Excessive daytime sleepiness is associated with relative delta frequency power among patients with mild OSA.

Background: Excessive daytime sleepiness (EDS) is a cause of low quality of life among obstructive sleep apnoea (OSA) patients. Current methods of assessing and predicting EDS are limited due to time constraints or differences in subjective experience and scoring. Electroencephalogram (EEG) power spectral densities (PSDs) have shown differences between OSA and non-OSA patients, and fatigued and non-fatigued patients. Therefore, polysomnographic EEG PSDs may be useful to assess the extent of EDS among patients with OSA. Methods: Patients presenting to Israel Loewenstein hospital reporting daytime sleepiness who recorded mild OSA on polysomnography and undertook a multiple sleep latency test. Alpha, beta, and delta relative powers were assessed between patients categorized as non-sleepy (mean sleep latency (MSL) ≥10 min) and sleepy (MSL <10 min). Results: 139 patients (74% male) were included for analysis. 73 (53%) were categorized as sleepy (median MSL 6.5 min). There were no significant differences in demographics or polysomnographic parameters between sleepy and non-sleepy groups. In multivariate analysis, increasing relative delta frequency power was associated with increased odds of sleepiness (OR 1.025 (95% CI 1.024-1.026)), while relative alpha and beta powers were associated with decreased odds. The effect size of delta PSD on sleepiness was significantly greater than that of either alpha or beta frequencies. Conclusion: Delta PSD during polysomnography is significantly associated with a greater degree of objective daytime sleepiness among patients with mild OSA. Further research is needed to corroborate our findings and identify the direction of potential causal correlation between delta PSD and EDS.

Nocturnal oxygen resaturation parameters are associated with cardiorespiratory comorbidities.

BACKGROUND: There are strong associations between oxygen desaturations and cardiovascular outcomes. Additionally, oxygen resaturation rates are linked to excessive daytime sleepiness independent of oxygen desaturation severity. No studies have yet looked at the independent effects of comorbidities or medications on resaturation parameters. METHODS: The Sleep Heart Health Study data was utilised to derive oxygen saturation parameters from 5804 participants. Participants with a history of comorbidities or medication usage were compared against healthy participants with no comorbidity/medication history. RESULTS: 4293 participants (50.4% female, median age 64 years) were included in the analysis. Females recorded significantly faster resaturation rates (mean 0.61%/s) than males (mean 0.57%/s, p < 0.001), regardless of comorbidities. After adjusting for demographics, sleep parameters, and desaturation parameters, resaturation rate was reduced with hypertension (-0.09 (95% CI -0.16, -0.03)), myocardial infarction (-0.13 (95% CI -0.21, -0.04)) and heart failure (-0.19 (95% CI -0.33, -0.05)), or when using anti-hypertensives (-0.10 (95% CI -0.17, -0.03)), mental health medications (-0.18 (95% CI -0.27, -0.08)) or anticoagulants (-0.41 (95% CI -0.56, -0.26)). Desaturation to Resaturation ratio for duration was decreased with mental health (-0.21 (95% CI -0.34, -0.08)) or diabetic medications (-0.24 (95% CI -0.41, -0.07)), and desaturation to resaturation ratio for area decreased with heart failure (-0.25 (95% CI -0.42, -0.08)). CONCLUSIONS: Comorbidities and medications significantly affect nocturnal resaturation parameters, independent of desaturation parameters. However, the causal relationship remains unclear. Further research can enhance our knowledge and develop more precise and safer interventions for individuals affected by certain comorbidities.

Interhemispheric differences of electroencephalography signal characteristics in different sleep stages.

