# Diagnostic Value of Combined Detection of Pelvic Ultrasound and Serum LH, FSH, and E2 Levels in Children with Idiopathic Central Precocious Puberty

Authors: Zhen He; Bo Yuan
Journal: Evidence-Based Complementary and Alternative Medicine
 (2022)

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## Abstract

Objective. To study the diagnostic value of combined detection of pelvic ultrasound and serum LH, FSH, and E2 levels in children with idiopathic central precocious puberty (ICPP). Methods. 30 cases of children with ICPP admitted to our hospital from January 2019 to January 2021 were selected as the experimental group, and 30 healthy people during the same period were selected as the control group. Both groups received pelvic ultrasound and serum LH, FSH, and E2 detection; the two groups were compared in terms of serum indicators, combined diagnosis, specificity, and sensitivity. Results. There were statistical differences in height, leptin, bone age, and areola diameter between the two groups (p<0.05). The length of the uterus, the volume of the uterus, the area of the ovary, the volume of the ovary, and the maximum diameter of the follicle in the experimental group were larger than those in the control group (p<0.05). The endometrial thickness of the experimental group was significantly greater than that of the control group (p<0.05). The levels of serum LH, FSH, and E2 in the experimental group were significantly higher than those in the control group (p<0.05). The area of the combined detection was significantly larger than that of the single detection. The combined detection was superior to the single detection with respect to the area, standard error a, asymptotic Sig. B, and asymptotic 95% confidence interval (p<0.05). The sensitivity of the combined detection was significantly higher than that of the single detection. Conclusion. The combined detection of pelvic ultrasound and serum LH, FSH, and E2 levels may be a preferred technique for the diagnosis of children with ICPP due to its benefits of high sensitivity and accuracy. It is worthy of clinical promotion and application.


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## Body

## 1. Introduction

Precocious puberty, a dysplastic disease in which secondary sexual characteristics appear in girls before 8 years old and in boys before 9 years old, is a far more common endocrine disease in children. With the transformation of people’s lifestyles, the incidence of precocious puberty in children has shown a gradual upward trend. Precocious puberty is usually characterized by early puberty and developmental abnormalities. According to the pathogenesis, it can be divided into central precocious puberty, peripheral precocious puberty, and incomplete or partial precocious puberty [1–3]. Idiopathic central precocious puberty (ICPP) is caused by declined sensitivity of hypothalamus to negative feedback of sex hormones and premature increase in the secretion and release of gonadotropin-releasing hormone, which afflict more girls than boys in clinical practice [4, 5]. Previous studies have shown that adolescent growth rate peaks ahead will lead to early closure of bone age and bone scale, resulting in short stature and poor physical coordination and posing negative impact on the physical and mental health of patients [6, 7].Currently, the gonadotropin-releasing hormone (GnRH) stimulation test is widely adopted to diagnose ICPP [8]. For those who are more likely to consider true (central) precocious puberty, especially those who need to consider GnRHa treatment, except for a few who have reached the standard of not needing a GnRH provocation test, a GnRH provocation test is required to determine whether it is true precocious puberty. However, for patients with a high possibility of pseudoprecocious puberty, the GnRH provocation test may not be suitable for the time being. Because if it is false after provocation, it does not mean that it is still false after a few months, and it is necessary to repeat the provocation at a later stage to bring pain or unnecessary examination to the child; therefore, this still deserves a further investigation [9]. Both TCM and Western medicine have developed other techniques as diagnostic tools, and more are being researched. With the development of ultrasound technology, pelvic ultrasound has been frequently used in the diagnosis of ICPP, with the merits of being noninvasive, easy to operate, short time-consuming, and having strong repeatability [10]. Relevant studies have shown that serum luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) levels have a certain diagnostic value in the diagnosis of ICPP. Based on these, we attempted to explore the value of combined detection of pelvic ultrasound and serum LH, FSH, and E2 levels in children with ICPP.


## 2. Materials and Methods

### 2.1. Subjects

Thirty children with ICPP admitted to our hospital from January 2019 to January 2021 were selected as the experimental group, and 30 healthy individuals who were examined during the same period were selected as the control group. Both groups of subjects were girls. The age of the children in the experimental group was 5–10 years old, with an average age of (7.12 ± 2.35) years and an average body weight of (28.57 ± 4.91) kg; the control group aged 6–10 years old, with an average age of (7.84 ± 1.97) years old and an average body weight of (28.36 ± 4.82) kg.This study was approved by the ethics committee of the No. 2 Hospital of Baoding, Approval No. 2711/383.


