Developing Fractional Exhaled Nitric Oxide Predicted and Upper Limit of Normal Values for a Disadvantaged Population

Andrew J. Collaro; Anne B. Chang; Julie M. Marchant; Don Vicendese; Mark D. Chatfield; Johanna F. Cole; Tamara L. Blake; Margaret S. McElrea

doi:10.1016/j.chest.2022.10.014

Developing Fractional Exhaled Nitric Oxide Predicted and Upper Limit of Normal Values for a Disadvantaged Population

Andrew J. Collaro, Anne B. Chang, Julie M. Marchant, Don Vicendese, Mark D. Chatfield, Johanna F. Cole, Tamara L. Blake, Margaret S. McElrea

Child and Maternal Health

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Background: Fractional exhaled nitric oxide (FENO), used as a biomarker, is influenced by several factors including ethnicity. Normative data are essential for interpretation, and currently single cutoff values are used in children and adults. Research Question: Accounting for factors that influence FENO, (1) what are appropriate predicted and upper limit of normal (ULN) FENO values in an underserved population (First Nations Australians), (2) how do these values compare with age-based interpretive guidelines, and (3) what factors influence FENO and what is the size of the effect? Study Design and Methods: FENO data of First Nations Australians (age < 16 years, n = 862; age ≥ 16 years, n = 348) were obtained. Medical history using participant questionnaires and medical records were used to define healthy participants. Flexible regression using spline functions, as used by the Global Lung Function Initiative, were used to generate predicted and ULN values. Results: Look-up tables for predicted and ULN values using age (4-76 years) and height (100-200 cm) were generated and are supplied with a calculator for clinician use. In healthy First Nations children (age < 18 years), ULN values ranged between 25 and 60 parts per billion (ppb) when considering only biologically plausible age and height combinations. For healthy adults, ULN values ranged between 39 and 88 ppb. Neither the current FENO interpretation guidelines, nor the currently recommended cutoff of 50 ppb for First Nations children 16 years of age or younger were appropriate for use in this cohort. Our modelling revealed that predicted and ULN values of healthy participants varied nonlinearly with age and height. Interpretation: Because single pediatric, adult, or all-age FENO cutoff values used by current interpretive guidelines to define abnormality fail to account for factors that modify FENO values, we propose predicted and ULN values for First Nations Australians 4 to 76 years of age. Creating age- and height-adjusted predicted and ULN values could be considered for other ethnicities.

Original language	English
Pages (from-to)	624-633
Number of pages	10
Journal	Chest
Volume	163
Issue number	3
DOIs	https://doi.org/10.1016/j.chest.2022.10.014
Publication status	Published - Mar 2023

Bibliographical note

Funding Information:
Author contributions: A. J. C. had full access to the data and takes responsibility for the integrity of the data and accuracy of the analysis. A. J. C. A. B. C. J. M. M. and M. S. M. contributed to the study design. A. J. C. A. B. C. J. M. M. M. S. M. T. L. B. and J. F. C. contributed to data collection. A. J. C. M. D. C. and D. V. contributed to the statistical analysis. All authors contributed to the interpretation of the data, participated in the writing and critical revision of the manuscript, and have approved the final version for submission. A. J. C. and M. S. M. verified the underlying data. Other contributions: The authors thank Vera Assan (Indigenous Healthworker), Lesley Versteegh EN (Aboriginal Research Nurse), Allan Takken and Brian Peacock (Indigenous Project Officers, Indigenous Respiratory Outreach Care) for invaluable assistance in completing this study and the study participants, families, schools, community elders, and leaders for their support and participation. Additional information: The e-Appendixes and e-Figures are available online under “Supplementary Data.”