OBJECTIVE: The current electroencephalography (EEG) measurement setup is complex, laborious to set up, and uncomfortable for patients. We hypothesize that differences in EEG signal characteristics for sleep staging between the left and right hemispheres are negligible; therefore, there is potential to simplify the current measurement setup. We aimed to investigate the technical hemispheric differences in EEG signal characteristics along with electrooculography (EOG) signals during different sleep stages. METHODS: Type II portable polysomnography (PSG) recordings of 50 patients were studied. Amplitudes and power spectral densities (PSDs) of the EEG and EOG signals were compared between the left (C3-M2, F3-M2, O1-M2, and E1-M2) and the right (C4-M1, F4-M1, O2-M1, and E2-M2) hemispheres. Regression analysis was performed to investigate the potential influence of sleep stages on the hemispheric differences in PSDs. Wilcoxon signed-rank tests were also employed to calculate the effect size of hemispheres across different frequency bands and sleep stages. RESULTS: The results showed statistically significant differences in signal characteristics between hemispheres, but the absolute differences were minor. The median hemispheric differences in amplitudes were smaller than 3 µv with large interquartile ranges during all sleep stages. The absolute and relative PSD characteristics were highly similar between hemispheres in different sleep stages. Additionally, there were negligible differences in the effect size between hemispheres across all sleep stages. CONCLUSIONS: Technical signal differences between hemispheres were minor across all sleep stages, indicating that both hemispheres contain similar information needed for sleep staging. A reduced measurement setup could be suitable for sleep staging without the loss of relevant information.

Acute Cardiorespiratory Coupling Impairment in Worsening Sleep Apnea-Related Intermittent Hypoxemia.

OBJECTIVE: Hypoxic load is one of the main characteristics of obstructive sleep apnea (OSA) contributing to sympathetic overdrive and weakened cardiorespiratory coupling (CRC). Whether this association changes with increasing hypoxic load has remained obscure. Therefore, we aimed to study our hypothesis that increasing hypoxic load acutely decreases the CRC. METHODS: We retrospectively analyzed the electrocardiography and nasal pressure signals in 5-min segment pairs (n = 36 926) recorded during clinical polysomnographies of 603 patients with suspected OSA. The segment pairs were pooled into five groups based on the hypoxic load severity described with the the total integrated area under the blood oxygen saturation curve during desaturations. In these severity groups, we determined the frequency-domain heart rate variability (HRV) parameters, the HRV and respiratory high-frequency (HF, 0.15-0.4 Hz) peaks, and the difference between those peaks. We also computed the spectral HF coherence between HRV and respiration in the HF band. RESULTS: The ratio of low-frequency (LF, 0.04-0.15 Hz) to HF power increased from 1.047 to 1.805 (p < 0.001); the difference between the HRV and respiratory HF peaks increased from 0.001 Hz to 0.039 Hz (p < 0.001); and the spectral coherence between HRV and respiration in the HF band decreased from 0.813 to 0.689 (p < 0.001) as the hypoxic load increased. CONCLUSION AND SIGNIFICANCE: The vagal modulation decreases and CRC weakens significantly with increasing hypoxic load. Thus, the hypoxic load could be utilized more thoroughly in contemporary OSA diagnostics to better assess the severity of OSA-related cardiac stress.

Reaction time in psychomotor vigilance task is related to hypoxic load in males with sleep apnea.

Oxygen saturation (SpO2 )-based parameters are more strongly linked to impaired daytime vigilance than the conventional diagnostic metrics in patients with obstructive sleep apnea (OSA). However, whether the association between SpO2 -based parameters and impaired daytime vigilance is modulated by sex, remains unknown. Hence, we investigated the interplay between sex and detailed SpO2 -based metrics and their association with impaired vigilance in patients with OSA. The study population consisted of 855 (473 males, 382 females) patients with suspected OSA who underwent overnight polysomnography and psychomotor vigilance task (PVT). The population was grouped by sex and divided into quartiles (Q1-Q4) based on median reaction times (RTs) in the PVT. In addition to conventional diagnostic metrics, desaturation severity (DesSev), fall severity (FallSev), and recovery severity (RecovSev) were compared between the sexes and between the best (Q1) and worst (Q4) performing quartiles by using cumulative distribution functions (CDFs). Additionally, sex-specific covariate-adjusted linear regression models were used to investigate the connection between the parameters and RTs. The CDFs showed significantly higher hypoxic load in Q4 in males compared to females. In addition, the DesSev (ß = 8.05, p < 0.01), FallSev (ß = 6.48, p = 0.02), RecovSev (ß = 9.13, p < 0.01), and Oxygen Desaturation Index (ß = 12.29, p < 0.01) were associated with increased RTs only in males. Conversely, the Arousal Index (ß = 10.75-11.04, p < 0.01) was associated with impaired vigilance in females. The severity of intermittent hypoxaemia was strongly associated with longer RTs in males whereas the Arousal Index had the strongest association in females. Thus, the impact of hypoxic load on impaired vigilance seems to be stronger in males than females.