### 2.2. Inclusion Criteria and Exclusion Criteria

Inclusion criteria were ① comply with the clinical diagnostic criteria of ICPP in theGuidelines for the Diagnosis and Treatment of Central (True) Precocious Puberty; ② all the children are girls; ③ secondary sexual characteristics appear before 8 years old; ④ bone age exceeds the actual age by 1 year or more; ⑤ this study was approved by the hospital ethics committee, and the patients and their families knew the purpose and procedure of the study and signed an informed consent form.Exclusion criteria were ① with peripheral precocious puberty; ② with simple early breast development, endocrine disease, and tumor disease; ③ with genitourinary system disease, malnutrition, and hypothyroidism.


### 2.3. Methods

Pelvic ultrasound examination. All subjects underwent pelvic ultrasound examination; the color Doppler ultrasound system of Aloka Prosound 6, with ASU-9147 probe, and a frequency of 2.5–7.0 MHz was used. The supine position was adopted, and the length, anteroposterior diameter, transverse diameter, ovarian length, anterior and posterior diameter, and transverse diameter of the uterus on the sagittal, coronal, ovarian, and coronal views of the uterus were measured when the bladder was well filled; when there are multiple follicles, the diameter of the largest follicle was measured, and when no obvious follicles were seen, it was recorded as 0; the diameter of the areola was measured. The volume of the uterus and ovary = long diameter × transverse diameter × front and rear diameter × 0.523.Serum LH, FSH, and E2 levels and serum leptin detection. 3 mL of fasting venous blood was collected from all subjects in the morning and centrifuged (3000 r/min, 10 min), then the supernatant was obtained, and the automatic fluorescence immunoassay system Unicel DX180 from Beckman, USA, was used to determine serum LH, FSH, and E2 levels.


### 2.4. Observation Indicators

(1) The physiological indicators of the two groups were compared; the height of the two groups of subjects were measured; the left hand and wrist joint X-rays were filmed to evaluate bone age using the Chinese wrist evaluation method and standard (CHN). (2) The length of the uterus, the volume of the uterus, the area of the ovary, the volume of the ovary, the maximum diameter of the follicle, and the thickness of the endometrium were compared between the two groups. (3) The levels of serum LH, FSH, and E2 and the combined diagnosis of the two groups were compared.


### 2.5. Statistical Analysis

The data were analyzed by SPSS20.0, and the graphics were plotted by GraPhPad Prism 7 (GraPhPad Software, San Diego, USA); the count data were expressed as [n (%)] and examined by x2, and the measurement data were expressed as (x¯±s) and tested by the t-test. Statistical significance was declared at p<0.05.


## 2.1. Subjects

Thirty children with ICPP admitted to our hospital from January 2019 to January 2021 were selected as the experimental group, and 30 healthy individuals who were examined during the same period were selected as the control group. Both groups of subjects were girls. The age of the children in the experimental group was 5–10 years old, with an average age of (7.12 ± 2.35) years and an average body weight of (28.57 ± 4.91) kg; the control group aged 6–10 years old, with an average age of (7.84 ± 1.97) years old and an average body weight of (28.36 ± 4.82) kg.This study was approved by the ethics committee of the No. 2 Hospital of Baoding, Approval No. 2711/383.


## 2.2. Inclusion Criteria and Exclusion Criteria

Inclusion criteria were ① comply with the clinical diagnostic criteria of ICPP in theGuidelines for the Diagnosis and Treatment of Central (True) Precocious Puberty; ② all the children are girls; ③ secondary sexual characteristics appear before 8 years old; ④ bone age exceeds the actual age by 1 year or more; ⑤ this study was approved by the hospital ethics committee, and the patients and their families knew the purpose and procedure of the study and signed an informed consent form.Exclusion criteria were ① with peripheral precocious puberty; ② with simple early breast development, endocrine disease, and tumor disease; ③ with genitourinary system disease, malnutrition, and hypothyroidism.


