients 39. This event
appears when vasoactive hormones secreted
by metastases (i.e serotonin, histamine, or
tachykinins), are no longer metabolized and
inactivated by the liver and reach the general
circulation 40. The classic symptom of episod-
ic diarrhea was previously described by more
than 70% of patients as consequence of car-
cinoid syndrome 41. This data point is similar
with what we found in our study. Additionally,
it is important to note that the clinical pres-
ence of diarrhea and/or abdominal pain can
often lead to misdiagnosis, confusing carci-
noid syndrome as small bowel obstructions
or irritable bowel disease 42. Unfortunately,
there is a delay between the onset of symp-
toms and the diagnosis of carcinoid tumor;
the median time reported range from 2 to 20
years 43. It is well established that early diag-
nosis of any type of cancer can improve the
quality of life and survival and patients with
carcinoid syndrome have a significantly worse
quality of life than patients with only NETs 44.
Supporting this fact, our findings underscore
the need to further identify all symptoms as-
sociated with NETs in an effort to aid physi-
cians to speed up the diagnosis.
Unsurprisingly, the lungs are the most
frequently found NET during the fifteen years
studied. Importantly, we demonstrated that
skin was the fourth most frequently NETs
discovered. Based on previous work, NETs in
the skin or soft tissue delay late manifesta-
tions of disease when represent metastases
from other organs 45. However, notably, ac-
cording to the World Health Organization
Clinical related factors to neuroendocrine tumors in Ecuadorian patients 27
Vol. 63(1): 19 - 31, 2022
books on skin and soft tissue tumors stated
that primary cutaneous and soft tissue NETs
are extremely rare, except for Merkel cell car-
cinoma of the skin 46. Therefore, only a few
case studies of soft tissue NETs are available
in the literature 47. Our findings show that
8% of all cases in the fifteen years studied
were skin NET, mostly in elderly men. Sup-
porting this finding, previous studies showed
that Merkel cell carcinoma are most com-
monly found in elderly and in sun-exposed
skin 48, 49, patients typically have fair-skin and
the median age of diagnosis of 65 years 49. It
is interesting to note that the most common
symptom reported in our work is skin dam-
age with unknown or asymptomatic causes.
This evidence is corroborated by other stud-
ies. Despite the diversity of skin manifesta-
tions, the tumor is typically painless and de-
velops as a small, less than 2 centimeters,
violaceous papule, plaque, cyst, or infiltra-
tive nodule 50. The tumor has a multifacto-
rial cause and the exact mechanism by which
it acts in the organism it is not fully elucidat-
ed, but Merkel cell polyomavirus is thought
to be a major contributor to the pathogen-
esis of this malignancy 51.
Altogether, the results provided suggest
that the most frequent clinical symptoms
(cough and intestinal obstruction) were posi-
tively related to the type of NETs. When look-
ing at the prevalence of NETs, the lungs were
the most frequent site, which reinforces the
hypothesis of the vulnerability of this organ.
Further research is needed and should focus on
identifying symptoms of NETs with the objec-
tive of early diagnosis. Furthermore, the preva-
lence of NETs specific in each population must
be underscored in future research.
The logistic biplot technique allows the
generation of relevant information based on
clinical antecedents, as it was for this study
on the presence or absence of the disease,
taking into account patients with different
neuroendocrine tumors.
This study was supported by the De-
partment of Mathematics and Statistics. In-
stitute of Basic Sciences and Research Insti-
tute of the Technical University of Manabí.
The authors would like to thank the SOLCA
Portoviejo for support and facilitate data and
Robin Siteneski for English corrections.
Declaration of competing interest
The authors declare that no financial
support or compensation has been received
from any individual or corporate entity over
the past three years for research or profes-
sional service and there is no personal finan-
cial holding that could be perceived as con-
stituting a potential conflict of interest.
Authors’ ORCID numbers
Karime Montes Escobar (KME)
José Luis Vicente Villardon (JLVV)
Daniel Fabricio Alarcón Cano
(DFAC) 0000-0002-9680-1050
Aline Sitenesky (AS)
Authors’ contribution
Interpretation of data, analysis and
writing the manuscript (KME)
Supervision and writing (JLVV)
Data collected (DFAC)
Writing the manuscript and prepared
the final draft (AS).
All authors have read and approved
the final version of submitted manu-
28 Montes-Escobar et al.
Investigación Clínica 63(1): 2022
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