Oxygen resaturation rate is significantly associated with objectively assessed excessive daytime sleepiness in suspected obstructive sleep apnoea patients.

INTRODUCTION: Commonly utilised metrics such as the apnoea-hypopnoea index show limited correlation to excessive daytime sleepiness (EDS). Oxygen desaturation parameters show better predictive power, however oxygen resaturation parameters have not yet been investigated. Oxygen resaturation may represent increased cardiovascular fitness and thus we hypothesized that a higher resaturation rate would be protective against EDS. METHODS: Oxygen saturation parameters were computed via ABOSA software for adult patients referred for polysomnography and multiple sleep latency test in Israel Loewenstein hospital 2001-2011. EDS was defined as a mean sleep latency (MSL) below 8 min. RESULTS: 1629 patients (75% male, 53% obese, median age of 54 years) were included for analysis. The average desaturation event nadir was 90.4% and resaturation rate 0.59%/second. Median MSL was 9.6 min, and 606 patients met criteria for EDS. Patients who were younger, female, and with larger desaturations had significantly higher resaturation rates (p < 0.001). In multivariate models, adjusted for age, sex, body mass index, and average desaturation depth, resaturation rate showed a significant negative correlation with MSL (z-score standardised beta, -1 (95%CI -0.49, -1.52)), and significantly increased odds ratio (OR) of EDS (OR, 1.28 (95%CI 1.07, 1.53)). The beta associated with resaturation rate was larger, though non-significantly, than that of desaturation depth (difference 0.36 (95% CI -1.34, 0.62), p = 0.470). CONCLUSION: Oxygen resaturation parameters show significant associations with objectively assessed EDS independent of desaturation parameters. Thus, resaturation and desaturation parameters may reflect differing underlying mechanistic pathways and both be considered novel and appropriate markers for assessing sleep-disordered breathing and associated outcomes.

Utilizing Envelope Analysis of a Nasal Pressure Signal for Sleep Apnea Severity Estimation.

Obstructive sleep apnea (OSA) severity assessment is based on manually scored respiratory events and their arbitrary definitions. Thus, we present an alternative method to objectively evaluate OSA severity independently of the manual scorings and scoring rules. A retrospective envelope analysis was conducted on 847 suspected OSA patients. Four parameters were calculated from the difference between the nasal pressure signal's upper and lower envelopes: average (AV), median (MD), standard deviation (SD), and coefficient of variation (CoV). We computed the parameters from the entirety of the recorded signals to perform binary classifications of patients using three different apnea-hypopnea index (AHI) thresholds (5-15-30). Additionally, the calculations were undertaken in 30-second epochs to estimate the ability of the parameters to detect manually scored respiratory events. Classification performances were assessed with areas under the curves (AUCs). As a result, the SD (AUCs ≥ 0.86) and CoV (AUCs ≥ 0.82) were the best classifiers for all AHI thresholds. Furthermore, non-OSA and severe OSA patients were separated well with SD (AUC = 0.97) and CoV (AUC = 0.95). Respiratory events within the epochs were identified moderately with MD (AUC = 0.76) and CoV (AUC = 0.82). In conclusion, envelope analysis is a promising alternative method by which to assess OSA severity without relying on manual scoring or the scoring rules of respiratory events.

Obstructive sleep apnea-related intermittent hypoxaemia is associated with impaired vigilance.

Obstructive sleep apnea (OSA)-related intermittent hypoxaemia is a potential risk factor for different OSA comorbidities, for example cardiovascular disease. However, conflicting results are found as to whether intermittent hypoxaemia is associated with impaired vigilance. Therefore, we aimed to investigate how desaturation characteristics differ between the non-impaired vigilance and impaired vigilance patient groups formed based on psychomotor vigilance task (PVT) performance and compared with traditional OSA severity parameters. The study population comprised 863 patients with suspected OSA who underwent a PVT test before polysomnography. The conventional OSA parameters, for example, the apnea-hypopnea index, oxygen desaturation index, and arousal index were computed. Furthermore, the median desaturation area, fall area, recovery area, and desaturation depth were computed with the pre-event baseline reference and with reference to the 100% oxygen saturation level. Patients were grouped into best- and worst-performing quartiles based on the number of lapses in PVT (Q1: PVT lapses <5 and Q4: PVT lapses >36). The association between parameters and impaired vigilance was evaluated by cumulative distribution functions (CDFs) and binomial logistic regression. Based on the CDFs, patients in Q4 had larger desaturation areas, recovery areas, and deeper desaturations when these were referenced to 100% saturation compared with Q1. The odds ratio (OR) of the median desaturation area (OR = 1.56), recovery area (OR = 1.71), and depth (OR = 1.65) were significantly elevated in Q4 in regression models. However, conventional OSA parameters were not significantly associated with impaired vigilance (ORs: 0.79-1.09). Considering desaturation parameters with a 100% SpO2 reference in the diagnosis of OSA could provide additional information on the severity of OSA and related daytime vigilance impairment.