Funding Information:
The pediatric Indigenous Respiratory Reference Values study was funded by the Queensland Health Aboriginal and Torres Strait Islander Health Branch and The Prince Charles Hospital Foundation (TPCHF) New Investigator grant [Grant NI2017-34]. The Healthy Indigenous Lung Testing in Adults study was funded by TPCHF Innovation Grant [Grant INN2018-24], Queensland Health Statewide Clinical Network Project Funding, and Northern Australia Tropical Disease Collaborative Research Programme (HOT NORTH round 6). A. J. C. is supported by a National Health and Medical Research Council (NHMRC) Postgraduate Scholarship [Grant APP2003334]. A. B. C. is supported by an NHMRC Senior Practitioner Fellowship [Grant APP1154302]. D. V. and J. M. M. are supported by fellowships from the NHMRC Centre of Research Excellence for Bronchiectasis in Children [Grant APP1170958].

Publisher Copyright:
© 2022 American College of Chest Physicians

Access to Document

10.1016/j.chest.2022.10.014

Cite this

@article{fae7bfc8dd424b3bac72c7f53d187e63,

title = "Developing Fractional Exhaled Nitric Oxide Predicted and Upper Limit of Normal Values for a Disadvantaged Population",

abstract = "Background: Fractional exhaled nitric oxide (FENO), used as a biomarker, is influenced by several factors including ethnicity. Normative data are essential for interpretation, and currently single cutoff values are used in children and adults. Research Question: Accounting for factors that influence FENO, (1) what are appropriate predicted and upper limit of normal (ULN) FENO values in an underserved population (First Nations Australians), (2) how do these values compare with age-based interpretive guidelines, and (3) what factors influence FENO and what is the size of the effect? Study Design and Methods: FENO data of First Nations Australians (age < 16 years, n = 862; age ≥ 16 years, n = 348) were obtained. Medical history using participant questionnaires and medical records were used to define healthy participants. Flexible regression using spline functions, as used by the Global Lung Function Initiative, were used to generate predicted and ULN values. Results: Look-up tables for predicted and ULN values using age (4-76 years) and height (100-200 cm) were generated and are supplied with a calculator for clinician use. In healthy First Nations children (age < 18 years), ULN values ranged between 25 and 60 parts per billion (ppb) when considering only biologically plausible age and height combinations. For healthy adults, ULN values ranged between 39 and 88 ppb. Neither the current FENO interpretation guidelines, nor the currently recommended cutoff of 50 ppb for First Nations children 16 years of age or younger were appropriate for use in this cohort. Our modelling revealed that predicted and ULN values of healthy participants varied nonlinearly with age and height. Interpretation: Because single pediatric, adult, or all-age FENO cutoff values used by current interpretive guidelines to define abnormality fail to account for factors that modify FENO values, we propose predicted and ULN values for First Nations Australians 4 to 76 years of age. Creating age- and height-adjusted predicted and ULN values could be considered for other ethnicities.",

keywords = "FENO, nitric oxide, NO, ppb, reference values, ULN",

author = "Collaro, {Andrew J.} and Chang, {Anne B.} and Marchant, {Julie M.} and Don Vicendese and Chatfield, {Mark D.} and Cole, {Johanna F.} and Blake, {Tamara L.} and McElrea, {Margaret S.}",

