<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04473066</url>
  </required_header>
  <id_info>
    <org_study_id>HMRF-07181276</org_study_id>
    <nct_id>NCT04473066</nct_id>
  </id_info>
  <brief_title>Long-term Follow-up of Children With OSA Treated With AT</brief_title>
  <official_title>Long-term Follow-up of Children With Obstructive Sleep Apnoea Treated With Adenotonsillectomy: Cardiovascular Perspectives</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chinese University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Chinese University of Hong Kong</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Objectives: To assess the cardiovascular outcomes of children with obstructive sleep apnoea&#xD;
      (OSA) at a mean of 5 years after they had undergone adenotonsillectomy (AT), compared to OSA&#xD;
      children who did not undergo AT, and normal controls without OSA.&#xD;
&#xD;
      Hypothesis to be tested: (1) children with OSA underwent AT would have lower cardiovascular&#xD;
      risks, namely lower ambulatory blood pressure (ABP), better cardiac function, lower carotid&#xD;
      intima-media thickness (CIMT) and lower carotid arterial thickness when compared to those&#xD;
      with OSA but did not undergo AT, and that (2) children with OSA, despite treatment with AT,&#xD;
      would have higher cardiovascular risks than non-OSA controls. Design: A two-centre&#xD;
      prospective case-control follow-up study Subjects: Potential subjects for this follow-up&#xD;
      study have been identified from two local hospitals, Prince of Wales and Kwong Wah Hospitals.&#xD;
      AT-treated group (n=90) - Children had moderate-to-severe OSA (obstructive apnoea hypopnoea&#xD;
      index (OAHI) &gt;=3 events/h) and underwent AT when they were aged 5-12 years. Refused AT group&#xD;
      (n=45) - Children had moderate-to-severe OSA but refused AT. Non-OSA control group (n=45) -&#xD;
      Non-snoring controls with OAHI &lt;1 event/h . Main outcome measures: 24-hour ABP, cardiac&#xD;
      function measured by echocardiography, CIMT and carotid arterial stiffness.&#xD;
&#xD;
      Data analysis: Apart from group comparisons, multiple linear regression and logistic&#xD;
      regression analysis will also be used to examine whether cardiovascular outcomes are&#xD;
      associated with AT, pre- and post-AT OAHI while adjusted for confounders.&#xD;
&#xD;
      Expected results: AT improves cardiovascular outcomes of children with OSA. However they&#xD;
      still had higher cardiovascular risks than normal controls even after AT.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aims and Hypotheses to be Tested:&#xD;
&#xD;
      The primary aim of this study is to assess cardiovascular outcomes of children with OSA at a&#xD;
      mean of 5 years after they had undergone AT, compared to OSA children without surgical&#xD;
      treatment and children without OSA. The secondary aim is to explore factors associated with&#xD;
      cardiovascular outcomes in subjects with OSA after AT.&#xD;
&#xD;
      We hypothesise that (1) children with OSA underwent AT would have lower cardiovascular risks,&#xD;
      namely lower ABP, better cardiac function, lower carotid intima-media thickness (CIMT) and&#xD;
      lower carotid arterial stiffness when compared to those with OSA but did not undergo AT, and&#xD;
      that (2) children with OSA, despite treatment with AT, would have higher cardiovascular risks&#xD;
      than non-OSA controls.&#xD;
&#xD;
      Study design: A two-centre prospective case-control follow-up study.&#xD;
&#xD;
      Sample size estimation:&#xD;
&#xD;
      We have conducted a pilot study to compare 12 children with residual OSA after AT (defined as&#xD;
      post-AT OAHI &gt;=3/h) and 12 age-, sex- and BMI-matched non-snoring controls. The results&#xD;
      showed that children with residual OSA had a higher nighttime systolic BP (NSBP) than&#xD;
      non-snoring controls (98.9 c.f. 95.6 mm Hg, mean difference = 3.35 mmHg, common SD = 6.54&#xD;
      mmHg, effect size = 0.51). We have a total of 130 subjects with moderate-to-severe OSA who&#xD;
      had undergone AT. As the main aim of this study is to assess the treatment effects of AT, we&#xD;
      will try to recruit as many AT-treated subjects as possible. Assuming a response rate of 70%,&#xD;
      90 subjects will be recruited. If 45 normal controls were also recruited (case/control ratio&#xD;
      = 2:1), the study would provide a power of 87% to detect the difference with a 5% type I&#xD;
      error rate. The minimum number of subjects required to detect the difference with an 80%&#xD;
      power and a 5% type I error rate are 72 cases and 36 controls if the case/control ratio is&#xD;
      2:1. A sample size of 90 AT-treated subjects will also provide an 80% power to detect the&#xD;
      potential effects of pre-AT OAHI and follow-up OAHI on cardiovascular outcomes with medium&#xD;
      effect size (assuming a partial R-squared of 0.1), while adjusted for age, sex and BMI in&#xD;
      multiple linear regression model within the AT group.&#xD;
&#xD;
      Besides, we have also conducted a separate pilot study comparing a group of 18 children with&#xD;
      moderate-to-severe OSA treated with AT and a group of 18 age-, sex- and BMI-matched children&#xD;
      with similar OSA severity without AT. The results showed that the nighttime systolic BP in&#xD;
      the AT group was reduced by a mean of 2.3 mmHg at a 9-month follow-up visit, whereas the&#xD;
      non-AT group had an increase in nighttime systolic BP by a mean of 2.3 mmHg (mean difference&#xD;
      = 4.52 mmHg, common SD = 7.34 mmHg, effect size = 0.62). We have a total of 63 candidates for&#xD;
      AT who had refused to undergo AT. Assuming a response rate of 70%, 45 subjects will be&#xD;
      recruited. A total of 90 cases (AT-treated) and 45 controls (refused AT) provides a power of&#xD;
      95% to detect the expected difference with a type I error rate of 5%. The minimum number of&#xD;
      subjects required to detect the difference with an 80% power and a 5% type I error rate are&#xD;
      50 cases and 25 controls if the case/control ratio is 2:1. All sample size and power&#xD;
      calculations were done using G*Power (Version 3.1.9.2).&#xD;