Obstructive sleep apnoea-related respiratory events and desaturation severity are associated with the cardiac response.

Background: Obstructive sleep apnoea (OSA) causes, among other things, intermittent blood oxygen desaturations, increasing the sympathetic tone. Yet the effect of desaturations on heart rate variability (HRV), a simple and noninvasive method for assessing sympathovagal balance, has not been comprehensively studied. We aimed to study whether desaturation severity affects the immediate HRV. Methods: We retrospectively analysed the electrocardiography signals in 5-min segments (n=39 132) recorded during clinical polysomnographies of 642 patients with suspected OSA. HRV parameters were calculated for each segment. The segments were pooled into severity groups based on the desaturation severity (i.e. the integrated area under the blood oxygen saturation curve) and the respiratory event rate within the segment. Covariate-adjusted regression analyses were performed to investigate possible confounding effects. Results: With increasing respiratory event rate, the normalised high-frequency band power (HFNU) decreased from 0.517 to 0.364 (p<0.01), the normalised low-frequency band power (LFNU) increased from 0.483 to 0.636 (p<0.01) and the mean RR interval decreased from 915 to 869 ms (p<0.01). Similarly, with increasing desaturation severity, the HFNU decreased from 0.499 to 0.364 (p<0.01), the LFNU increased from 0.501 to 0.636 (p<0.01) and the mean RR interval decreased from 952 to 854 ms (p<0.01). Desaturation severity-related findings were confirmed by considering the confounding factors in the regression analyses. Conclusion: The short-term HRV response differs based on the desaturation severity and the respiratory event rate in patients with suspected OSA. Therefore, a more detailed analysis of HRV and desaturation characteristics could enhance OSA severity estimation.

Desaturation event scoring criteria affect the perceived severity of nocturnal hypoxic load.

OBJECTIVES/BACKGROUND: Interest in using blood oxygen desaturations in the diagnostics of sleep apnea has risen in recent years. However, no standardized criteria for desaturation scoring exist which complicates the drawing of solid conclusions from literature. PATIENTS/METHODS: We investigated how different desaturation scoring criteria affect the severity of nocturnal hypoxic load and the prediction of impaired daytime vigilance in 845 patients. Desaturations were scored based on three features: 1) minimum oxygen saturation drop during the event (2-20%, 1% interval), 2) minimum duration of the event (2-20s, 1s interval), and 3) maximum plateau duration within the event (5-60s, 5s interval), resulting in 4332 different scoring criteria. The hypoxic load was described with oxygen desaturation index (ODI), desaturation severity (DesSev), and desaturation duration (DesDur) parameters. Association between hypoxic load and impaired vigilance was investigated with covariate-adjusted area under curve (AUC) analyses by dividing patients into normal (≤5 lapses) and impaired (≥36 lapses) vigilance groups based on psychomotor vigilance task performance. RESULTS: The severity of hypoxic load varied greatly between different scoring criteria. For example, median ODI ranged between 0.4 and 12.9 events/h, DesSev 0.01-0.23 %-point, and DesDur 0.3-9.6 %-point when the minimum transient drop criterion of 3% was used and other two features were altered. Overall, the minimum transient drop criterion had the largest effect on parameter values. All models with differently determined parameters predicted impaired vigilance moderately (AUC = 0.722-0.734). CONCLUSIONS: Desaturation scoring criteria greatly affected the severity of hypoxic load. However, the difference in the prediction of impaired vigilance between different criteria was rather small.

ABOSA - Freely available automatic blood oxygen saturation signal analysis software: Structure and validation.

