The measurement of Fractional Exhaled nitric oxide (FENO) was one of two NHANES 2007-8 examination components on respiratory health sponsored by the National Heart, Lung, and Blood Institute of the National Institute of Health. Spirometry, including a 2nd test post-Bronchodilator Spirometry was also conducted. Nitric Oxide (NO) is a chemical normally produced in the respiratory tract and can be detected in the exhaled breath. It is a noninvasive marker of airway inflammation. FENO has been shown to be higher in persons with asthma, chronic obstructive pulmonary disease (COPD) and other respiratory conditions as compared to levels found in healthy persons. FENO measurements have also been used as a tool to monitor compliance with treatment with inhaled steroids in asthmatics.
The objective of the nitric oxide data collection was to produce baseline FENO measurements and reference ranges for the U.S. healthy population as well as those with asthma and COPD, and those who are smokers. The data collection was also intended to help define the prevalence of undiagnosed airway inflammation in the US, and to examine the association between airway inflammation, other measurements of lung function and capacity, and physical and laboratory measures.
Survey participants, ages 6 to 79 years, were eligible for FENO testing. Examinees that had current chest pain or a physical problem with forceful expiration, or those who were using supplemental oxygen were medically-excluded from participating.
Protocol and Procedure
FENO was measured using the Aerocrine NIOX MINO®, a portable, hand-held NO analyzer (Aerocrine AB, Solna, Sweden) approved by the FDA in 2008. This device relies on an electrochemical sensor to detect exhaled NO levels and provides measurements of from 5 to 300 ppb in whole numbers. The testing was conducted with participants sitting in front of a mirror so they could see display prompts on the NO analyzer screen. Holding the device, participants were asked to first empty their lungs, then to place their mouth on the disposable analyzer's filter mouthpiece and to fill their lungs to capacity with NO-free air. Participants are then asked to blow out all of their air at a constant pressure while exhaled NO from the bronchial tree is measured. The NIOX MINO® has a dynamic flow restrictor to stabilize flow rate at 50 ml/sec. The device automatically provides auditory and visual cues to assist in performing the test correctly. The health technicians also coach participants to maintain the air flow at a slow, fixed, steady rate. The standard exhalation time, as specified by the manufacturer, was 10 seconds for examinees who were at or above 130 cm in height, and 6 seconds for those below 130 cm. The Respiratory Health ENO Procedures Manual provides detailed description of the examination procedure. The manual is available at : https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2007
The test result, an integer between 5-300 ppb, is displayed on the screen of the device 140 seconds after a valid test is completed. Codes indicating a result either above or below the range of the device detection limit, as well as error codes are also displayed on the screen. It is common for current smokers to have repeat FENO levels below the limit of detection. Results indicating a value above the limit of detection are unusual, and subsequent measurements are most often within the normal range of the test device.
The NHANES protocol required two valid FENO measurements that were reproducible, in accordance with testing procedures recommended by the manufacturer and similar to those published by the American Thoracic Society and European Respiratory Society. If either or both of the first two valid FENO measurements was below 30 ppb and the measurements were within 2 ppb of each other, or if both measurements were over 30 ppb and within 10% of each other, then the test was considered reproducible and complete. Two values below the limit of detection were also considered reproducible. If the reproducibility criteria were not met within the first two exhalations, a participant had 2 additional exhalations to satisfy the criteria (up to a total of 4 trials). The examinee's exhalations for which the NIOX MINO® did not display a valid reading, i.e. exhalations that were either too strong or too weak, or any other reasons for failing to achieve a successful exhalation were recorded as attempts. Examinees were not always able to meet the criteria for a reproducible measurement even within the ten attempts allowed to perform the exhalation, as indicated by the exam status variable ENXSTAT.
Quality Assurance & Quality Control
The Chief Health Technician, at each MEC, monitored ongoing staff performance in the field. Health technician performance was also monitored using direct observation during periodic site visits. The NIOX MINO® monitor was cleaned and calibrated in accordance with the requirements via regularly scheduled quality control checks by the Health Technicians and verified by supervisory staff. Ambient air testing was conducted daily, and temperature and humidity collection in the respiratory health room was ongoing. A QC sensor verification was conducted at FENO levels of 15 and 75 ppb and and a QC filter checks were also conducted to check a “blank sample” at 0 ppb. Each pre-calibrated NIOX MINO® sensor has a maximum of 300 measurements and sensors were replaced in the device when 30 measurements remained. Generally, 2-3 sensors were used at each NHANES MEC location. The sensor shelf life is 1 year from the date of manufacture, and the device shelf life is 3.5 years from the date of manufacture, or up to 1500 uses. The Respiratory Health ENO Procedures Manual provides detailed descriptions of the quality assurance and quality control measures that were used over the course of the 2007-8 data collection period.