&#xD;
      Our target is to recruit a total of 180 subjects, comprising of 90 OSA subjects treated with&#xD;
      AT, 45 non-snoring controls and 45 OSA subjects without AT for this follow-up study. We are&#xD;
      confident to recruit the target number of subjects as we have been following up the OSA&#xD;
      patients regularly in out-patient clinic and we also have a sufficient amount of normal&#xD;
      control subjects for matching and recruitment.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      All participants will have to visit our unit once to undergo anthropometric measurement,&#xD;
      overnight polysomnography (PSG), 24-hour ABPM, echocardiographic and arterial assessments.&#xD;
      They will be arranged to come to our sleep laboratory at around 9 am in the morning.&#xD;
      Twenty-four hour ABPM will be started after resting for 10 minutes upon arrival.&#xD;
      Echocardiographic and arterial assessments will be subsequently arranged. They will stay&#xD;
      until the next morning after completion of overnight sleep study and 24-h ABPM. For those who&#xD;
      are reluctant to complete the whole study protocol, especially for control subjects who may&#xD;
      not be willing to stay overnight for the sleep study, their symptoms will be documented by a&#xD;
      self- or parent-report questionnaire (appendix 2), and they will have to come to our unit to&#xD;
      undergo all the cardiovascular assessments and take the ABP monitor back home and return to&#xD;
      us the next day when the 24-h monitoring is completed. Those failed to complete all the&#xD;
      outcome assessments will be excluded.&#xD;
&#xD;
      Data processing and analysis:&#xD;
&#xD;
      The AT-treated group will be compared to the refused AT group and the non-snoring controls to&#xD;
      assess the between-group differences in various cardiovascular outcomes. Student's t tests,&#xD;
      Mann-Whitney U tests and chi-square tests will be used for the comparisons of normally&#xD;
      distributed, non-normally distributed and categorical data, respectively. Linear and logistic&#xD;
      regression analysis will be used to test whether OSA severity at baseline and follow-up and&#xD;
      AT are associated with continuous (e.g. CIMT) and binary (e.g. hypertension) cardiovascular&#xD;
      outcomes, respectively, while adjusting for age, gender and body size. Subgroup analysis will&#xD;
      also be performed within the AT-treated group to explore factors associated with&#xD;
      cardiovascular outcomes after AT. Particularly, the association of pre-AT and follow-up OAHI&#xD;
      with various cardiovascular outcomes will be tested. Significance level will be set as 5%.&#xD;
      All the analyses will be performed using the statistical software packages SPSS (SPSS Inc.,&#xD;
      Chicago, Illinois, USA).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 19, 2021</start_date>
  <completion_date type="Anticipated">July 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>24-hour ambulatory blood pressure measurements</measure>
    <time_frame>At a mean of 5 years after intervention</time_frame>
    <description>All subjects will undergo 24-hour ABPM on the same day as PSG. An validated oscillometric monitor (SpaceLabs 90217, SpaceLabs Medical, Redmond, Washington, USA) will be used. Systolic, diastolic and mean arterial BP will be measured every half-hourly during the period starting from 2200h to 0800h (nighttime period) and every 15 minutes outside of this period (daytime period). The exact cutoff time dividing wake and sleep BP will be defined individually according to the concurrent sleep study. The proper cuff (cuff size should have a bladder width that is approximately 40% of the arm circumference midway between the olecranon and the acromion precesses) is chosen according to the length of the arm of the subject and it will be placed in the nondominant arm of the child.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cardiac function</measure>
    <time_frame>At a mean of 5 years after intervention</time_frame>
    <description>Based on M-mode assessment of the parasternal short-axis view at the mid-ventricular level, the left ventricular (LV) wall thickness and interventricular septum thickness at end-diastole will be determined. The fractional shortening and LV mass will be calculated according to standard formulae. The pulmonary arterial pressure will be estimated using the tricuspid regurgitation (TR) jet and pulmonary artery acceleration time.&#xD;
Tissue Doppler echocardiography will be performed with the sample volume positioned at the basal right ventricular (RV) and LV free-wall and interventricular septal annular junction.&#xD;
Speckle-tracking echocardiography will be performed for evaluation of myocardial deformation.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Carotid intima-media thickness</measure>
    <time_frame>At a mean of 5 years after intervention</time_frame>
    <description>The intima-media thickness (IMT) of the right and left common carotid arteries far wall at about 10 mm proximal to the carotid bulb will be measured using a 7 to 15-MHz high frequency linear-array transducer. Intima-media thickness of bilateral common carotid arteries will be automatically measured with electronic callipers. The average of three measurements from each side will be used for further analyses.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Arterial stiffness</measure>
    <time_frame>At a mean of 5 years after intervention</time_frame>
    <description>Carotid arterial stiffness of the right and left carotid arteries at about 10 mm proximal to the carotid bulb will be determined by calculation of the stiffness index.[41] Measurements of the end-diastolic (Dd) and systolic (Ds) diameters will be obtained between the far wall and near wall intima. For each systolic and diastolic diameter, three measurements from each side will be averaged and the means will be subsequently used in the calculation of the stiffness index as ln (SBP/DBP)/(ΔD/D), where SBP is right brachial systolic blood pressure, DBP is right brachial diastolic blood pressure, ΔD is the difference between systolic and diastolic diameters, and D is the diastolic diameter.</description>
