Assessment of Acute Mountain Sickness: How to integrate the advantages of the Lake Louise Score and the Chinese AMS Score

Aims: To compare the differences in acute mountain sickness (AMS) incidence between two AMS diagnostic scoring criteria, including the Lake Louise Score and the Chinese AMS Score. Methods: A total of 2486 young men completed questionnaires after ying from Chendu (500 m) to Lasha (3658 m). The AMS incidence was investigated using a questionnaire that contained the scoring criteria for the LLS and CAS. To determine the grouping of all the symptoms on the AMS questionnaire, a systematic cluster analysis and two-step cluster analysis were used to analyse various symptoms and cases separately. Results: The AMS incidence was 37.5% (n = 932) according to the LLS, in which the cut-off point depended on headache and a total score ≥ 3, and 59.3% (n = 1473) according to the CAS, in which the cut-off point depended on headache, vomiting or a total score ≥ 5. The LLS and CAS outcomes had a signicant positive correlation (Spearman’s rho = 0.918, P < 0.05) and were moderately consistent (kappa value = 0.488, P < 0.001). The positive AMS incidence determined by the CAS was signicantly higher than that by the LLS (P < 0.001). Compared with the LLS, the sensitivity was 100%, the specicity was 65.23%, the positive predictive value was 63.34%, and the negative predictive value was 100% for the CAS in the diagnosis of AMS. The CAS identied all AMS subjects diagnosed by the LLS, and an additional 541 subjects. Of all the symptoms investigated, the dominant symptoms were fatigue (59.3%), dizziness (55.0%), headache (50.6%), chest tightness (40.4%), and shortness of breath (37.2%), and the last two symptoms were not included in the LLS. The cluster analysis show that chest distress, shortness of breath and palpitations were relatively independent of the major symptoms assessed by the LLS. Conclusion: The CAS had testing characteristics for diagnosing AMS similar to those of the Lake Louise Questionnaire Score, and the CAS diagnosed a higher prevalence of AMS than the LLS. generally consistent trend with the LLS. The CAS diagnosed a higher prevalence of AMS than the LLS at 3658 m when travelled to by aircraft. Chest distress and shortness of breath are high frequency symptoms of AMS. It is suggested that they should be included in the scoring system in the next revision to better diagnosis and study AMS.

relationship between the LLS and CAS diagnostic criteria for AMS to explore whether the limited symptoms of the LLS could cover the actual state of AMS well in a large sample population and whether the CAS including more symptoms is useful for improving the LLS.

Methods 1 Subjects
We enrolled 2503 participants at 500 m, 17 of whom were excluded for incomplete data. Thus, we analysed data obtained from the remaining 2486 subjects. Participants were required to have abstained from tobacco and alcohol for the previous 6 months, and other disease factors were excluded. The participants were all healthy young men (average age 18.33 ± 1.23 years, range 16 to 24 years) and lived below 2500 m altitude; no subject had a medical or AMS history.
In December 2012, the subjects were transported by plane for almost two and a half hours from Chengdu (500 m) to Lhasa in Tibet (3658 m). Before entering the plateau, the subjects underwent high-altitude health education and uni ed preventive measures but did not take preventive drugs. After arriving on the plateau, the individuals with serious symptoms were treated with drugs after a doctor's diagnosis. This study was approved by the Ethics Committee of the Army Military Medical University.

Questionnaires And Scoring Systems
We designed a questionnaire that included all the detailed symptoms covered by the LLS and CAS. Headache, gastrointestinal symptoms, fatigue and/or weakness, dizziness/lightheadedness, and sleep disturbance were each assigned a grade of 0 to 3 points. The remaining symptoms, i.e., palpitations, shortness of breath, chest distress, dazzling/blurred vision, anorexia, abdominal distension, diarrhoea, constipation, cyanosis of the lips, and numbness of the extremities, were recorded as 0 or 1 point. The questionnaire also collected demographic information on the subjects: age, ethnicity, individual history of AMS, smoker or non-smoker status, and permanent residence.
At 9 o'clock in the morning on the second day after arrival on the plateau, a questionnaire was issued by 5 trained investigators. AMS symptom scores were evaluated according to the LLS and CAS.