## 2.3. Methods

Pelvic ultrasound examination. All subjects underwent pelvic ultrasound examination; the color Doppler ultrasound system of Aloka Prosound 6, with ASU-9147 probe, and a frequency of 2.5–7.0 MHz was used. The supine position was adopted, and the length, anteroposterior diameter, transverse diameter, ovarian length, anterior and posterior diameter, and transverse diameter of the uterus on the sagittal, coronal, ovarian, and coronal views of the uterus were measured when the bladder was well filled; when there are multiple follicles, the diameter of the largest follicle was measured, and when no obvious follicles were seen, it was recorded as 0; the diameter of the areola was measured. The volume of the uterus and ovary = long diameter × transverse diameter × front and rear diameter × 0.523.Serum LH, FSH, and E2 levels and serum leptin detection. 3 mL of fasting venous blood was collected from all subjects in the morning and centrifuged (3000 r/min, 10 min), then the supernatant was obtained, and the automatic fluorescence immunoassay system Unicel DX180 from Beckman, USA, was used to determine serum LH, FSH, and E2 levels.


## 2.4. Observation Indicators

(1) The physiological indicators of the two groups were compared; the height of the two groups of subjects were measured; the left hand and wrist joint X-rays were filmed to evaluate bone age using the Chinese wrist evaluation method and standard (CHN). (2) The length of the uterus, the volume of the uterus, the area of the ovary, the volume of the ovary, the maximum diameter of the follicle, and the thickness of the endometrium were compared between the two groups. (3) The levels of serum LH, FSH, and E2 and the combined diagnosis of the two groups were compared.


## 2.5. Statistical Analysis

The data were analyzed by SPSS20.0, and the graphics were plotted by GraPhPad Prism 7 (GraPhPad Software, San Diego, USA); the count data were expressed as [n (%)] and examined by x2, and the measurement data were expressed as (x¯±s) and tested by the t-test. Statistical significance was declared at p<0.05.


## 3. Results

### 3.1. Comparison of the Physiological Indicators of the Two Groups

There were statistical differences in height, leptin, bone age, and areola diameter between the two groups (p<0.05) (Table 1).Table 1
Comparison of the physiological indicators of the two groups (x ± s).
GroupsnHeight (cm)Leptin (ng/mL)Bone age (year)Areola diameter (cm)Control group30131.4 ± 5.43.38 ± 1.128.5 ± 1.32.2 ± 0.5Experimental group30145.32 ± 6.99.74 ± 2.3610.8 ± 1.73.7 ± 1.4t8.70213.3355.8865.527p<0.001<0.001<0.001<0.001


### 3.2. Comparison of the Relevant Parameters of Pelvic Ultrasound Examination between the Two Groups

The length of the uterus, the volume of the uterus, the area of the ovary, the volume of the ovary, and the maximum diameter of the follicle in the experimental group were drastically larger than those in the control group, and the difference was significant (p<0.05) (Table 2).Table 2
Comparison of related parameters of pelvic ultrasound examination between the two groups (x¯±s).
GroupsnUterine long diameter (cm)Uterine volume (cm3)Ovarian area (cm2)Ovarian volume (cm2)Maximum diameter of follicle (mm)Control group301.91 ± 0.301.25 ± 0.651.63 ± 0.720.87 ± 0.492.32 ± 0.21Experimental group302.53 ± 0.442.67 ± 1.842.75 ± 1.242.76 ± 0.636.63 ± 2.17t6.3773.9864.27812.97010.828p<0.001<0.001<0.001<0.001<0.001


### 3.3. Comparison of Endometrial Thickness between the Two Groups

The endometrial thickness of the experimental group was significantly greater than that of the control group, and the difference was statistically significant (p<0.05), as shown in Figure 1.Figure 1
Comparison of the endometrial thickness between the two groups (x ± s). The coordinate represents the control group and the experimental group; the ordinate represents the endometrial thickness; the endometrial thickness of the control group was (1.69 ± 0.35) mm; the horizontal value of the endometrial thickness in the experimental group was (3.57 ± 1.20) mm; ∗indicates that there was a significant difference in the endometrial thickness between the control group and the experimental group (t = 8.238, p<0.001).