note = "Funding Information: Author contributions: A. J. C. had full access to the data and takes responsibility for the integrity of the data and accuracy of the analysis. A. J. C. A. B. C. J. M. M. and M. S. M. contributed to the study design. A. J. C. A. B. C. J. M. M. M. S. M. T. L. B. and J. F. C. contributed to data collection. A. J. C. M. D. C. and D. V. contributed to the statistical analysis. All authors contributed to the interpretation of the data, participated in the writing and critical revision of the manuscript, and have approved the final version for submission. A. J. C. and M. S. M. verified the underlying data. Other contributions: The authors thank Vera Assan (Indigenous Healthworker), Lesley Versteegh EN (Aboriginal Research Nurse), Allan Takken and Brian Peacock (Indigenous Project Officers, Indigenous Respiratory Outreach Care) for invaluable assistance in completing this study and the study participants, families, schools, community elders, and leaders for their support and participation. Additional information: The e-Appendixes and e-Figures are available online under “Supplementary Data.” Funding Information: The pediatric Indigenous Respiratory Reference Values study was funded by the Queensland Health Aboriginal and Torres Strait Islander Health Branch and The Prince Charles Hospital Foundation (TPCHF) New Investigator grant [Grant NI2017-34]. The Healthy Indigenous Lung Testing in Adults study was funded by TPCHF Innovation Grant [Grant INN2018-24], Queensland Health Statewide Clinical Network Project Funding, and Northern Australia Tropical Disease Collaborative Research Programme (HOT NORTH round 6). A. J. C. is supported by a National Health and Medical Research Council (NHMRC) Postgraduate Scholarship [Grant APP2003334]. A. B. C. is supported by an NHMRC Senior Practitioner Fellowship [Grant APP1154302]. D. V. and J. M. M. are supported by fellowships from the NHMRC Centre of Research Excellence for Bronchiectasis in Children [Grant APP1170958]. Publisher Copyright: {\textcopyright} 2022 American College of Chest Physicians",

year = "2023",

month = mar,

doi = "10.1016/j.chest.2022.10.014",

language = "English",

volume = "163",

pages = "624--633",

journal = "Chest",

issn = "0012-3692",

publisher = "American College of Chest Physicians",

number = "3",

}

TY - JOUR

T1 - Developing Fractional Exhaled Nitric Oxide Predicted and Upper Limit of Normal Values for a Disadvantaged Population

AU - Collaro, Andrew J.

AU - Chang, Anne B.

AU - Marchant, Julie M.

AU - Vicendese, Don

AU - Chatfield, Mark D.

AU - Cole, Johanna F.

AU - Blake, Tamara L.

AU - McElrea, Margaret S.

N1 - Funding Information: Author contributions: A. J. C. had full access to the data and takes responsibility for the integrity of the data and accuracy of the analysis. A. J. C. A. B. C. J. M. M. and M. S. M. contributed to the study design. A. J. C. A. B. C. J. M. M. M. S. M. T. L. B. and J. F. C. contributed to data collection. A. J. C. M. D. C. and D. V. contributed to the statistical analysis. All authors contributed to the interpretation of the data, participated in the writing and critical revision of the manuscript, and have approved the final version for submission. A. J. C. and M. S. M. verified the underlying data. Other contributions: The authors thank Vera Assan (Indigenous Healthworker), Lesley Versteegh EN (Aboriginal Research Nurse), Allan Takken and Brian Peacock (Indigenous Project Officers, Indigenous Respiratory Outreach Care) for invaluable assistance in completing this study and the study participants, families, schools, community elders, and leaders for their support and participation. Additional information: The e-Appendixes and e-Figures are available online under “Supplementary Data.” Funding Information: The pediatric Indigenous Respiratory Reference Values study was funded by the Queensland Health Aboriginal and Torres Strait Islander Health Branch and The Prince Charles Hospital Foundation (TPCHF) New Investigator grant [Grant NI2017-34]. The Healthy Indigenous Lung Testing in Adults study was funded by TPCHF Innovation Grant [Grant INN2018-24], Queensland Health Statewide Clinical Network Project Funding, and Northern Australia Tropical Disease Collaborative Research Programme (HOT NORTH round 6). A. J. C. is supported by a National Health and Medical Research Council (NHMRC) Postgraduate Scholarship [Grant APP2003334]. A. B. C. is supported by an NHMRC Senior Practitioner Fellowship [Grant APP1154302]. D. V. and J. M. M. are supported by fellowships from the NHMRC Centre of Research Excellence for Bronchiectasis in Children [Grant APP1170958]. Publisher Copyright: © 2022 American College of Chest Physicians

