Invest Clin 63(1): 19 - 31, 2022 https://doi.org/10.54817/IC.v63n1a02

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: aline.siteneski@gmail.com

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

biplot.

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

INTRODUCTION

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.

MATERIAL AND METHODS

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.

RESULTS

Population characteristics and NETs

symptoms

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%

RECTAL 8 9%

SKIN 8 9%

UNKNOWN PRIMARY 8 9%

PANCREAS 5 5%

GANGLIA 4 4%

LIVER 4 4%

DUODENUM 3 3%

APPENDIX 2 2%

CECAL APPENDIX 2 2%

CERVIX 2 2%

COLON 2 2%

RETROPERITONEUM 2 2%

RIGHT COLON 2 2%

COLEDOCO 1 1%

ENDOMETRIC 1 1%

ILEUM 1 1%

LEFT COLON 1 1%

SOFT TISSUES 1 1%

UTERINE NECK 1 1%

VESICAL TUMOR 1 1%

TOTAL 94 100%

Table 2

Represent sociodemographic characteristic,

mortality, primary site and histologic grade

of NETs patients.

Variable Parameters No. Patients

(n)

Porcentage

Age

<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%

Histologic

grade

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

DISCUSSION

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.

ACKNOWLEDGMENTS AND FUNDING

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)

0000-0002-9555-0392

• José Luis Vicente Villardon (JLVV)

0000-0003-1416-6813

• Daniel Fabricio Alarcón Cano

(DFAC) 0000-0002-9680-1050

• Aline Sitenesky (AS)

0000-0001-6692-7253

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-

script.

28 Montes-Escobar et al.

Investigación Clínica 63(1): 2022

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