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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Med.</journal-id>
<journal-title>Frontiers in Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Med.</abbrev-journal-title>
<issn pub-type="epub">2296-858X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fmed.2024.1482788</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Medicine</subject>
<subj-group>
<subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Machine-learning models to predict myopia in children and adolescents</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes" equal-contrib="yes">
<name><surname>Mu</surname> <given-names>Jingfeng</given-names></name>
<xref ref-type="corresp" rid="c001"><sup>&#x002A;</sup></xref>
<xref ref-type="author-notes" rid="fn0001"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2561580/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name><surname>Zhong</surname> <given-names>Haoxi</given-names></name>
<xref ref-type="author-notes" rid="fn0001"><sup>&#x2020;</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Jiang</surname> <given-names>Mingjie</given-names></name>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
</contrib>
</contrib-group>
<aff><institution>Shenzhen Eye Hospital</institution>, <addr-line>Shenzhen</addr-line>, <country>China</country></aff>
<author-notes>
<fn fn-type="edited-by" id="fn0002">
<p>Edited by: Xinyu Liu, Singapore Eye Research Institute (SERI), Singapore</p>
</fn>
<fn fn-type="edited-by" id="fn0003">
<p>Reviewed by: Zhengcun Pei, Tianjin University, China</p>
<p>Bhim Bahadur Rai, Australian National University, Australia</p>
</fn>
<corresp id="c001">&#x002A;Correspondence: Jingfeng Mu, <email>1014120300@qq.com</email></corresp>
<fn fn-type="equal" id="fn0001">
<p><sup>&#x2020;</sup>These authors have contributed equally to this work</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>19</day>
<month>11</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>11</volume>
<elocation-id>1482788</elocation-id>
<history>
<date date-type="received">
<day>04</day>
<month>09</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>07</day>
<month>11</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x00A9; 2024 Mu, Zhong and Jiang.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Mu, Zhong and Jiang</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec id="sec1">
<title>Objectives</title>
<p>To explore machine-learning applications in myopia prediction and analyze the influencing factors of myopia.</p>
</sec>
<sec id="sec2">
<title>Methods</title>
<p>Stratified cluster random sampling was used to select elementary school students in Shenzhen, China for inclusion in this case-control study. Myopia screening, ocular biological parameter measurements, and questionnaires were conducted. Random forest (RF), decision tree (DT), extreme gradient boosting trees (XGBoost), support vector machine (SVM), and logistic regression (LR) algorithms were used to construct five myopia prediction models using R software (version 4.3.0). These myopia prediction models were used to investigate the relationship between ocular biological parameters, environmental factors, behavioral factors, genetic factors, and myopia.</p>
</sec>
<sec id="sec3">
<title>Results</title>
<p>This study included 2,947 elementary school students, with a myopia prevalence rate of 47.2%. All five prediction models had an area under the receiver operating characteristic curve (AUC) above 0.75, with prediction accuracy and precision exceeding 0.70. The AUCs in the testing set were 0.846, 0.837, 0.833, and 0.815 for SVM, LR, RF, and XGBoost, respectively, indicating their superior predictive performance to that of DT (0.791). In the RF model, the five most important variables were axial length, age, sex, maternal myopia, and feeding pattern. LR identified axial length was the most significant risk factor for myopia [odds ratio (OR) =8.203], followed by sex (OR&#x2009;=&#x2009;2.349), maternal myopia (OR&#x2009;=&#x2009;1.437), Reading and writing posture (OR&#x2009;=&#x2009;1.270), infant feeding pattern (OR&#x2009;=&#x2009;1.207), and age (OR&#x2009;=&#x2009;1.168); corneal radius (OR&#x2009;=&#x2009;0.034) and anterior chamber depth (OR&#x2009;=&#x2009;0.516) served as protective factors.</p>
</sec>
<sec id="sec4">
<title>Conclusion</title>
<p>Myopia prediction models based on machine learning demonstrated favorable predictive performance and accurately identified myopia risk factors, and may therefore aid in the implementation of myopia prevention and control measures among high-risk individuals.</p>
</sec>
</abstract>
<kwd-group>
<kwd>machine learning</kwd>
<kwd>myopia</kwd>
<kwd>influencing factors</kwd>
<kwd>children and adolescents</kwd>
<kwd>predictive model</kwd>
</kwd-group>
<contract-num rid="cn1">JCYJ20230807114608016</contract-num>
<contract-sponsor id="cn1">Shenzhen Science and Technology Program</contract-sponsor>
<counts>
<fig-count count="6"/>
<table-count count="2"/>
<equation-count count="0"/>
<ref-count count="48"/>
<page-count count="10"/>
<word-count count="5542"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Ophthalmology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="sec5">
<title>Introduction</title>