The Lake Louise Scoring system
The LLS examines ve symptoms: headache, gastrointestinal symptoms, fatigue/weakness, dizziness/light-headedness, and di culty sleeping. Each symptom was divided into none (score of 0), mild (1), moderate (2), and severe (3) ( Table 1). The presence of headache plus a cumulative score of 3 or greater is usually considered positive for AMS. Mild AMS was considered 3-5 points, and moderate or severe AMS was considered a score of 6 or greater (Table 2).
Although the LLS was adjusted in 2018 to remove sleep disturbance as a questionnaire item [20], considering the consistency and coherence of the research, we still used the old version of the LLS here.
A mild reaction was considered to be positive for AMS [16,21].   The Bonferroni-corrected chi-square method was used for comparisons between groups. Cluster analysis of symptoms was based on systematic cluster analysis. The cluster method was an inter-group link, and the measurement standard was Pearson correlation with 1 correlation coe cient as the distance between symptoms. Case clustering was performed with two-step clustering, and the log-likelihood was used to measure the distance. The clustering judgement was based on the Bayesian information criterion (BIC). All tests were two-tailed, and a P-value < 0.05 was considered signi cant.

1.The incidence of AMS determined by the two scoring systems
In all 2486 subjects, the incidence of AMS was 37.5% (n = 932) using the LLS and 59.3% using the CAS (n = 1473). There was a signi cant positive correlation between the LLS and CAS outcomes (Spearman's rho = 0.918, P < 0.05) (Fig. 1). The diagnostic results of the CAS and LLS were generally consistent, and the kappa value in the chi-square test was 0.488 (P < 0.001). The results of McNemar's test showed that there was a difference in the diagnosis between the two scoring standards. The positive rate of CAS-determined AMS was signi cantly higher than that of LLS-determined AMS (χ = 565.61, P = 0.000).
Both the CAS and LLS were evaluated by symptomatology scoring in a similar way. However, due to the different symptoms and weights assigned ( Table 1,   Table 2), the incidence determined by the CAS assessment was higher than that by the LLS (59.3% vs 37.5%). The CAS had diagnostic accuracy for moderate and severe AMS similar to that of the LLS (16.9% vs 17.2%). However, the difference was signi cant for mild AMS (42.3% vs 20.3%) (Fig. 2).

Diagnostic Accuracy Of The Cas
As the current mainstream standard for AMS diagnosis, validated by LLS diagnoses of AMS, the AUC was 0.820 (0.804-0.837; P < 0.01),indicating that the CAS was an accurately veri ed means of determining AMS diagnoses. The Youden index was 0.652. Taking the LLS as a reference, the sensitivity, speci city, positive predictive value and negative predictive value of the CAS for the diagnosis of AMS were 100%, 65.18%, 63.20%, and 100%, respectively.

Dominant symptoms
We found that the ve dominant symptoms in all subjects were fatigue (59.3%), dizziness (55.0%), headache (50.6%), chest tightness (40.4%), and shortness of breath (37.2%) (Fig. 3, Table 3). Among them, chest tightness and shortness of breath were from the CAS scoring system and were not mentioned in the LLS system.
Ratio: The frequency of the symptoms/total number All the symptoms on the AMS questionnaire were analysed by correlation based on whether they appeared at the same time and were clustered by systematic cluster analysis. The results showed that the distance between 6 symptoms, such as blurred vision and 5 variables from the LLS, was far. Because of its low frequency in the population, it could not be considered a main symptom of AMS. The distance between 3 symptoms, such as palpitation, chest distress and shortness of breath, was small, and the symptoms were relatively independent. Taking a height of 0.72 as the point of penetration, the symptoms can be divided into two modules: (1) headache, dizziness, fatigue, di culty sleeping, vomiting and anorexia, which are basically consistent with the 5 categories of the LLS, and (2) shortness of breath, palpitations, and chest tightness. The incidence of these symptoms was high in the population, and they are relatively independent of the classic LLS symptoms. The LLS scoring system cannot express the occurrence of these symptoms, so they should be regarded as important symptoms of AMS and were combined into 1 category at height = 0.86. (Fig. 4).
AMS symptoms cluster analysis based on systematic cluster analysis. The cluster method was an inter-group link, and the measurement standard was Pearson correlation with 1-correlation coe cient as the distance between symptoms.

