Keratoconus (KC) is a corneal disorder characterized by an anterior protrusion of the cornea and corneal thinning. (Gomes et al., 2015). It affects all ethnic groups, with the highest prevalence reported in China (0.9%, approximately 12.5 million), India (2.3%, approximately 30 million), and Iran (4% of the rural population, approximately 3.4 million). (Hashemi et al., 2020; Rafat et al., 2022). KC is the leading indication for corneal transplantation, accompanied by serious vision deterioration and irregular astigmatism, and the social and financial burden is remarkable. (Rebenitsch et al., 2011; Rafat et al., 2022).

As a progressive disease, KC typically occurs at puberty and continues to progress until the third or fourth decade of life. (Mukhtar and Ambati, 2018). In addition, several studies have reported that KC is more frequently presented at an advanced stage in young patients than in adults, and pediatric patients with limited cognitive ability are less aware of unilateral visual loss. (Leoni-Mesplie et al., 2012; Ferdi et al., 2019). The persistent underrepresentation of children in KC research has resulted in an inadequate evidence base; therefore, increasing attention to pediatric KC patients is of great value in evaluating the occurrence and development of KC.

Moderate or severe stages of KC are easily diagnosed according to slit lamp findings and topography signs, whereas the detection of abnormal corneas in very early stages or subclinical forms is still a challenge for clinicians. (Mas Tur et al., 2017; Cao et al., 2021; Zhang et al., 2022). Epidemiological studies have revealed that corneal topographic, tomographic, and biomechanical parameters can accurately distinguish a KC or subclinical KC (SKC) eye from a normal eye. (Vinciguerra et al., 2016; Sedaghat et al., 2018; Kataria et al., 2019; Koh et al., 2019). However, the above study mostly focused on adults, who received examinations before refractive surgery mainly to avoid postoperative ectasia. As the clinical manifestation of KC in children is somewhat different from adults, the diagnosis results obtained in adults may not apply to pediatric patients. (Mukhtar and Ambati, 2018; Anitha et al., 2021). However, the diagnosis of pediatric KC is still limited. (Leoni-Mesplie et al., 2012; Wajnsztajn et al., 2021). A retrospective observational study conducted in Egypt reported the eight most useful Pentacam indices in identifying 48 eyes of pediatric KC and SKC. (Hashem et al., 2022). Furthermore, the corneal biomechanics, which are thought to be the initiators of the disease even before notable changes in corneal morphology, were not evaluated in the above study. (Scarcelli et al., 2014; Vinciguerra et al., 2016). A prospective study conducted in Atlanta showed that pediatric KC patients with trisomy 21 had thinner corneas and lower corneal resistance factors than control patients, which were inconsistent with the results in adults. (Neustein and Lenhart, 2022). The above corneal biomechanics were measured by ORA, which has a limited examination area on the cornea and a worse discriminative ability in KC eyes than Corvis ST. (Esporcatte et al., 2023). As an ultra-high speed Scheimpflug camera, Corvis ST can produce various corneal biomechanical parameters and its discriminative ability has been demonstrated to be high in adults. Additionally, studies in pediatric KC patients have been limited. (Vinciguerra et al., 2016; Kataria et al., 2019).

With the advancement of technology, machine learning methods can improve diagnostic ability by incorporating a large amount of data. (Angraal et al., 2020). Several studies have reported the application of machine learning techniques in the field of KC and refractive surgery screening; however, their application has been limited in pediatric KC patients. (Ruiz Hidalgo et al., 2016; Malyugin et al., 2021). Thus, the current study aimed to evaluate the clinical characteristics of KC and SKC eyes in pediatric patients, and explore the diagnostic ability of corneal tomographic and biomechanical parameters in discriminating pediatric SKC eyes, to provide references for the early diagnosis and management of pediatric patients.

As KC in young patients is reported to be more likely to progress than in adults, the sensitivity index and cutoff values of parameters in pediatric patients is different than in adult patients. (Hashem et al., 2022; Neustein and Lenhart, 2022). The machine learning analysis, analyzing a large number of variables, found that the comprehensive index, containing PE, DA ratio max [2 mm], and SP A1, improved the diagnostic capability to differentiate pediatric SKC eyes.