BACKGROUND AND OBJECTIVE: Many sleep recording software used in clinical settings have some tools to automatically analyze the blood oxygen saturation (SpO2) signal by detecting desaturations. However, these tools are often inadequate for scientific research as they do not provide SpO2 signal-based parameters which are superior in the estimation of sleep apnea severity and related medical consequences. In addition, these software require expensive licenses and they lack batch analysis tools. Thus, we developed the first freely available automatic blood oxygen saturation analysis software (ABOSA) that provides sophisticated SpO2 signal-based parameters and enables batch analysis of large datasets. METHODS: ABOSA was programmed with MATLAB. ABOSA automatically detects desaturation and recovery events from the SpO2 signals (EDF files) and calculates numerous parameters, such as oxygen desaturation index (ODI) and desaturation severity (DesSev). The accuracy of the ABOSA software was evaluated by comparing its desaturation scorings to manual scorings in Kuopio (n = 1981) and Loewenstein (n = 930) sleep apnea patient datasets. Validation was performed in a second-by-second manner by calculating Matthew's correlation coefficients (MCC) and median differences in parameter values. Finally, the performance of the ABOSA software was compared to two commercial software, Noxturnal and Profusion, in 100 patient subpopulations. As Noxturnal or Profusion does not calculate novel desaturation parameters, these were calculated with custom-made functions. RESULTS: The agreements between ABOSA and manual scorings were great in both Kuopio (MCC = 0.801) and Loewenstein (MCC = 0.898) datasets. However, ABOSA slightly overestimated the desaturation parameter values. The median differences in ODIs were 0.8 (Kuopio) and 0.0 (Loewenstein) events/h. Similarly, the median differences in DesSevs were 0.02 (Kuopio) and 0.01 (Loewenstein) percentage points. In a second-by-second analysis, ABOSA performed very similarly to Noxturnal and Profusion software in both Kuopio (MCCABOSA = 0.807, MCCNoxturnal = 0.807, MCCProfusion = 0.811) and Loewenstein (MCCABOSA = 0.904, MCCNoxturnal = 0.911, MCCProfusion = 0.871) datasets. Based on Noxturnal and Profusion scorings, the desaturation parameter values were similarly overestimated compared to ABOSA. CONCLUSIONS: ABOSA is an accurate and freely available software that calculates both traditional clinical parameters and novel parameters, provides a detailed characterization of desaturation and recovery events, and enables batch analysis of large datasets. These are features that no other software currently provides making ABOSA uniquely suitable for scientific research use.

Novel oxygen desaturation parameters are associated with cardiac troponin I: Data from the Akershus Sleep Apnea Project.

Novel diagnostic markers for obstructive sleep apnea beyond the apnea-hypopnea index (AHI) have been introduced. There are no studies on their association with markers of subclinical myocardial injury. We assessed the association between novel desaturation parameters and elevated cardiac troponin I and T. Participants with polysomnography (498) from the Akershus Sleep Apnea study were divided into normal and elevated biomarker groups based on sex-specific concentration thresholds (cardiac troponin I: ≥4 ng/L for women, ≥6 ng/L for men; and cardiac troponin T: ≥7 ng/L for women, ≥8 ng/L for men). Severity of obstructive sleep apnea was evaluated with the AHI, oxygen desaturation index, total sleep time with oxygen saturation below 90% (T90), lowest oxygen saturation (Min SpO2 %), and novel oxygen desaturation parameters: desaturation duration and desaturation severity. How the AHI and novel desaturation parameters predicted elevated cardiac troponin I and cardiac troponin T levels was assessed by the area under the curve (AUC). Based on multivariable-adjusted linear regression, the AHI (ß = 0.004, p = 0.012), desaturation duration (ß = 0.007, p = 0.004), and desaturation severity (ß = 0.147, p = 0.002) were associated with cardiac troponin I levels but not cardiac troponin T. T90 was associated with cardiac troponin I (ß = 0.006, p = 0.009) and cardiac troponin T (ß = 0.005, p = 0.007). The AUC for the AHI 0.592 (standard error 0.043) was not significantly different from the AUC of T90 (SD 0.640, p = 0.08), desaturation duration 0.609 (SD 0.044, p = 0.42) or desaturation severity 0.616 (SD 0.043, p = 0.26) in predicting myocardial injury as assessed by cardiac troponin I. Oxygen desaturation parameters and the AHI were associated with cardiac troponin I levels but not cardiac troponin T levels. Novel oxygen desaturation parameters did not improve the prediction of subclinical myocardial injury compared to the AHI.