<p>Myopia is a global public health concern (<xref ref-type="bibr" rid="ref1">1</xref>) that affected 1.4 billion individuals worldwide in 2020 with a prevalence of 22.9%. It has been projected that this number will increase to 4.7 billion individuals by 2050, resulting in a prevalence of 49.8% (<xref ref-type="bibr" rid="ref2">2</xref>). In 2020, 52.7% of children and adolescents in China were myopic (<xref ref-type="bibr" rid="ref3">3</xref>), which contributed to the position of China as the country with the highest number of individuals with myopia (<xref ref-type="bibr" rid="ref4">4</xref>). Myopia often develops during childhood and adolescence, and myopia development during this period is more likely to progress to high myopia, increasing the risk of various eye diseases such as glaucoma, cataracts, macular degeneration, and retinal detachment. High or pathological myopia significantly increases the risk of blindness (<xref ref-type="bibr" rid="ref5">5</xref>) and is a major cause of blindness (<xref ref-type="bibr" rid="ref6">6</xref>). Myopia imposes an economic burden on society (<xref ref-type="bibr" rid="ref7">7</xref>). In Singapore, an average of $148 is spent on myopia-related costs per adolescent with myopia per year (<xref ref-type="bibr" rid="ref8">8</xref>). Globally, uncorrected refractive errors result in an estimated annual economic loss of approximately $202 billion (<xref ref-type="bibr" rid="ref9">9</xref>).</p>
<p>Currently, the etiology of myopia remains unclear, although its development in children and adolescents is thought to be influenced by a combination of environmental, behavioral, and genetic factors (<xref ref-type="bibr" rid="ref10">10</xref>). Myopia has been associated with sex (<xref ref-type="bibr" rid="ref10">10</xref>), age (<xref ref-type="bibr" rid="ref10">10</xref>), near work (<xref ref-type="bibr" rid="ref11">11</xref>, <xref ref-type="bibr" rid="ref12">12</xref>), time spent outdoors (<xref ref-type="bibr" rid="ref10">10</xref>), duration of electronic device use (<xref ref-type="bibr" rid="ref10">10</xref>), sleep (<xref ref-type="bibr" rid="ref13">13</xref>), and parental myopia (<xref ref-type="bibr" rid="ref14">14</xref>). Exploring influencing factors of myopia occurrence and development and conducting myopia risk assessments are of significant importance for improving the ocular health of children and adolescents. Owing to potential interactions among various influencing factors, such as the co-occurrence of increased screen time, long periods of near work, and reduced time spent outdoors, conventional statistical methods may fail to identify covariance and potential confounding factors (<xref ref-type="bibr" rid="ref15">15</xref>). Therefore, novel analytical methods are required to mitigate the influence of confounding factors, identify covariates, and measure the magnitude and significance of interactions between variables.</p>
<p>Continuous advancements in computer technology have increased the use of artificial intelligence (AI) in many fields of medicine, including ophthalmology (<xref ref-type="bibr" rid="ref16">16</xref>). The application of AI in the study of ophthalmic diseases has evolved from its initial focus on diabetic retinopathy (<xref ref-type="bibr" rid="ref17">17</xref>), age-related macular degeneration (<xref ref-type="bibr" rid="ref18">18</xref>), and glaucoma (<xref ref-type="bibr" rid="ref19">19</xref>) to encompass anterior segment disorders such as refractive errors (<xref ref-type="bibr" rid="ref20">20</xref>). Machine learning, a core component of AI, is increasingly used in the diagnosis, treatment, and prognostic assessment of various diseases (<xref ref-type="bibr" rid="ref21">21</xref>) and has recently been applied to myopia research, including in the prediction of axial length and identification of influencing factors (<xref ref-type="bibr" rid="ref21">21</xref>&#x2013;<xref ref-type="bibr" rid="ref25">25</xref>). However, the use of machine learning for the prediction of myopia risk remains relatively rare. Previous myopia prediction studies based on machine learning have often failed to comprehensively include feature variables and targeted indicators (<xref ref-type="bibr" rid="ref26">26</xref>). This study therefore constructed myopia prediction models using multiple indicators, including behavioral habits, dietary habits, genetic factors, and ocular biological parameters, and five machine-learning algorithms: random forest (RF), decision tree (DT), extreme gradient boosting trees (XGBoost), support vector machine (SVM), and logistic regression (LR). The aims of the study were to explore machine-learning applications in myopia prediction, analyze the factors influencing myopia, and provide scientific evidence for targeted myopia prevention, control measures, and policy recommendations.</p>
</sec>
<sec sec-type="methods" id="sec6">
<title>Methods</title>
<sec id="sec7">
<title>Sample size</title>
<p>Sample size was estimated in accordance with the methodology outlined by Riley et al. (<xref ref-type="bibr" rid="ref27">27</xref>) using the pmsampsize() function in R software (The R Foundation for Statistical Computing, Vienna, Austria). This calculation determined that a minimum of 2,060 study participants were required, with the non-response rate set at 20%.</p>
</sec>
<sec id="sec8">
<title>Study participants</title>
<p>A stratified cluster sampling method was used to select the study population of 2,947 primary school students (744, 528, 527, 360, 459, and 329 in grades 1, 2, 3, 4, 5, and 6, respectively) from Shenzhen in June 2022. The study was approved by the Ethics Committee of Shenzhen Eye Hospital (Approval No. 20201230-06), and informed consent was obtained from the legal guardians of all the participants.</p>
<p>The inclusion criteria were as follows: (1) current enrollment in a primary school in Shenzhen, (2) ability to cooperate with ophthalmic examinations, and (3) guardians able to complete questionnaires. The exclusion criteria were as follows: (1) presence of organic eye diseases, and (2) inability to complete ophthalmic examinations.</p>