Pentacam is one of the most common techniques in clinical application, as the uniqueness of this device is that it includes tomographic data, topometric data, pachymetry, elevation data, and combined data. (Motlagh et al., 2019). In the present study, BAD-D and PE were highly capable of differentiating pediatric KC and SKC eyes, which was consistent with previous findings in adult patients with similar criteria. BAD-D is a multivariate index that considers several separate indices, and its AUC value in diagnosing adult KC was 0.990, and the cutoff value providing the best Youden index was 2.38 in the study by Hashemi et al., 2016. In the study by Ambrosio et al. (2013) the AUC value in detecting adult SKC eyes was 0.975 and the cutoff value providing the best Youden index was 1.22. PE represents the maximum evaluation of the corneal posterior in a zone above the standardized reference shape, and this variable is widely regarded as the earliest indicator of ecstatic change. (Saad and Gatinel, 2010; Motlagh et al., 2019). The AUC value of PE in diagnosing adult KC was 0.991, and the cutoff value providing the best Youden index was 12 μm in the study by Ambrosio et al., 2013. The AUC value in detecting SKC was 0.882 and the cutoff value providing the best Youden index was 7.5 μm in the study by Du XL et al. (Du et al., 2015), which were both higher than in pediatric patients at the same cutoff values in the current study. In general, the diagnostic efficacy of corneal tomographic variables in pediatric patients was higher than in adult patients at a similar cutoff value, which suggested that caution is warranted when using these parameters in different age groups. (Hashem et al., 2022).

The diagnostic criteria of corneal tomographic parameters in pediatric KC are still limited. (Motlagh et al., 2019; Hashem et al., 2022). A prospective study reported that pediatric KC with trisomy 21 has a thinner cornea, with a lower TCT and higher values of Kmax and K2 than normal children, which was consistent with the current results. (Neustein and Lenhart, 2022). In addition, the current study found that the CCT and K1 were significantly different between KC and the control, whereas no significant difference was found in the study by Neustein and Lenhart, 2022 These discrepancies may be attributed to the sample size, ethnicity, and characters of the subjects. In addition, Hashem et al., 2022 reported that relational thickness and other OCULUS values analyzed for the 8-mm zone (CAIRO 8) were the most effective for KC detection in pediatric eyes, which is inconsistent with the present study. On one hand, the parameters included in the analyses were not completely consistent, e.g., BAD-D, which has been widely demonstrated to be one of the best indices for identifying KC and SKC eyes, was not mentioned in the study by Hashem AO et al., and CAIRO 8 was not analyzed in the present study. (Hashemi et al., 2016; Hashem et al., 2022). On the other hand, Hashem et al., 2022 included 40 KC and 8 SKC eyes as a whole case group, despite the inconsistency between SKC and KC eyes, and the KC and SKC eyes were analyzed separately in the current study. The limited sample of pediatric SKC eyes would result in a lack of research evidence of the diagnosis criteria of pediatric SKC eyes. In addition, our previous study reported that pediatric unilateral patients account for 7.82% of all KC patients (86/1,100), (Yang et al., 2022), which might be related to the fact that the minimum age approved for corneal refractive surgery is 18 years and corneal tomography and biomechanics are not commonly examined in children. (Ortega-Usobiaga et al., 2022). Thus, more attention should be paid to children with sight loss, and deep studies are needed to further verify the ability of corneal topographic parameters in pediatric patients.