### 3.4. Comparison of the Levels of Serum LH, FSH, and E2 between the Two Groups

Serum LH, FSH, and E2 levels of the control group were (1.98 ± 0.34) IU/L, (2.86 ± 1.42) IU/L, and (38.47 ± 12.36) Pmol/mL, respectively; the levels of serum LH, FSH, and E2 in the experimental group were (27.33 ± 15.05) IU/L, (17.21 ± 4.22) IU/L, and (99.74 ± 19.51) Pmol/mL, respectively. The levels of serum LH, FSH, and E2 in the experimental group were evidently higher than those in the control group, and the difference was statistically significant (p<0.05), as shown in Figure 2.Figure 2
Comparison of serum LH, FSH, and E2 levels between the two groups (x ± s). The abscissa represents the control group and the experimental group, and the ordinate represents the level of serum LH, FSH, and E2. (a) ∗indicates that there was a significant difference in the LH level between the control group and the experimental group (t = 9.223, p<0.001); (b) ∗∗indicates that there was a significant difference in FSH levels between the control group and the experimental group (t = 17.653, p<0.001); (c) ∗∗∗ means that there was a significant difference in E2 levels of the control group and the experimental group (t = 15.658, p<0.001).
(a)(b)(c)


### 3.5. Comparison of Single and Combined Detection of Serum LH, FSH, and E2 Indicators

The area of the combined detection was significantly larger than that of the single detection, as shown in Figure3.Figure 3
Comparison of single and combined detection of serum LH, FSH, and E2 indicators.


### 3.6. Comparison of the Area, Standard Error A, Asymptotic Sig. B, and Asymptotic 95% Confidence Interval of Each Indicator

The combined detection was superior to the single detection (p<0.05) (Table 3)Table 3
Comparison of the area, standard error a, asymptotic Sig. B, and asymptotic 95% confidence interval of each indicator.
AreaStandard error AAsymptotic Sig. BAsymptotic 95% confidence intervalLower limitUpper limitLH0.8330.05600.7240.943FSH0.8500.05400.7450.955E20.7670.06400.6420.891LH + FSH + E20.7670.0640.0000.6420.891Pelvic ultrasound0.8000.0600.0000.6820.918Pelvic ultrasound + LH0.8330.0560.0000.7240.943Pelvic ultrasound + FSH0.7330.0660.0020.6030.864Pelvic ultrasound + E20.7670.0640.0000.6420.891Combined detection0.9500.0330.0000.0001.000


### 3.7. Comparison of the Sensitivity and Specificity of Each Index

The sensitivity of the combined detection was significantly higher than that of the single detection, as shown in Table4.Table 4
Comparison of the sensitivity and specificity of each index.
Positive if greater than or equal to aSensitivitySpecificityLH−1.00001.0001.0000.50000.7670.1002.00000.0000.000FSH−1.00001.0001.0000.50000.8330.1332.00000.0000.000E2−1.00001.0001.0000.50000.7000.1672.00000.0000.000LH + FSH + E2−1.00001.0001.0000.50000.7330.2002.00000.0000.000Pelvic ultrasound−1.00001.0001.0000.50000.7670.1672.00000.0000.000Pelvic ultrasound + LH−1.00001.0001.0000.50000.8000.1332.00000.0000.000Pelvic ultrasound + FSH−1.00001.0001.0000.50000.7000.2332.00000.0000.000Pelvic ultrasound + E2−1.00001.0001.0000.50000.7330.2002.00000.0000.000Combined detection−1.00001.0001.0000.50000.9330.0332.00000.0000.000


## 3.1. Comparison of the Physiological Indicators of the Two Groups

There were statistical differences in height, leptin, bone age, and areola diameter between the two groups (p<0.05) (Table 1).Table 1
Comparison of the physiological indicators of the two groups (x ± s).
GroupsnHeight (cm)Leptin (ng/mL)Bone age (year)Areola diameter (cm)Control group30131.4 ± 5.43.38 ± 1.128.5 ± 1.32.2 ± 0.5Experimental group30145.32 ± 6.99.74 ± 2.3610.8 ± 1.73.7 ± 1.4t8.70213.3355.8865.527p<0.001<0.001<0.001<0.001