Main Symptoms Of Lls Negative And Cas Positive
We found that all subjects diagnosed with AMS by the LLS (n = 932) were also positive for AMS according to the CAS. However, a total of 541 subjects were judged AMS positive by the CAS and AMS negative by the LLS. Among them, the CAS identi ed 523 as mild, 14 as moderate and 4 as severe. No severe mountain sickness, such as acute pulmonary oedema or acute brain oedema, occurred. The symptoms with the highest incidence were headache in 327 (60.6%), dizziness in 280 (51.9%), chest distress in 256 (47.3%), fatigue in 252 (46.6%), shortness of breath in 243 (44.9%), cyclosis of the lips in 189 (34.8%) and palpitations in 169 (31.1%) (Fig. 5). Chest distress, shortness of breath and so on led to the higher total CAS score of this part of the population, which met the CAS diagnostic criteria for AMS, but these symptoms were not included in the LLS, which led to the totally different results of 541 people using the two scoring systems.
The 541 cases were clustered using two-step clustering. After pre-clustering, six symptoms were considered less important variables (abdominal distention, diarrhoea, constipation, cyanosis of the lips, blurred vision, numbness of the extremities) and were deleted, and the remaining nine symptoms were used for two-step clustering again to obtain two clusters. Category 1 included 214 people (39.6%) without headache but with fatigue, dizziness, palpitations, chest distress, shortness of breath, and 327 people (60.4%) with headache and no other symptoms were included in Category 2. The distribution of clustering symptoms is shown in Fig. 3a, and the comparison of clustering symptoms is shown in Fig. 3b.
In addition, we found that there were no headaches (with a score of 0) in the four subjects who were identi ed as having severe AMS but that there were very serious gastroenteric symptoms, with a score of 3. At the same time, 3 people had fatigue/weakness, and 3 people had di culty sleeping. According to the CAS standards, there were also some people with shortness of breath, chest distress, dazzling/blurred vision, cyanosis of the lips, numbness of the extremities and other symptoms. Their total LLS score was greater than 5.