With the increasing understanding that the changes in corneal biomechanics precede tomography, more attention has been focused on corneal biomechanics in the early diagnosis of KC. (Vinciguerra et al., 2016; Moshirfar et al., 2019; Herber et al., 2022). Corvis ST has been increasingly evaluated in the detection of early adult KC. Evidence of Corvis ST parameters in pediatric KC and SKC is still lacking. (Li et al., 2023). SP A1 is a novel stiffness parameter that is defined as resultant pressure divided by deflection at the first applanation, and the KC eye tends to have a smaller value that represents a weaker cornea. (Vinciguerra et al., 2016; Yang et al., 2020). The present study found that SP A1 in pediatric SKC eyes was lower than that in control eyes after adjusting for IOP and corneal thickness, which indicated that the cornea of the pediatric SKC eye weakened. In addition, the abilities of CBI, SP A1, and DA ratio max (2 mm) in diagnosing pediatric KC eyes were high, which was consistent with previous studies of adult KC. (Kataria et al., 2019; Moshirfar et al., 2019; Ren et al., 2021). DA ratio max [2 mm] is the deformation amplitude measured 2 mm from the corneal center, and a higher value represents a softer cornea or one that is less resistant to cornea deformation. (Yang et al., 2019). CBI, a parameter of the logistic regression analysis, was useful in discriminating KC when the value was higher than 0.5. (Vinciguerra et al., 2016). The AUCs of SP A1 and integrated radius in the present study were higher than those in a previous study of adult SKC patients, which further indicated that the corneal tests for the evaluation of adults might not be reliable at identifying pediatric patients. (Neustein and Lenhart, 2022). Integrated radius is the integrated area under the curve of the inverse radius, and the KC eye has a higher value than the normal eye. (Ren et al., 2021). In addition, the accuracy of CBI in detecting adult SKC is excellent and relatively higher than that in pediatric SKC eyes in the present study. (Kataria et al., 2019; Ren et al., 2021). The results suggested that the criteria and cutoff values of corneal biomechanics in adult KC and SKC may not suitable for pediatric patients, which should be paid more attention to in clinical application and more comparative studies are needed in the future.

TBI is combined data that are synergistically integrated and has been widely demonstrated to be useful in detecting corneal ectasia. (Koh et al., 2019; Moshirfar et al., 2019). The present study found that TBI was the best variable in detecting pediatric KC eyes. As for diagnosing pediatric SKC eyes, the AUC of TBI in the present study was lower than that in adult SKC eyes. (Ambrosio et al., 2017; Koc et al., 2019). In addition, the ability of TBI was weaker than the combined model obtained through machine analysis. The comprehensive index of PE, DA ratio max [2 mm], and SP A1 could effectively discriminate pediatric SKC eyes from control eyes, providing a reference for exploring the early detection of pediatric patients. The current diagnosis criteria included corneal tomographic and corneal biomechanical parameters, and the accuracy of diagnosing pediatric SKC eye was significantly higher than CBI, DA ratio max [2 mm], SP A1, PE, and integrated radius. Several dynamic corneal response (DCR) parameters of insufficient diagnostic ability could improve the diagnostic ability but cannot currently be considered standalone parameters for screening purposes. (Ali et al., 2014). The accuracy of other DCR variables in detecting SKC eyes was limited reported, and the combined diagnostic mechanism of these parameters needs further evaluation in engineering mechanics.

At present, insufficient attention is being paid to vision loss in children, which has a higher progressive rate than adult patients. Early diagnosis of pediatric KC and further effective early treatments can prevent the need for corneal transplantation and improve the quality of life of patients. (Neustein and Lenhart, 2022). Several limitations must be acknowledged. First, the sample of pediatric SKC eyes included in current study was not large enough, although the population was drawn from a relatively large KC population. Second, the study was conducted in a single center, with strict grouping criteria and matched with age and gender to control bias. Therefore, the results still need to be further validated at other centers. Third, the machine learning methods improved the prediction ability of pediatric SKC eyes, but the validation for the machine learning analysis result was lacking. Including a large number of subjects in the validation analysis is necessary and the study is ongoing and continuing to collect unilateral pediatric KC patients for further validation. Thus, a multicenter pediatric study with a large sample size is needed in the future. Finally, the present machine learning method assumed the input variables and outcomes were probably linear, and non-linear was not considered. Therefore, the possibility of assessing alternative classifiers based on algorithms other than a linear model should be conducted in the future.

In conclusion, the ability of corneal tomographic and biomechanical variables and their cutoff values in detecting pediatric KC and SKC eyes was inconsistent in adult patients, and combined parameters had better discriminative efficacy than single instrument variables in detecting SKC eyes. Relative findings will provide sensitive indices for the follow-up management of unilateral pediatric KC and a reference for the early diagnosis of children suspected to have KC.