## 3.2. Comparison of the Relevant Parameters of Pelvic Ultrasound Examination between the Two Groups

The length of the uterus, the volume of the uterus, the area of the ovary, the volume of the ovary, and the maximum diameter of the follicle in the experimental group were drastically larger than those in the control group, and the difference was significant (p<0.05) (Table 2).Table 2
Comparison of related parameters of pelvic ultrasound examination between the two groups (x¯±s).
GroupsnUterine long diameter (cm)Uterine volume (cm3)Ovarian area (cm2)Ovarian volume (cm2)Maximum diameter of follicle (mm)Control group301.91 ± 0.301.25 ± 0.651.63 ± 0.720.87 ± 0.492.32 ± 0.21Experimental group302.53 ± 0.442.67 ± 1.842.75 ± 1.242.76 ± 0.636.63 ± 2.17t6.3773.9864.27812.97010.828p<0.001<0.001<0.001<0.001<0.001


## 3.3. Comparison of Endometrial Thickness between the Two Groups

The endometrial thickness of the experimental group was significantly greater than that of the control group, and the difference was statistically significant (p<0.05), as shown in Figure 1.Figure 1
Comparison of the endometrial thickness between the two groups (x ± s). The coordinate represents the control group and the experimental group; the ordinate represents the endometrial thickness; the endometrial thickness of the control group was (1.69 ± 0.35) mm; the horizontal value of the endometrial thickness in the experimental group was (3.57 ± 1.20) mm; ∗indicates that there was a significant difference in the endometrial thickness between the control group and the experimental group (t = 8.238, p<0.001).


## 3.4. Comparison of the Levels of Serum LH, FSH, and E2 between the Two Groups

Serum LH, FSH, and E2 levels of the control group were (1.98 ± 0.34) IU/L, (2.86 ± 1.42) IU/L, and (38.47 ± 12.36) Pmol/mL, respectively; the levels of serum LH, FSH, and E2 in the experimental group were (27.33 ± 15.05) IU/L, (17.21 ± 4.22) IU/L, and (99.74 ± 19.51) Pmol/mL, respectively. The levels of serum LH, FSH, and E2 in the experimental group were evidently higher than those in the control group, and the difference was statistically significant (p<0.05), as shown in Figure 2.Figure 2
Comparison of serum LH, FSH, and E2 levels between the two groups (x ± s). The abscissa represents the control group and the experimental group, and the ordinate represents the level of serum LH, FSH, and E2. (a) ∗indicates that there was a significant difference in the LH level between the control group and the experimental group (t = 9.223, p<0.001); (b) ∗∗indicates that there was a significant difference in FSH levels between the control group and the experimental group (t = 17.653, p<0.001); (c) ∗∗∗ means that there was a significant difference in E2 levels of the control group and the experimental group (t = 15.658, p<0.001).
(a)(b)(c)


## 3.5. Comparison of Single and Combined Detection of Serum LH, FSH, and E2 Indicators

The area of the combined detection was significantly larger than that of the single detection, as shown in Figure3.Figure 3
Comparison of single and combined detection of serum LH, FSH, and E2 indicators.


## 3.6. Comparison of the Area, Standard Error A, Asymptotic Sig. B, and Asymptotic 95% Confidence Interval of Each Indicator

The combined detection was superior to the single detection (p<0.05) (Table 3)Table 3
Comparison of the area, standard error a, asymptotic Sig. B, and asymptotic 95% confidence interval of each indicator.
AreaStandard error AAsymptotic Sig. BAsymptotic 95% confidence intervalLower limitUpper limitLH0.8330.05600.7240.943FSH0.8500.05400.7450.955E20.7670.06400.6420.891LH + FSH + E20.7670.0640.0000.6420.891Pelvic ultrasound0.8000.0600.0000.6820.918Pelvic ultrasound + LH0.8330.0560.0000.7240.943Pelvic ultrasound + FSH0.7330.0660.0020.6030.864Pelvic ultrasound + E20.7670.0640.0000.6420.891Combined detection0.9500.0330.0000.0001.000


## 3.7. Comparison of the Sensitivity and Specificity of Each Index

The sensitivity of the combined detection was significantly higher than that of the single detection, as shown in Table4.Table 4
Comparison of the sensitivity and specificity of each index.
Positive if greater than or equal to aSensitivitySpecificityLH−1.00001.0001.0000.50000.7670.1002.00000.0000.000FSH−1.00001.0001.0000.50000.8330.1332.00000.0000.000E2−1.00001.0001.0000.50000.7000.1672.00000.0000.000LH + FSH + E2−1.00001.0001.0000.50000.7330.2002.00000.0000.000Pelvic ultrasound−1.00001.0001.0000.50000.7670.1672.00000.0000.000Pelvic ultrasound + LH−1.00001.0001.0000.50000.8000.1332.00000.0000.000Pelvic ultrasound + FSH−1.00001.0001.0000.50000.7000.2332.00000.0000.000Pelvic ultrasound + E2−1.00001.0001.0000.50000.7330.2002.00000.0000.000Combined detection−1.00001.0001.0000.50000.9330.0332.00000.0000.000