  </primary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">180</enrollment>
  <condition>Obstructive Sleep Apnea</condition>
  <arm_group>
    <arm_group_label>Adenotonsillectomy (AT)</arm_group_label>
    <description>Children diagnosed with moderate-to-severe OSA (OAHI ≥3/h) and tonsillar hypertrophy (tonsil grade ≥2) at the age of 5-12 years old and underwent AT since 2012.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Refused AT</arm_group_label>
    <description>Children diagnosed with moderate-to-severe OSA and tonsillar hypertrophy but refused AT in the same period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal control</arm_group_label>
    <description>Children reported to have no habitual snoring (less than 3 nights per week) and confirmed to have no OSA (OAHI &lt;1/h) by overnight sleep study in the same period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Adenotonsillectomoy +/- turbinate reduction</intervention_name>
    <description>Tonsillectomies were performed by bipolar electrocautery while adenoidectomies were done by monopolar suction diathermy. Turbinate reduction (by either submucosal bipolar diathermy or radiofrequency) would be offered if the subject had on-going history of allergic rhinitis and examination revealed at least grade II turbinate hypertrophy. (Grade I = no turbinate hypertrophy; Grade II = turbinate hypertrophy without touching the septum; Grade III = turbinate hypertrophy touching the septum).</description>
    <arm_group_label>Adenotonsillectomy (AT)</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Potential subjects for this follow-up study have been identified from two local hospitals,&#xD;
        Prince of Wales Hospital and Kwong Wah Hospital. Since 2012, a total of 193 candidates for&#xD;
        AT have been identified, of whom 130 underwent AT, whilst the remaining 63 (33%) preferred&#xD;
        more conservative treatment. Non-snoring controls have been identified in several of our&#xD;
        previous studies that involved normal controls, including OSA family study and primary&#xD;
        snoring follow-up study, and an ongoing study which validates a prediction model for&#xD;
        childhood OSA. At the time of writing, a total of 258 non-snoring controls have been&#xD;
        identified from various studies since 2012.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        General inclusion criteria:&#xD;
&#xD;
          -  Participants and their parents must understand Chinese;&#xD;
&#xD;
          -  Aged 5-12 years at diagnosis.&#xD;
&#xD;
        Inclusion criteria for AT group:&#xD;
&#xD;
          -  Previously diagnosed with moderate-to-severe OSA (OAHI ≥3/h);&#xD;
&#xD;
          -  Tonsillar hypertrophy (tonsil grade ≥2);&#xD;
&#xD;
          -  Underwent AT.&#xD;
&#xD;
        Inclusion criteria for Refused AT group:&#xD;
&#xD;
          -  Previously diagnosed with moderate-to-severe OSA (OAHI ≥3/h);&#xD;
&#xD;
          -  Tonsillar hypertrophy (tonsil grade ≥2);&#xD;
&#xD;
          -  Refused AT.&#xD;
&#xD;
        Inclusion criteria for Normal Control group:&#xD;
&#xD;
          -  Previously confirmed to have no OSA (OAHI &lt;1/h);&#xD;
&#xD;
          -  Reported to have no habitual snoring (less than 3 nights per week).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Additional upper airway surgery other than the one done at baseline visit;&#xD;
&#xD;
          -  Known medical conditions that affects the cardiovascular system;&#xD;
&#xD;
          -  Any use of medications that alters cardiovascular system.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chun Ting Au, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>junau@cuhk.edu.hk</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Chun Ting Au, PhD</last_name>
    <phone>+852-35052917</phone>
    <email>junau@cuhk.edu.hk</email>
  </overall_contact>
  <location>
    <facility>
      <name>Department of Paediatrics, Kwong Wah Hospital</name>
      <address>
        <city>Hong Kong</city>
        <state>Kowloon</state>
        <country>Hong Kong</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ka Li Kwok, FRCPCH</last_name>
      <phone>+852-35175930</phone>
      <email>kwokklc@ha.org.hk</email>
    </contact>
    <investigator>
      <last_name>Ka Li Kwok, FRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Department of Paediatrics, The Chinese University of Hong Kong</name>
      <address>
        <city>Sha Tin</city>
        <country>Hong Kong</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chun Ting Au, PhD</last_name>
      <phone>35052917</phone>
      <email>junau@cuhk.edu.hk</email>
    </contact>
    <investigator>
      <last_name>Albert M Li, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 13, 2020</study_first_submitted>
  <study_first_submitted_qc>July 14, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 16, 2020</study_first_posted>
  <last_update_submitted>February 7, 2023</last_update_submitted>
  <last_update_submitted_qc>February 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Chinese University of Hong Kong</investigator_affiliation>
    <investigator_full_name>Chun-Ting AU, PhD</investigator_full_name>
    <investigator_title>Research Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>obstructive sleep apnea, adenotonsillectomy, cardiovascular</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Apnea</mesh_term>
    <mesh_term>Sleep Apnea Syndromes</mesh_term>
    <mesh_term>Sleep Apnea, Obstructive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Deidentified individual participant data that underlie the results in this article (text, tables and figures) will be made available, in addition to study protocol. The data will be made available upon publication to researchers who provide a methodologically sound proposal for individual participant data meta-analysis.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04473066
org study id: HMRF-07181276
nct id: NCT04473066
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Objectives: To assess the cardiovascular outcomes of children with obstructive sleep apnoea
      (OSA) at a mean of 5 years after they had undergone adenotonsillectomy (AT), compared to OSA
      children who did not undergo AT, and normal controls without OSA.