</sec>
<sec id="sec9">
<title>Data collection</title>
<sec id="sec10">
<title>Myopia screening</title>
<p>Myopia screening was performed using visual acuity tests and dioptric detection, and conducted by ophthalmologists following the Chinese Health Standard (WS/T 663-2020) (<xref ref-type="bibr" rid="ref28">28</xref>). Visual acuity was assessed using visual acuity charts, and non-cycloplegic refraction was performed using an autorefractometer. Autorefraction was performed three times per eye, and the average value was calculated to obtain a reliable refractive error reading for each participant.</p>
</sec>
<sec id="sec11">
<title>Ocular biometric measurements</title>
<p>The ocular biometric parameters of the study participants were measured using an optical biometer. The measured parameters included axial length, central corneal thickness, corneal radius, anterior chamber depth, and lens thickness.</p>
</sec>
<sec id="sec12">
<title>Questionnaire</title>
<p>A questionnaire was developed to include the following content: (1) sociodemographic characteristics, including sex, age, height, and weight; (2) parental myopia status; (3) dietary habits, including the frequency of consumption of sugary foods, sugary beverages, fried foods, vegetables, and fruits; and (4) behavioral factors, including reading and writing posture, duration of continuous reading and writing, sleep duration, and time spent outdoors. Teachers distributed the questionnaires to the guardians of the study participants, who completed them online.</p>
<p>The questionnaire included items assessing adherence to the traditional Chinese guideline known as &#x201C;yi quan, yi chi, yi cun,&#x201D; which translates to &#x201C;one fist, one foot, one inch.&#x201D; This principle relates to specific distances that should be maintained during reading and writing to promote proper posture and reduce the risk of myopia among schoolchildren. One fist: a distance of one fist (approximately 10&#x2009;cm) is advised between the chest of a student and the edge of their desk. One foot: a distance of one foot (approximately 33&#x2009;cm) should be maintained between the eyes of the student and their reading material. One inch: pens or pencils should be held at a distance of one inch (approximately 3.3&#x2009;cm) from the tip.</p>
</sec>
<sec id="sec13">
<title>Diagnostic criteria for myopia</title>
<p>Participants with an uncorrected visual acuity &#x003C;5.0 and spherical equivalent refraction &#x003C; &#x2212;0.50 diopter and Participants those wore orthokeratology lenses were defined as myopic (<xref ref-type="bibr" rid="ref28">28</xref>). Myopia was classified based on the spherical equivalent refraction of the right eye. Mild myopia is defined as &#x2212;3.00 diopter &#x2264;spherical equivalent refraction &#x003C;&#x2212;0.50 diopter, moderate myopia is defined as &#x2212;6.00 diopter &#x2264;spherical equivalent refraction &#x003C;&#x2212;3.00 diopter, and high myopia is defined as spherical equivalent refraction &#x003C;&#x2212;6.00 diopter.</p>
</sec>
</sec>
<sec id="sec14">
<title>Construction and evaluation of prediction models</title>
<sec id="sec15">
<title>Feature variables</title>
<p>Multivariate logistic regression was used to identify the statistically significant influencing factors of myopia, namely feature variables.</p>
</sec>
<sec id="sec16">
<title>Data splitting</title>
<p>Stratified random sampling (according to myopia status) was used to classify the 2,947 study participants into training (2,064 students) and testing sets (883 students) at a ratio of 7:3.</p>
</sec>
<sec id="sec17">
<title>Data modeling</title>
<p>Feature variables were incorporated into the machine-learning model. The five machine-learning algorithms RF, DT, XGBoost, SVM, and LR were used to construct myopia prediction models from the training data set. The machine-learning modeling process is illustrated in <xref ref-type="fig" rid="fig1">Figure 1</xref>.</p>
<fig position="float" id="fig1">
<label>Figure 1</label>
<caption>
<p>Flow chart of the study.</p>
</caption>
<graphic xlink:href="fmed-11-1482788-g001.tif"/>
</fig>
</sec>
<sec id="sec18">
<title>Model evaluation</title>
<p>The testing set was used to determine model performance metrics such as accuracy, precision, recall, and <italic>F</italic><sub>1</sub>-score. The receiver operating characteristic (ROC) curves were plotted and used to calculate the area under the curve (AUC) and 95% confidence interval. The DeLong test (<xref ref-type="bibr" rid="ref29">29</xref>) was conducted to assess and compare the performance of the models.</p>
</sec>
<sec id="sec19">
<title>Analysis of feature variable importance</title>
<p>The importance of independent variables reflects their relationship with the dependent variable and explains their contribution to the predictive performance of the model. Mean decrease accuracy and odds ratios (ORs) were used to assess the importance of feature variables to the prediction models. The OR represents the odds of an event in group 1 compared to those in group 2, where odds means the event over non-event.</p>
</sec>
</sec>
<sec id="sec20">
<title>Statistical analysis</title>
<p>Machine-learning prediction models were constructed, and statistical analyses were performed using R software (version 4.3.0). <inline-formula>
<mml:math id="M1">
<mml:mover accent="true">
<mml:mi>x</mml:mi>
<mml:mo stretchy="true">&#x00AF;</mml:mo>
</mml:mover>
<mml:mo>&#x00B1;</mml:mo>
<mml:mi>s</mml:mi>
</mml:math>