Discussion
This study compared the outcomes of two scoring criteria (the Lake Louise Score (LLS; score of ≥ 3) and the Chinese AMS Score (CAS; score of ≥ 5)) on the assessment of AMS in a large group including a total of 2486 subjects who rapidly entered a high-altitude area (3658 m) by plane. To the best of our knowledge, this is the rst large-sample study on the incidence of AMS as determined by the LLS and CAS diagnostic criteria. The CAS had testing characteristics for diagnosing AMS similar to those of the LLS and showed a generally consistent trend with the LLS, and the CAS diagnosed a higher prevalence of AMS than the LLS criteria did.
The results of this study show that the incidence of AMS diagnosed by the LLS and CAS was 37.5% and 59.3%, respectively. In studies that used an airplane approach, Harrison et al. [23] reported an AMS incidence of 33.3% using the LLS criteria, and Ren et al. [24] reported an AMS incidence of 57.2% using the standard CAS; our results are consistent with both of theirs. Because AMS evaluation lacks reliable biomarkers and clinical indicators, it mainly depends on the determination of some neurological, gastrointestinal and respiratory symptoms at high altitude. Both the CAS and LLS were evaluated by symptomatology scoring in a similar way. However, due to the different symptoms and weights assigned, the incidence determined by the CAS assessment was higher than that by the LLS (59.3% vs 37.5%). This was consistent with previous studies [8,9]. The CAS had diagnostic accuracy for moderate and severe AMS similar to those of the LLS (16.9% vs 17.2%). However, the difference was signi cant for mild AMS (42.3% vs 20.3%).
To help improve the AMS diagnostic criteria, some scholars compared and evaluated the different scoring criteria. [25] [26] [27] [11] Some Chinese scholars have studied the difference between the LLS and CAS in de ning AMS. Chen et al. [9] surveyed 339 males residing at sea level who travelled by train and car to 3200 m. Wu et al. [8] surveyed 58 males who went by train and recorded the AMS incidence when they reached different altitude sites, ending at 3658 m. They found that CAS outcomes were in good agreement with LLS outcomes and can accurately diagnose AMS, suggesting that combining the LLS and the CAS in applications of clinical diagnosis can more objectively diagnose AMS than one scoring system alone.
The LLS and CAS are self-report questionnaires that diagnose AMS using a subject's self-assessment of symptom intensity. The two scoring criteria have different scoring rules, resulting in different diagnostic results [20]. The LLS highlights the importance of headache as the main criterion for the diagnosis of AMS and demands the presence of headache, and a total score of 3 or more can diagnose AMS. It is generally believed that acute mountain sickness is associated with high-altitude cerebral oedema and that this pathophysiological process should be explored. It is believed that the vasodilation caused by hypoxia or its effectors may cause headache by activating the trigeminovascular system [28]. An alternative hypothesis is that early AMS is caused by mild high-altitude cerebral oedema [29]. AMS is the pathogenetic precursor to high-altitude cerebral oedema.
However, there are ongoing controversies about whether headache is a necessary criterion for the diagnosis of AMS [22,30]. The CAS criteria mainly emphasize headache and vomiting, which are major but nonspeci c symptoms in the diagnosis of AMS, and the weight of headache is still very high.
in the CAS can help medical staff to nd more unadaptable people in time and to initiate appropriate treatment to alleviate the further development of symptoms.
The in uence of high altitude on organisms involves nearly every organ system. However, the LLS did not include the symptoms of the effects of hypoxia on the respiratory system because scholars considered the primary signi cance of AMS to be its potential for progression to HACE. [32] However, high-altitude pulmonary edema (HAPE) is also a high-altitude illness with an incidence rate of approximately 0.1%. HAPE that is ignored or unrecognized may pass rapidly through a stage of dyspnoea and progress overnight to severe encephalopathy and coma [32]. According to the survey results, the incidence of chest distress was 40.4%, ranking fourth among symptoms, and the incidence of shortness of breath was 37.2%, ranking fth among symptoms, both of which are symptoms of the in uence of a hypoxic environment on the respiratory system. The cluster analysis results also con rmed this point; shortness of breath and chest distress were relatively independent of the ve symptoms on the LLS. Therefore, it is suggested that the two symptoms involved in the CAS should be included in the scoring system in future revisions of the standard. This helps AMS diagnostic instruments identify more potential patients and provide timely medical services to improve the living comfort and mobility of patients. The AMS diagnostic criteria have been continuously improving [20]. To better diagnosis and study AMS, we hope that our research can provide some help for the improvement of AMS scoring criteria.
Although this study had a large sample size, the participants were all young men, preventing generalizations from our sample to women and other age groups.
The monitoring index was simple, as it only analysed and compared the main indexes and scores for AMS, but physiological indexes, such as pulse, blood pressure or blood oxygen saturation, were not recorded.

Conclusion
The CAS is a widely used diagnostic standard for AMS in China. Headache is considered a major but nonspeci c symptom in the diagnosis of AMS, and the CAS also contains 15 other symptoms. In our study, the CAS had testing characteristics for diagnosing AMS similar to those of the LLS and showed a generally consistent trend with the LLS. The CAS diagnosed a higher prevalence of AMS than the LLS at 3658 m when travelled to by aircraft. Chest distress and shortness of breath are high frequency symptoms of AMS. It is suggested that they should be included in the scoring system in the next revision to better diagnosis and study AMS. Availability of data and materials The datasets are available from the corresponding author on reasonable request.

Competing Interest
The authors declare that they have no competing interests. Authors' contributions YG and JC participated in the design of this study. YW and JC performed the experiment. YW ,ZZ and PL performed the data processing and statistical analysis. YW drafted the manuscript and PL, JX, SZ revised the manuscript. All authors read and agreed to its content and approved the nal manuscript.

Figure 2
Results for the degree of acute mountain sickness according to the Lake Louise Score (LLS) and the Chinese AMS Score (CAS) Figure 3 Page 12/13 Difference in the positive rate of symptoms in the population.