      Hypothesis to be tested: (1) children with OSA underwent AT would have lower cardiovascular
      risks, namely lower ambulatory blood pressure (ABP), better cardiac function, lower carotid
      intima-media thickness (CIMT) and lower carotid arterial thickness when compared to those
      with OSA but did not undergo AT, and that (2) children with OSA, despite treatment with AT,
      would have higher cardiovascular risks than non-OSA controls. Design: A two-centre
      prospective case-control follow-up study Subjects: Potential subjects for this follow-up
      study have been identified from two local hospitals, Prince of Wales and Kwong Wah Hospitals.
      AT-treated group (n=90) - Children had moderate-to-severe OSA (obstructive apnoea hypopnoea
      index (OAHI) >=3 events/h) and underwent AT when they were aged 5-12 years. Refused AT group
      (n=45) - Children had moderate-to-severe OSA but refused AT. Non-OSA control group (n=45) -
      Non-snoring controls with OAHI <1 event/h . Main outcome measures: 24-hour ABP, cardiac
      function measured by echocardiography, CIMT and carotid arterial stiffness.

      Data analysis: Apart from group comparisons, multiple linear regression and logistic
      regression analysis will also be used to examine whether cardiovascular outcomes are
      associated with AT, pre- and post-AT OAHI while adjusted for confounders.