Periodically, batches of used sensors were returned to the manufacturer (Aerocrine) to determine if they still met the test specification quality control criteria. Results from these checks were provided to NCHS. A linear regression model based on the age of the sensor at the time of re-testing and the age of sensor at use was provided by the manufacturer to adjust any drift from the initial calibration specifications of 15% or greater at 200 ppb. The model for the adjustment assumes a linear drift over the lifetime of the sensor. In the NHANES 2007-8 data, less than 5% of the examinees had measurements that were adjusted. The median adjustment was 9% lower than the original measurement at the time of collection.
Data Processing and Editing
Data were reviewed and edited as necessary to ensure internal data consistency.
Screening Questions ENX040 –ENX100: A series of questions that vary by age were administered in the examination to support data analysis and interpretation. Examinees 12 and older were asked the questions while waiting for the test results after the first acceptable exhalation. Parents of youth 6-11 years were asked these questions, as well as the two medical exclusion questions (ENQ010 and ENQ020) prior to the exam.
Exhaled NO Status Code (ENXSTAT): This single variable provides a completion code for the component:
1: Two measurements met the reproducibility criteria (as described in the Protocol/Procedures section of this document). Only examinees with this status code have a calculated mean FENO value (ENXMEAN).
2: At least one acceptable measurement was obtained. For those with two or more measurements, results were not reproducible.
3: Unable to perform test. Attempted the exhalation up to 10 times but were not successful in achieving a measurement.
4: Medically excluded. Responded positively to or did not answer one of two exclusion questions (ENQ010, ENQ020) prior to the test.
5: Test was not conducted for reason described in ENXCMT.
ENXTR1G, ENXTR2G, ENXTR3G, ENXTR4G: These variables indicate a trial status, respectively, for each of the valid FENO readings that were obtained; i.e., whether an exhalation produced a measurement that was within range of the acceptable device specifications (5-300 ppb), or whether it was either above or below the instrument's limit of detection. If all attempts were used (up to 10 total, across all trials) or the examinee wished to terminate the exam, then a “could not obtain result ” response was recorded.
ENXTR1Q, ENXTR2Q, ENXTR3Q, ENXTR4Q: These variables indicate the numeric value for the FENO reading if it fell within the NIOX MINO® measurement range (5-300 ppb). If the trial status indicates that the measurement was not within the range or could not be obtained, then the FENO measurement will be missing.
ENXMEAN: For analytic purposes,this variable was created for the average of two reproducible measurements. Results from up to 4 successful exhalation trials (ENXTR1Q, ENXTR2Q, ENXTR3Q, ENXTR4Q) were used to assess reproducibility, and the two reproducible FENO measurements were averaged to create a mean value (ENXMEAN). Two measurements below the limit of detection of the device (i.e., less than 5 ppb) were also considered reproducible and given a “fill” value of 3.5 ppb. This value was determined using the same calculation applied to the NHANES laboratory data - the limit of detection divided by the square root of two. Analysts may choose to use an alternate value for FENO levels below the limit of detections, or to exclude records with these values from their analyses.
Sample Weights: The NHANES full sample 2-Year MEC Exam Weights (WTMEC2YR) should be used to analyze the 2007-8 FENO data. Please refer to the NHANES Analytic Guidelines (https://wwwn.cdc.gov/nchs/nhanes/analyticguidelines.aspx) and the on-line NHANES Tutorial (https://www.cdc.gov/nchs/tutorials/) for further details on the use of sample weights and other analytic issues.
Additional 2007-8 NHANES Data on Respiratory Health:
The NHANES 2007-8 Respiratory Health Component also included Spirometry (SPX_E) and Household Interview Questionaire data on a prior diagnosis of asthma and COPD (MCQ_E), recent respiratory symptoms such as cough and wheezing (RDQ_E), and data for the participant's current prescription medications (RXQ_RX_E; RXQ_DRUG). In addition raw data for the spirometry curves attempted by each participant is released in a separate dataset (SPXRAW_E). The raw data permits users to graph a participant's spirometry test curves. It is also intended for the use of data analysts who may want to perform more advanced modeling studies with the raw data.