</inline-formula> was used to describe for normally distributed continuous data; intergroup comparisons were performed using independent samples <italic>t</italic>-tests. Non-normally distributed continuous data are expressed as P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>), and intergroup comparisons were conducted using the Wilcoxon rank-sum test. Count data are presented as frequencies, and intergroup comparisons were performed using the chi-squared test. The significance level (<italic>&#x03B1;</italic>) for all tests was set at 0.05, with <italic>p</italic>&#x2009;&#x003C;&#x2009;0.05 indicating statistical significance.</p>
</sec>
</sec>
<sec sec-type="results" id="sec21">
<title>Results</title>
<sec id="sec22">
<title>Basic information</title>
<p>The study included 2,947 primary school students (1,617 boys and 1,330 girls). The minimum age of the participants was 6&#x2009;years, and their maximum age was 12&#x2009;years, with a 50th percentile of 9&#x2009;years. The prevalence of myopia among the participants was 47.2%. The prevalence of myopia increased with age, and was 24.1, 33.3, 52.6, 55.6, 67.8, and 75.7% in grades 1, 2, 3, 4, 5, and 6, respectively (<italic>&#x03C7;</italic><sup>2</sup> =&#x2009;436.475, <italic>p</italic> &#x003C;&#x2009;0.001). The prevalence of myopia was significantly higher in girls (50.5%) than in boys (44.5%) (<italic>&#x03C7;</italic><sup>2</sup> =&#x2009;10.539, <italic>p</italic> &#x003C;&#x2009;0.001). Myopia became more severe with age, with the prevalence of moderate myopia increasing significantly from 0.7% at the age of 6&#x2009;years to 26.3% at the age of 12&#x2009;years (<xref ref-type="fig" rid="fig2">Figure 2</xref>).</p>
<fig position="float" id="fig2">
<label>Figure 2</label>
<caption>
<p>Prevalence of myopia among participants.</p>
</caption>
<graphic xlink:href="fmed-11-1482788-g002.tif"/>
</fig>
</sec>
<sec id="sec23">
<title>Feature variables</title>
<p>Logistic regression analysis identified eight statistically significant influencing factors of myopia: age (OR&#x2009;=&#x2009;1.168), sex (OR&#x2009;=&#x2009;2.349), maternal myopia (OR&#x2009;=&#x2009;1.437), infant feeding pattern (OR&#x2009;=&#x2009;1.207), reading and writing posture (OR&#x2009;=&#x2009;1.270), axial length (OR&#x2009;=&#x2009;8.203), anterior chamber depth (OR&#x2009;=&#x2009;0.516), and corneal radius (OR&#x2009;=&#x2009;0.034) (<xref ref-type="fig" rid="fig3">Figure 3</xref>).</p>
<fig position="float" id="fig3">
<label>Figure 3</label>
<caption>
<p>Odds ratios of feature variables in the myopia prediction model based on logistic regression.</p>
</caption>
<graphic xlink:href="fmed-11-1482788-g003.tif"/>
</fig>
</sec>
<sec id="sec24">
<title>Comparison of training and testing sets</title>
<p>The quantitative data were not normally distributed and are presented as P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>) (<xref ref-type="fig" rid="fig4">Figure 4</xref>). The prevalence of myopia and feature variables did not differ significantly between the training and testing sets (<italic>p</italic>&#x2009;&#x003C;&#x2009;0.05), indicating a balanced allocation between the two datasets (<xref ref-type="table" rid="tab1">Table 1</xref>).</p>
<fig position="float" id="fig4">
<label>Figure 4</label>
<caption>
<p>Distribution of quantitative data in the study.</p>
</caption>
<graphic xlink:href="fmed-11-1482788-g004.tif"/>
</fig>
<table-wrap position="float" id="tab1">
<label>Table 1</label>
<caption>
<p>Comparison of myopia and feature variables between training and testing sets.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top" char="&#x00D7;">Variables</th>
<th align="center" valign="top">Training set</th>
<th align="center" valign="top">Testing set</th>
<th align="center" valign="top">Statistical value</th>
<th align="center" valign="top"><italic>p</italic></th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="middle" colspan="5">Myopia (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="middle">No</td>
<td align="center" valign="middle">1,089</td>
<td align="center" valign="middle">466</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.000</td>
<td align="center" valign="middle" rowspan="2">0.995</td>
</tr>
<tr>
<td align="left" valign="middle">Yes</td>
<td align="center" valign="middle">975</td>
<td align="center" valign="middle">417</td>
</tr>
<tr>
<td align="left" valign="middle">SE (D)</td>
<td align="center" valign="middle">&#x2212;0.625 (&#x2212;1.625, 0)</td>
<td align="center" valign="middle">&#x2212;0.625 (&#x2212;1.75, 0)</td>
<td align="center" valign="middle"><italic>z</italic> =&#x2009;1.099</td>
<td align="center" valign="middle">0.272</td>
</tr>
<tr>
<td align="left" valign="middle">Age [P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>), years]</td>
<td align="center" valign="middle">9 (7, 10)</td>
<td align="center" valign="middle">9 (7, 11)</td>
<td align="center" valign="middle"><italic>z</italic> =&#x2009;&#x2212;0.814</td>
<td align="center" valign="middle">0.416</td>
</tr>
<tr>
<td align="left" valign="top">Body mass index [P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>), kg/m<sup>2</sup>]</td>
<td align="center" valign="middle">16.5 (14.9, 19.2)</td>
<td align="center" valign="middle">16.6 (14.8, 19.2)</td>
<td align="center" valign="middle"><italic>z</italic> =&#x2009;&#x2212;0.677</td>
<td align="center" valign="middle">0.499</td>
</tr>
<tr>
<td align="left" valign="top">Axial length [P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>), mm]</td>
<td align="center" valign="middle">23.58 (22.95, 24.28)</td>
<td align="center" valign="middle">23.61 (23.01, 24.29)</td>