PY - 2023/3

Y1 - 2023/3

N2 - Background: Fractional exhaled nitric oxide (FENO), used as a biomarker, is influenced by several factors including ethnicity. Normative data are essential for interpretation, and currently single cutoff values are used in children and adults. Research Question: Accounting for factors that influence FENO, (1) what are appropriate predicted and upper limit of normal (ULN) FENO values in an underserved population (First Nations Australians), (2) how do these values compare with age-based interpretive guidelines, and (3) what factors influence FENO and what is the size of the effect? Study Design and Methods: FENO data of First Nations Australians (age < 16 years, n = 862; age ≥ 16 years, n = 348) were obtained. Medical history using participant questionnaires and medical records were used to define healthy participants. Flexible regression using spline functions, as used by the Global Lung Function Initiative, were used to generate predicted and ULN values. Results: Look-up tables for predicted and ULN values using age (4-76 years) and height (100-200 cm) were generated and are supplied with a calculator for clinician use. In healthy First Nations children (age < 18 years), ULN values ranged between 25 and 60 parts per billion (ppb) when considering only biologically plausible age and height combinations. For healthy adults, ULN values ranged between 39 and 88 ppb. Neither the current FENO interpretation guidelines, nor the currently recommended cutoff of 50 ppb for First Nations children 16 years of age or younger were appropriate for use in this cohort. Our modelling revealed that predicted and ULN values of healthy participants varied nonlinearly with age and height. Interpretation: Because single pediatric, adult, or all-age FENO cutoff values used by current interpretive guidelines to define abnormality fail to account for factors that modify FENO values, we propose predicted and ULN values for First Nations Australians 4 to 76 years of age. Creating age- and height-adjusted predicted and ULN values could be considered for other ethnicities.

AB - Background: Fractional exhaled nitric oxide (FENO), used as a biomarker, is influenced by several factors including ethnicity. Normative data are essential for interpretation, and currently single cutoff values are used in children and adults. Research Question: Accounting for factors that influence FENO, (1) what are appropriate predicted and upper limit of normal (ULN) FENO values in an underserved population (First Nations Australians), (2) how do these values compare with age-based interpretive guidelines, and (3) what factors influence FENO and what is the size of the effect? Study Design and Methods: FENO data of First Nations Australians (age < 16 years, n = 862; age ≥ 16 years, n = 348) were obtained. Medical history using participant questionnaires and medical records were used to define healthy participants. Flexible regression using spline functions, as used by the Global Lung Function Initiative, were used to generate predicted and ULN values. Results: Look-up tables for predicted and ULN values using age (4-76 years) and height (100-200 cm) were generated and are supplied with a calculator for clinician use. In healthy First Nations children (age < 18 years), ULN values ranged between 25 and 60 parts per billion (ppb) when considering only biologically plausible age and height combinations. For healthy adults, ULN values ranged between 39 and 88 ppb. Neither the current FENO interpretation guidelines, nor the currently recommended cutoff of 50 ppb for First Nations children 16 years of age or younger were appropriate for use in this cohort. Our modelling revealed that predicted and ULN values of healthy participants varied nonlinearly with age and height. Interpretation: Because single pediatric, adult, or all-age FENO cutoff values used by current interpretive guidelines to define abnormality fail to account for factors that modify FENO values, we propose predicted and ULN values for First Nations Australians 4 to 76 years of age. Creating age- and height-adjusted predicted and ULN values could be considered for other ethnicities.

KW - FENO

KW - nitric oxide

KW - NO

KW - ppb

KW - reference values

KW - ULN

UR - http://www.scopus.com/inward/record.url?scp=85148713240&partnerID=8YFLogxK

U2 - 10.1016/j.chest.2022.10.014

DO - 10.1016/j.chest.2022.10.014

M3 - Article

C2 - 36279906

AN - SCOPUS:85148713240

SN - 0012-3692

VL - 163

SP - 624

EP - 633

JO - Chest

JF - Chest

IS - 3

ER -

Developing Fractional Exhaled Nitric Oxide Predicted and Upper Limit of Normal Values for a Disadvantaged Population

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this