      Expected results: AT improves cardiovascular outcomes of children with OSA. However they
      still had higher cardiovascular risks than normal controls even after AT.
Aims and Hypotheses to be Tested:

      The primary aim of this study is to assess cardiovascular outcomes of children with OSA at a
      mean of 5 years after they had undergone AT, compared to OSA children without surgical
      treatment and children without OSA. The secondary aim is to explore factors associated with
      cardiovascular outcomes in subjects with OSA after AT.

      We hypothesise that (1) children with OSA underwent AT would have lower cardiovascular risks,
      namely lower ABP, better cardiac function, lower carotid intima-media thickness (CIMT) and
      lower carotid arterial stiffness when compared to those with OSA but did not undergo AT, and
      that (2) children with OSA, despite treatment with AT, would have higher cardiovascular risks
      than non-OSA controls.

      Study design: A two-centre prospective case-control follow-up study.

      Sample size estimation:

      We have conducted a pilot study to compare 12 children with residual OSA after AT (defined as
      post-AT OAHI >=3/h) and 12 age-, sex- and BMI-matched non-snoring controls. The results
      showed that children with residual OSA had a higher nighttime systolic BP (NSBP) than
      non-snoring controls (98.9 c.f. 95.6 mm Hg, mean difference = 3.35 mmHg, common SD = 6.54
      mmHg, effect size = 0.51). We have a total of 130 subjects with moderate-to-severe OSA who
      had undergone AT. As the main aim of this study is to assess the treatment effects of AT, we
      will try to recruit as many AT-treated subjects as possible. Assuming a response rate of 70%,
      90 subjects will be recruited. If 45 normal controls were also recruited (case/control ratio
      = 2:1), the study would provide a power of 87% to detect the difference with a 5% type I
      error rate. The minimum number of subjects required to detect the difference with an 80%
      power and a 5% type I error rate are 72 cases and 36 controls if the case/control ratio is
      2:1. A sample size of 90 AT-treated subjects will also provide an 80% power to detect the
      potential effects of pre-AT OAHI and follow-up OAHI on cardiovascular outcomes with medium
      effect size (assuming a partial R-squared of 0.1), while adjusted for age, sex and BMI in
      multiple linear regression model within the AT group.