<td align="center" valign="middle"><italic>z</italic> =&#x2009;&#x2212;1.240</td>
<td align="center" valign="middle">0.215</td>
</tr>
<tr>
<td align="left" valign="top">Central corneal thickness [P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>), &#x03BC;m]</td>
<td align="center" valign="middle">549.00 (527.00, 572.00)</td>
<td align="center" valign="middle">552.00 (531.00, 574.00)</td>
<td align="center" valign="middle"><italic>z</italic> =&#x2009;&#x2212;1.988</td>
<td align="center" valign="middle">0.050</td>
</tr>
<tr>
<td align="left" valign="top">Anterior chamber depth [P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>), mm]</td>
<td align="center" valign="middle">3.14 (2.96, 3.31)</td>
<td align="center" valign="middle">3.14 (2.95, 3.33)</td>
<td align="center" valign="middle"><italic>z</italic> =&#x2009;0.109</td>
<td align="center" valign="middle">0.913</td>
</tr>
<tr>
<td align="left" valign="top">Lens thickness [P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>), mm]</td>
<td align="center" valign="middle">3.50 (3.37, 3.63)</td>
<td align="center" valign="middle">3.49 (3.36, 3.63)</td>
<td align="center" valign="middle"><italic>z</italic> =&#x2009;0.214</td>
<td align="center" valign="middle">0.830</td>
</tr>
<tr>
<td align="left" valign="top">Corneal radius [P<sub>50</sub> (P<sub>25</sub>, P<sub>75</sub>), mm]</td>
<td align="center" valign="middle">7.85 (7.66, 8.06)</td>
<td align="center" valign="middle">7.87 (7.66, 8.07)</td>
<td align="center" valign="middle"><italic>z</italic> = <italic>&#x2212;</italic>0.333</td>
<td align="center" valign="middle">0.739</td>
</tr>
<tr>
<td align="left" valign="top" colspan="5">Sex (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">Boy</td>
<td align="center" valign="middle">1,122</td>
<td align="center" valign="middle">495</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.720</td>
<td align="center" valign="middle" rowspan="2">0.396</td>
</tr>
<tr>
<td align="left" valign="top">Girl</td>
<td align="center" valign="middle">942</td>
<td align="center" valign="middle">388</td>
</tr>
<tr>
<td align="left" valign="top" colspan="5">Paternal myopia (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">No</td>
<td align="center" valign="middle">1,374</td>
<td align="center" valign="middle">598</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.372</td>
<td align="center" valign="middle" rowspan="2">0.542</td>
</tr>
<tr>
<td align="left" valign="top">Yes</td>
<td align="center" valign="middle">690</td>
<td align="center" valign="middle">285</td>
</tr>
<tr>
<td align="left" valign="top" colspan="5">Maternal myopia (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">No</td>
<td align="center" valign="middle">1,245</td>
<td align="center" valign="middle">559</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;2.324</td>
<td align="center" valign="middle" rowspan="2">0.127</td>
</tr>
<tr>
<td align="left" valign="top">Yes</td>
<td align="center" valign="middle">819</td>
<td align="center" valign="middle">324</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Birth (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">Eutocia</td>
<td align="center" valign="middle">1,139</td>
<td align="center" valign="middle">499</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.442</td>
<td align="center" valign="middle" rowspan="2">0.506</td>
</tr>
<tr>
<td align="left" valign="top">Caesarean</td>
<td align="center" valign="middle">925</td>
<td align="center" valign="middle">384</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Infant feeding pattern (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">Breast feeding</td>
<td align="center" valign="middle">1,057</td>
<td align="center" valign="middle">470</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;1.007</td>
<td align="center" valign="middle" rowspan="2">0.316</td>
</tr>
<tr>
<td align="left" valign="top">Non-breastfed</td>
<td align="center" valign="middle">1,007</td>
<td align="center" valign="middle">413</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Sugared beverages intake (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">&#x003C;3 time/week</td>
<td align="center" valign="middle">318</td>
<td align="center" valign="middle">151</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;1.326</td>
<td align="center" valign="middle" rowspan="2">0.250</td>
</tr>
<tr>
<td align="left" valign="top">&#x2265;3 time/week</td>
<td align="center" valign="middle">1,746</td>
<td align="center" valign="middle">732</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Sweet food intake (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">&#x003C;3 time/week</td>
<td align="center" valign="middle">93</td>
<td align="center" valign="middle">47</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.912</td>
<td align="center" valign="middle" rowspan="2">0.340</td>
</tr>
<tr>
<td align="left" valign="top">&#x2265;3 time/week</td>
<td align="center" valign="middle">1,971</td>
<td align="center" valign="middle">836</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Fried food intake (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">&#x003C;3 time/week</td>
<td align="center" valign="middle">259</td>
<td align="center" valign="middle">109</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.024</td>
<td align="center" valign="middle" rowspan="2">0.878</td>
</tr>
<tr>
<td align="left" valign="top">&#x2265;3 time/week</td>
<td align="center" valign="middle">1,805</td>
<td align="center" valign="middle">774</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Fruit intake (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">&#x2265;3 time/week</td>