## 4. Discussion

ICPP occurs mainly because the hypothalamus secretes and releases gonadotropin-releasing hormone (GnRH) in advance, activates the pituitary gland to secrete gonadotropins, promotes gonadal development, and causes the development of internal and external genitalia, leading to secondary sexual characteristics [11–13]. The occurrence of ICPP poses huge threats to children. Premature breast development and menstruation against the backdrop of immature sexual psychology and intelligence would incur social problems, which have an adverse impact on the personality development of children [14–16]. At present, GnRH excitation experiments are mostly used for diagnosis in clinical practice, with the disadvantages of being time-consuming, invasive, and having poor compliance. As ultrasound technology advances, pelvic ultrasound is widely used in the diagnosis of ICPP patients due to its advantages of simple operation, high safety, and accuracy and is gaining increasingly more attention and recognition [17–20]. In similarity to the findings of previous studies [19], in the present study, uterine length and diameter, uterine volume, ovarian area, ovarian volume, maximum follicle diameter, and endometrial thickness were greater in the experimental group than in the control group, suggesting that abnormal sexually secreted hormones can lead to early development of the reproductive organs in children with ICPP; pelvic ultrasound can detect the morphological changes of the children’s ovaries and uterus, monitor the development of the children, and provide a basis for the diagnosis of ICPP.Children with ICPP grow faster in height than their peers during sexual development. Bone age can be used to assess a child’s growth and development, to help predict the timing of a girl's menarche, and to aid in the diagnosis of endocrine disorders [21, 22]. Leptin, a circulating hormone secreted by adipose tissue, is the basic protein product of obesity. Due to the rapid development of gonads and sexual organs in children, it will enlarge the areola [23–25]. In this study, the two groups were statistically different regarding height, leptin, bone age, and areola diameter. Serum LH is an important gonadotropin secreted by the pituitary gland; FSH is a glycoprotein hormone secreted by pituitary gonadotropin cells; E2 is the main estrogen and important hormone that promotes the development of female internal and external genitalia and maintains female sexual function and secondary sexual characteristics.It is documented that [26] serum LH, FSH, and E2 levels are significantly increased in children with ICPP, which has a certain diagnostic value. In this study, serum LH, FSH, and E2 levels in the experimental group were remarkably higher than those in the control group, indicating that serum LH, FSH, and E2 levels are related to children with ICPP, providing a reference for the diagnosis of ICPP. In addition, the diagnostic value of combined detection of pelvic ultrasound and serum LH, FSH, and E2 levels in ICPP showed that the combined detection area was larger than the single detection area, and the sensitivity of the combined detection obtained a similar result, suggesting that pelvic ultrasound combined detection with serum LH, FSH, and E2 levels can yield a higher diagnostic value and a higher accuracy rate.Chinese medicine believes that the lesions of precocious puberty are mainly in the kidneys and liver [27]. The cause of the disease is mainly due to the imbalance of yin and yang of the kidneys in children. In addition, it may also be caused by disease or mental factors that cause the liver to become hot and inflamed, leading to the early appearance of secondary sexual characteristics [28]. Precocious puberty can be diagnosed by observing and recording the symptoms, tongue, and pulse of the child (such as breast development stages and changes in secondary sexual characteristics) and carrying out TCM classification with reference to Differential Diagnosis of TCM Syndrome. These research results make the diagnosis and treatment of integrated traditional Chinese and Western medicine possible and worthy of promotion.To conclude, the combined detection of pelvic ultrasound and serum LH, FSH, and E2 levels may be a preferred technique for the diagnosis of children with ICPP due to its benefits of high sensitivity and accuracy. It is worthy of clinical promotion and application. However, since we only selected girls as experimental samples in our experiment, it has some limitations. Boys should be included in follow-up experiments to explore more generalizable and practical diagnostic methods.



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