Diabetes and cardiovascular diseases are associated with the worsening of intermittent hypoxaemia.

Intermittent hypoxaemia is a risk factor for numerous diseases. However, the reverse pathway remains unclear. Therefore, we investigated whether pre-existing hypertension, diabetes or cardiovascular diseases are associated with the worsening of intermittent hypoxaemia. Among the included 2,535 Sleep Heart Health Study participants, hypertension (n = 1,164), diabetes (n = 170) and cardiovascular diseases (n = 265) were frequently present at baseline. All participants had undergone two polysomnographic recordings approximately 5.2 years apart. Covariate-adjusted linear regression analyses were utilized to investigate the difference in the severity of intermittent hypoxaemia at baseline between each comorbidity group and the group of participants free from all comorbidities (n = 1,264). Similarly, we investigated whether the pre-existing comorbidities are associated with the progression of intermittent hypoxaemia. Significantly higher oxygen desaturation index (ß = 1.77 [95% confidence interval: 0.41-3.13], p = 0.011), desaturation severity (ß = 0.07 [95% confidence interval: 0.00-0.14], p = 0.048) and desaturation duration (ß = 1.50 [95% confidence interval: 0.31-2.69], p = 0.013) were observed in participants with pre-existing cardiovascular diseases at baseline. Furthermore, the increase in oxygen desaturation index (ß = 3.59 [95% confidence interval: 1.78-5.39], p < 0.001), desaturation severity (ß = 0.08 [95% confidence interval: 0.02-0.14], p = 0.015) and desaturation duration (ß = 2.60 [95% confidence interval: 1.22-3.98], p < 0.001) during the follow-up were higher among participants with diabetes. Similarly, the increase in oxygen desaturation index (ß = 2.73 [95% confidence interval: 1.15-4.32], p = 0.001) and desaturation duration (ß = 1.85 [95% confidence interval: 0.62-3.08], p = 0.003) were higher among participants with cardiovascular diseases. These results suggest that patients with pre-existing diabetes or cardiovascular diseases are at increased risk for an expedited worsening of intermittent hypoxaemia. As intermittent hypoxaemia is an essential feature of sleep apnea, these patients could benefit from the screening and follow-up monitoring of sleep apnea.

Longer and Deeper Desaturations Are Associated With the Worsening of Mild Sleep Apnea: The Sleep Heart Health Study.

STUDY OBJECTIVES: Obesity, older age, and male sex are recognized risk factors for sleep apnea. However, it is unclear whether the severity of hypoxic burden, an essential feature of sleep apnea, is associated with the risk of sleep apnea worsening. Thus, we investigated our hypothesis that the worsening of sleep apnea is expedited in individuals with more severe desaturations. METHODS: The blood oxygen saturation (SpO2) signals of 805 Sleep Heart Health Study participants with mild sleep apnea [5 ≤ oxygen desaturation index (ODI) < 15] were analyzed at baseline and after a mean follow-up time of 5.2 years. Linear regression analysis, adjusted for relevant covariates, was utilized to study the association between baseline SpO2-derived parameters and change in sleep apnea severity, determined by a change in ODI. SpO2-derived parameters, consisting of ODI, desaturation severity (DesSev), desaturation duration (DesDur), average desaturation area (avg. DesArea), and average desaturation duration (avg. DesDur), were standardized to enable comparisons between the parameters. RESULTS: In the group consisting of both men and women, avg. DesDur (ß = 1.594, p = 0.001), avg. DesArea (ß = 1.316, p = 0.004), DesDur (ß = 0.998, p = 0.028), and DesSev (ß = 0.928, p = 0.040) were significantly associated with sleep apnea worsening, whereas ODI was not (ß = -0.029, p = 0.950). In sex-stratified analysis, avg. DesDur (ß = 1.987, p = 0.003), avg. DesArea (ß = 1.502, p = 0.024), and DesDur (ß = 1.374, p = 0.033) were significantly associated with sleep apnea worsening in men. CONCLUSION: Longer and deeper desaturations are more likely to expose a patient to the worsening of sleep apnea. This information could be useful in the planning of follow-up monitoring or lifestyle counseling in the early stage of the disease.