<td align="center" valign="middle">1,415</td>
<td align="center" valign="middle">621</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.909</td>
<td align="center" valign="middle" rowspan="2">0.340</td>
</tr>
<tr>
<td align="left" valign="top">&#x003C;3 time/week</td>
<td align="center" valign="middle">649</td>
<td align="center" valign="middle">262</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Vegetable intake (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">&#x2265;3 time/week</td>
<td align="center" valign="middle">1,460</td>
<td align="center" valign="middle">642</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;1.174</td>
<td align="center" valign="middle" rowspan="2">0.279</td>
</tr>
<tr>
<td align="left" valign="top">&#x003C;3 time/week</td>
<td align="center" valign="middle">604</td>
<td align="center" valign="middle">241</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Sleep duration (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">&#x2265;9&#x2009;h</td>
<td align="center" valign="middle">920</td>
<td align="center" valign="middle">391</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.021</td>
<td align="center" valign="middle" rowspan="2">0.884</td>
</tr>
<tr>
<td align="left" valign="top">&#x003C;9&#x2009;h</td>
<td align="center" valign="middle">1,144</td>
<td align="center" valign="middle">492</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Reading and writing posture (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">Correct</td>
<td align="center" valign="middle">788</td>
<td align="center" valign="middle">343</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.116</td>
<td align="center" valign="middle" rowspan="2">0.733</td>
</tr>
<tr>
<td align="left" valign="middle">Wrong</td>
<td align="center" valign="middle">1,276</td>
<td align="center" valign="middle">540</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Posture of holding pen (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="top">Correct</td>
<td align="center" valign="middle">1,318</td>
<td align="center" valign="middle">571</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.176</td>
<td align="center" valign="middle" rowspan="2">0.675</td>
</tr>
<tr>
<td align="left" valign="middle">Wrong</td>
<td align="center" valign="middle">746</td>
<td align="center" valign="middle">312</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5"><italic>Per capita</italic> monthly income (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="middle">&#x2265;10,000 yuan</td>
<td align="center" valign="middle">988</td>
<td align="center" valign="middle">405</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;0.994</td>
<td align="center" valign="middle" rowspan="2">0.319</td>
</tr>
<tr>
<td align="left" valign="middle">&#x003C;10,000 yuan</td>
<td align="center" valign="middle">1,076</td>
<td align="center" valign="middle">478</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Living area per person (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="middle">&#x2265;20&#x2009;m<sup>2</sup></td>
<td align="center" valign="middle">1,258</td>
<td align="center" valign="middle">567</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;2.793</td>
<td align="center" valign="middle" rowspan="2">0.095</td>
</tr>
<tr>
<td align="left" valign="middle">&#x003C;20&#x2009;m<sup>2</sup></td>
<td align="center" valign="middle">806</td>
<td align="center" valign="middle">316</td>
</tr>
<tr>
<td align="left" valign="middle" colspan="5">Time spent outdoors per day (<italic>n</italic>)</td>
</tr>
<tr>
<td align="left" valign="middle">&#x2265;2&#x2009;h</td>
<td align="center" valign="middle">757</td>
<td align="center" valign="middle">346</td>
<td align="center" valign="middle" rowspan="2"><italic>&#x03C7;</italic><sup>2</sup> =&#x2009;1.661</td>
<td align="center" valign="middle" rowspan="2">0.197</td>
</tr>
<tr>
<td align="left" valign="middle">&#x003C;2&#x2009;h</td>
<td align="center" valign="middle">1,307</td>
<td align="center" valign="middle">537</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="sec25">
<title>Evaluation of prediction models</title>
<p>The RF, DT, XGBoost, SVM, and LR prediction models were constructed using the training set and evaluated using testing set. The AUCs of the ROC curves were greater than 0.8 for all the models except the DT. Among the models, the SVM exhibited the highest accuracy, precision, recall, and <italic>F</italic><sub>1</sub>-score, indicating a superior predictive performance for myopia (<xref ref-type="table" rid="tab2">Table 2</xref> and <xref ref-type="fig" rid="fig5">Figure 5</xref>).</p>
<table-wrap position="float" id="tab2">
<label>Table 2</label>
<caption>
<p>Evaluation of predictive performance of models based on the testing set.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">Models</th>
<th align="center" valign="top">AUC (95% CI)</th>
<th align="center" valign="top">Accuracy</th>
<th align="center" valign="top">Precision</th>
<th align="center" valign="top">Recall</th>
<th align="center" valign="top"><italic>F</italic><sub>1</sub>
</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="bottom">Random forest</td>
<td align="char" valign="bottom" char="(">0.833 (0.803, 0.838)</td>
<td align="char" valign="bottom" char=".">0.764</td>
<td align="char" valign="bottom" char=".">0.738</td>
<td align="char" valign="bottom" char=".">0.776</td>
<td align="char" valign="bottom" char=".">0.756</td>
</tr>
<tr>
<td align="left" valign="bottom">Decision tree</td>
<td align="char" valign="bottom" char="(">0.791 (0.758, 0.824)</td>
<td align="char" valign="bottom" char=".">0.757</td>