      Besides, we have also conducted a separate pilot study comparing a group of 18 children with
      moderate-to-severe OSA treated with AT and a group of 18 age-, sex- and BMI-matched children
      with similar OSA severity without AT. The results showed that the nighttime systolic BP in
      the AT group was reduced by a mean of 2.3 mmHg at a 9-month follow-up visit, whereas the
      non-AT group had an increase in nighttime systolic BP by a mean of 2.3 mmHg (mean difference
      = 4.52 mmHg, common SD = 7.34 mmHg, effect size = 0.62). We have a total of 63 candidates for
      AT who had refused to undergo AT. Assuming a response rate of 70%, 45 subjects will be
      recruited. A total of 90 cases (AT-treated) and 45 controls (refused AT) provides a power of
      95% to detect the expected difference with a type I error rate of 5%. The minimum number of
      subjects required to detect the difference with an 80% power and a 5% type I error rate are
      50 cases and 25 controls if the case/control ratio is 2:1. All sample size and power
      calculations were done using G*Power (Version 3.1.9.2).

      Our target is to recruit a total of 180 subjects, comprising of 90 OSA subjects treated with
      AT, 45 non-snoring controls and 45 OSA subjects without AT for this follow-up study. We are
      confident to recruit the target number of subjects as we have been following up the OSA
      patients regularly in out-patient clinic and we also have a sufficient amount of normal
      control subjects for matching and recruitment.

      Methods:

      All participants will have to visit our unit once to undergo anthropometric measurement,
      overnight polysomnography (PSG), 24-hour ABPM, echocardiographic and arterial assessments.
      They will be arranged to come to our sleep laboratory at around 9 am in the morning.
      Twenty-four hour ABPM will be started after resting for 10 minutes upon arrival.
      Echocardiographic and arterial assessments will be subsequently arranged. They will stay
      until the next morning after completion of overnight sleep study and 24-h ABPM. For those who
      are reluctant to complete the whole study protocol, especially for control subjects who may
      not be willing to stay overnight for the sleep study, their symptoms will be documented by a
      self- or parent-report questionnaire (appendix 2), and they will have to come to our unit to
      undergo all the cardiovascular assessments and take the ABP monitor back home and return to
      us the next day when the 24-h monitoring is completed. Those failed to complete all the
      outcome assessments will be excluded.

      Data processing and analysis:

      The AT-treated group will be compared to the refused AT group and the non-snoring controls to
      assess the between-group differences in various cardiovascular outcomes. Student's t tests,
      Mann-Whitney U tests and chi-square tests will be used for the comparisons of normally
      distributed, non-normally distributed and categorical data, respectively. Linear and logistic
      regression analysis will be used to test whether OSA severity at baseline and follow-up and
      AT are associated with continuous (e.g. CIMT) and binary (e.g. hypertension) cardiovascular
      outcomes, respectively, while adjusting for age, gender and body size. Subgroup analysis will
      also be performed within the AT-treated group to explore factors associated with
      cardiovascular outcomes after AT. Particularly, the association of pre-AT and follow-up OAHI
      with various cardiovascular outcomes will be tested. Significance level will be set as 5%.
      All the analyses will be performed using the statistical software packages SPSS (SPSS Inc.,
      Chicago, Illinois, USA).
observational model: Case-Control
time perspective: Prospective
measure: 24-hour ambulatory blood pressure measurements
time frame: At a mean of 5 years after intervention
description: All subjects will undergo 24-hour ABPM on the same day as PSG. An validated oscillometric monitor (SpaceLabs 90217, SpaceLabs Medical, Redmond, Washington, USA) will be used. Systolic, diastolic and mean arterial BP will be measured every half-hourly during the period starting from 2200h to 0800h (nighttime period) and every 15 minutes outside of this period (daytime period). The exact cutoff time dividing wake and sleep BP will be defined individually according to the concurrent sleep study. The proper cuff (cuff size should have a bladder width that is approximately 40% of the arm circumference midway between the olecranon and the acromion precesses) is chosen according to the length of the arm of the subject and it will be placed in the nondominant arm of the child.
measure: Cardiac function
time frame: At a mean of 5 years after intervention
description: Based on M-mode assessment of the parasternal short-axis view at the mid-ventricular level, the left ventricular (LV) wall thickness and interventricular septum thickness at end-diastole will be determined. The fractional shortening and LV mass will be calculated according to standard formulae. The pulmonary arterial pressure will be estimated using the tricuspid regurgitation (TR) jet and pulmonary artery acceleration time.
Tissue Doppler echocardiography will be performed with the sample volume positioned at the basal right ventricular (RV) and LV free-wall and interventricular septal annular junction.
Speckle-tracking echocardiography will be performed for evaluation of myocardial deformation.
measure: Carotid intima-media thickness
time frame: At a mean of 5 years after intervention
description: The intima-media thickness (IMT) of the right and left common carotid arteries far wall at about 10 mm proximal to the carotid bulb will be measured using a 7 to 15-MHz high frequency linear-array transducer. Intima-media thickness of bilateral common carotid arteries will be automatically measured with electronic callipers. The average of three measurements from each side will be used for further analyses.
measure: Arterial stiffness
time frame: At a mean of 5 years after intervention
description: Carotid arterial stiffness of the right and left carotid arteries at about 10 mm proximal to the carotid bulb will be determined by calculation of the stiffness index.[41] Measurements of the end-diastolic (Dd) and systolic (Ds) diameters will be obtained between the far wall and near wall intima. For each systolic and diastolic diameter, three measurements from each side will be averaged and the means will be subsequently used in the calculation of the stiffness index as ln (SBP/DBP)/(ΔD/D), where SBP is right brachial systolic blood pressure, DBP is right brachial diastolic blood pressure, ΔD is the difference between systolic and diastolic diameters, and D is the diastolic diameter.
arm group label: Adenotonsillectomy (AT)
description: Children diagnosed with moderate-to-severe OSA (OAHI ≥3/h) and tonsillar hypertrophy (tonsil grade ≥2) at the age of 5-12 years old and underwent AT since 2012.
arm group label: Refused AT
description: Children diagnosed with moderate-to-severe OSA and tonsillar hypertrophy but refused AT in the same period.
arm group label: Normal control
description: Children reported to have no habitual snoring (less than 3 nights per week) and confirmed to have no OSA (OAHI <1/h) by overnight sleep study in the same period.
intervention type: Procedure
intervention name: Adenotonsillectomoy +/- turbinate reduction
description: Tonsillectomies were performed by bipolar electrocautery while adenoidectomies were done by monopolar suction diathermy. Turbinate reduction (by either submucosal bipolar diathermy or radiofrequency) would be offered if the subject had on-going history of allergic rhinitis and examination revealed at least grade II turbinate hypertrophy. (Grade I = no turbinate hypertrophy; Grade II = turbinate hypertrophy without touching the septum; Grade III = turbinate hypertrophy touching the septum).
arm group label: Adenotonsillectomy (AT)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 10 Years
maximum age: 21 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Chun Ting Au, PhD
role: Principal Investigator
affiliation: junau@cuhk.edu.hk
last name: Chun Ting Au, PhD
phone: +852-35052917
email: junau@cuhk.edu.hk
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: Hong Kong
responsible party type: Principal Investigator
investigator affiliation: Chinese University of Hong Kong
investigator full name: Chun-Ting AU, PhD
investigator title: Research Assistant Professor
mesh term: Apnea
mesh term: Sleep Apnea Syndromes
mesh term: Sleep Apnea, Obstructive
sharing ipd: Undecided
ipd description: Deidentified individual participant data that underlie the results in this article (text, tables and figures) will be made available, in addition to study protocol. The data will be made available upon publication to researchers who provide a methodologically sound proposal for individual participant data meta-analysis.