<td align="char" valign="bottom" char=".">0.785</td>
<td align="char" valign="bottom" char=".">0.670</td>
<td align="char" valign="bottom" char=".">0.723</td>
</tr>
<tr>
<td align="left" valign="bottom">eXtreme gradient boosting trees</td>
<td align="char" valign="bottom" char="(">0.815 (0.784, 0.846)</td>
<td align="char" valign="bottom" char=".">0.754</td>
<td align="char" valign="bottom" char=".">0.765</td>
<td align="char" valign="bottom" char=".">0.693</td>
<td align="char" valign="bottom" char=".">0.727</td>
</tr>
<tr>
<td align="left" valign="bottom">Support vector machine</td>
<td align="char" valign="bottom" char="(">0.846 (0.817, 0.875)</td>
<td align="char" valign="bottom" char=".">0.844</td>
<td align="char" valign="bottom" char=".">0.851</td>
<td align="char" valign="bottom" char=".">0.812</td>
<td align="char" valign="bottom" char=".">0.831</td>
</tr>
<tr>
<td align="left" valign="bottom">Logistic regression</td>
<td align="char" valign="bottom" char="(">0.837 (0.808, 0.866)</td>
<td align="char" valign="bottom" char=".">0.783</td>
<td align="char" valign="bottom" char=".">0.830</td>
<td align="char" valign="bottom" char=".">0.678</td>
<td align="char" valign="bottom" char=".">0.746</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>AUC, the area under the curve.</p>
</table-wrap-foot>
</table-wrap>
<fig position="float" id="fig5">
<label>Figure 5</label>
<caption>
<p>ROC curves of different machine-learning models. (A) Training set. (B) Testing set. ROC, receiver operating characteristic.</p>
</caption>
<graphic xlink:href="fmed-11-1482788-g005.tif"/>
</fig>
</sec>
<sec id="sec26">
<title>Importance of feature variables</title>
<p>As shown in <xref ref-type="fig" rid="fig5">Figure 5</xref>, the optimal prediction model in the training set was RF, whereas in the testing set the optimal myopia prediction model was SVM, followed by LR. Analysis of variable importance in the RF model revealed axial length, age, sex, maternal myopia, and infant feeding pattern to be the five most important variables, as shown in <xref ref-type="fig" rid="fig6">Figure 6</xref>.</p>
<fig position="float" id="fig6">
<label>Figure 6</label>
<caption>
<p>Importance of feature variables for the prediction model constructed using the random forest algorithm.</p>
</caption>
<graphic xlink:href="fmed-11-1482788-g006.tif"/>
</fig>
</sec>
</sec>
<sec sec-type="discussion" id="sec27">
<title>Discussion</title>
<p>In this study, the prevalence of myopia among 2,947 primary school students was 47.2%, with rates increasing with age. Five machine-learning algorithms were used to construct myopia risk prediction models that all achieved AUC values over 0.75 and accuracy and precision values over 0.7. The AUCs for prediction models created using the SVM, LR, RF, and XGBoost algorithms were 0.846, 0.837, 0.833, and 0.815, respectively, indicating superior predictive performance compared to that of the prediction models generated using the DT (AUC, 0.791) and XGBoost (AUC, 0.815) algorithms.</p>
<p>The machine-learning models in this study outperformed those constructed in previous studies. A study of primary school students in Jiamusi, China reported AUCs of 0.710, 0.606, 0.682, and 0.620 for RF, DT, XGBoost, and SVM models, respectively (<xref ref-type="bibr" rid="ref30">30</xref>). A study of primary and secondary school students in Chengdu, China reported AUCs of 0.768, 0.767, and 0.769 for LR, XGBoost, and SVM models, respectively (<xref ref-type="bibr" rid="ref26">26</xref>). One possible reason for this difference is that the previous studies involved a relatively narrow selection of feature variables, with one relying solely on questionnaires to collect information on participant behaviors (<xref ref-type="bibr" rid="ref26">26</xref>, <xref ref-type="bibr" rid="ref30">30</xref>). The present study collected addition information on the ocular biometric parameters closely associated with myopia.</p>
<p>Analysis of the importance of feature variables in myopia prediction models in the present study and revealed a close association between ocular biometric parameters and myopia. The refractive status of the eye has been shown to be determined by the lens, axial length, and corneal radius (<xref ref-type="bibr" rid="ref31">31</xref>), with axial length and corneal curvature being the most crucial factors affecting ocular refraction in children and adolescents (<xref ref-type="bibr" rid="ref32">32</xref>, <xref ref-type="bibr" rid="ref33">33</xref>). This is consistent with the findings of the present study, which showed that axial length, anterior chamber depth, and corneal radius were the principal biological parameters influencing myopia. Refractive errors result from a mismatch between the imaging focal length and the axial length. The active mechanism of emmetropization involves axial elongation, whereas the passive mechanism primarily involves the regulation of corneal and lens diopters (<xref ref-type="bibr" rid="ref34">34</xref>). Axial length gradually increases with age, with a 1-mm increase in axial length corresponding to a myopic shift of 0.69D in spherical equivalent refraction (<xref ref-type="bibr" rid="ref34">34</xref>). Studies have identified that the axial length/corneal radius ratio as an important parameter for determining myopia in children and adolescents, significantly superior to axial length alone (<xref ref-type="bibr" rid="ref34">34</xref>). However, the axial length/corneal radius ratio threshold for myopia determination varies among different populations, with reported optimal thresholds of 2.906 for Australian children and adolescents (<xref ref-type="bibr" rid="ref35">35</xref>) and 3.0 for Singaporean children and adolescents (<xref ref-type="bibr" rid="ref36">36</xref>). Changes in anterior chamber depth are inversely proportional to lens thickness, with studies indicating that, anterior chamber depth increases by up to 0.18&#x2009;mm due to lens deformation and displacement following ciliary muscle paralysis (<xref ref-type="bibr" rid="ref34">34</xref>).</p>
<p>Studies have reported associations between dietary habits (<xref ref-type="bibr" rid="ref37">37</xref>), sleep (<xref ref-type="bibr" rid="ref38">38</xref>), near work (<xref ref-type="bibr" rid="ref39">39</xref>), parental myopia (<xref ref-type="bibr" rid="ref39">39</xref>), and time spent outdoors (<xref ref-type="bibr" rid="ref40">40</xref>) and the occurrence and progression of myopia. The present study assessed the influence of environmental and behavioral factors on myopia through questionnaires, and identified sex as a significant factor, with girls at a greater risk of myopia than boys (<xref ref-type="bibr" rid="ref41">41</xref>). Consistent with this, the probability of myopia in East Asian females has been shown to be twice that in age-matched males, although studies in South Asian and Latin American populations did not find sex to be a significant factor (<xref ref-type="bibr" rid="ref42">42</xref>). The relationship between myopia and sex may be complicated by factors such as education, time spent outdoors, and economic conditions. The present study also identified parental myopia, specifically maternal myopia, as a significant influencing factor of myopia. Whole-genome studies have associated more than 150 nucleotide polymorphisms with myopia (<xref ref-type="bibr" rid="ref43">43</xref>).</p>
<p>In the present study, an incorrect reading and writing posture was found to increase the risk of myopia. This is consistent with previous research involving children aged 9&#x2013;11&#x2009;years, which showed that children who read and wrote at a distance of less than 30&#x2009;cm had higher degrees of myopia and greater progression of myopia over a 6-month period (<xref ref-type="bibr" rid="ref44">44</xref>). This may be the result of a compensatory mechanism, whereby children with existing myopia hold reading materials closer to see more clearly, further exacerbating myopia. The association between breastfeeding and myopia has been receiving increasing attention. The present study identified infant feeding pattern as an influencing factor of myopia. A previous study of children aged 6&#x2013;12&#x2009;years found that myopia prevalence was lower among breastfed children (51.8%) than among non-breastfed children (64.7%) (<xref ref-type="bibr" rid="ref45">45</xref>). Aksoy et al. (<xref ref-type="bibr" rid="ref46">46</xref>) demonstrated that in first- and second-grade elementary school students, non-breastfed children were more likely to have refractive errors than were children who were exclusively or partially breastfed. The present study additionally found that body mass index (BMI) influenced myopia in the RF model. Large-scale population studies have shown a J-shaped relationship between BMI and myopia, with both low and high BMI associated with myopia (<xref ref-type="bibr" rid="ref47">47</xref>).</p>
<p>The present study has some limitations. First, the diagnosis of myopia was based on non-cycloplegic refraction. Non-cycloplegic refraction has been shown to have high sensitivity and specificity in myopia screening among students (<xref ref-type="bibr" rid="ref48">48</xref>), and myopia prevalence may have been overestimated to some extent. Second, the use of a questionnaire introduces the possibility of recall bias. Finally, the case-control design of the study limited its ability to determine causal relationships. Future prospective cohort studies are required to further elucidate the etiology of myopia using machine-learning algorithms.</p>
<p>In conclusion, the present study identified axial elongation, female sex, thickening of the lens, maternal myopia, incorrect reading and writing posture, and increased age as risk factors for myopia; corneal radius was a protective factor against myopia. Machine-learning models constructed using these factors accurately predicted myopia and may be used to identify high-risk populations. Cohort studies will be conducted to validate the identified myopia risk factors and elucidate their causal relationships.</p>
</sec>
</body>
<back>
<sec sec-type="data-availability" id="sec28">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.</p>
</sec>
<sec sec-type="ethics-statement" id="sec29">
<title>Ethics statement</title>
<p>The studies involving humans were approved by the Ethics Committee of the Shenzhen Eye Hospital (No. 20201230-06). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants&#x2019; legal guardians/next of kin.</p>
</sec>
<sec sec-type="author-contributions" id="sec30">
<title>Author contributions</title>
<p>JM: Writing &#x2013; review &#x0026; editing, Writing &#x2013; original draft, Supervision, Methodology, Investigation. HZ: Writing &#x2013; original draft, Investigation, Formal analysis. MJ: Writing &#x2013; original draft, Investigation, Data curation.</p>
</sec>
<sec sec-type="funding-information" id="sec31">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by Shenzhen Science and Technology Program (JCYJ20230807114608016).</p>
</sec>
<sec sec-type="COI-statement" id="sec32">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="sec33">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<ref-list>
<title>References</title>
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