Observational Study

. 2019 Apr 26;19(1):88.

doi: 10.1186/s12874-019-0705-0.

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis

Theodore G Liou^{1

2}, Frederick R Adler^{3

4}, Natalia Argel⁵, Fadi Asfour⁶, Perry S Brown⁷, Barbara A Chatfield⁶, Cori L Daines⁸, Dixie Durham⁷, Jessica A Francis⁹, Barbara Glover¹⁰, Theresa Heynekamp¹¹, John R Hoidal⁹, Judy L Jensen⁹, Ruth Keogh¹², Carol M Kopecky¹³, Noah Lechtzin¹⁴, Yanping Li⁹, Jerimiah Lysinger¹⁵, Osmara Molina⁸, Craig Nakamura¹⁰, Kristyn A Packer⁹, Katie R Poch¹⁶, Alexandra L Quittner^{17

18}, Peggy Radford⁵, Abby J Redway¹¹, Scott D Sagel¹³, Shawna Sprandel¹⁵, Jennifer L Taylor-Cousar^{16

19}, Jane B Vroom^{9

6}, Ryan Yoshikawa¹⁰, John P Clancy²⁰, J Stuart Elborn²¹, Kenneth N Olivier²², David R Cox²³

Affiliations

¹ Adult Cystic Fibrosis Center, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah, 26 North Mario Capecchi Drive, Salt Lake City, UT, 84132, USA. ted.liou@utah.edu.
² Intermountain Pediatric Cystic Fibrosis Center, Division of Pediatric Pulmonology, Department of Pediatrics, University of Utah, 81 North Mario Capecchi Drive, Salt Lake City, UT, 84113, USA. ted.liou@utah.edu.
³ Departments of Mathematics, University of Utah, 155 South 1400 east, JWB 233, Salt Lake City, UT, 84112, USA.
⁴ School of Biological Sciences, University of Utah, 257 South 1400 East, Salt Lake City, UT, 84112, USA.
⁵ Cystic Fibrosis Center, Phoenix Children's Hospital, 1919 East Thomas Road, Phoenix, AZ, 85016, USA.
⁶ Intermountain Pediatric Cystic Fibrosis Center, Division of Pediatric Pulmonology, Department of Pediatrics, University of Utah, 81 North Mario Capecchi Drive, Salt Lake City, UT, 84113, USA.
⁷ St. Luke's Cystic Fibrosis Center of Idaho, 610 W. Hays Street, Boise, ID, 83702, USA.
⁸ Division of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, University of Arizona Health Sciences, 1501 N. Campbell Avenue, Room 3301, PO Box 245073, Tucson, AZ, 85724, USA.
⁹ Adult Cystic Fibrosis Center, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah, 26 North Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
¹⁰ Cystic Fibrosis Center, 3006 S. Maryland Pkwy, Suite #315, Las Vegas, NV, 89109, USA.
¹¹ Adult Cystic Fibrosis Program, Division of Pulmonary, Critical Care and Sleep Medicine, DoIM MSC10-5550, 1 University of New Mexico, Albuquerque, NM, 87131, USA.
¹² Department of Medical Statistics, London School of Hygiene and Tropical Medicine, Room G36, Keppel Street, London, WC1E 7HT, UK.
¹³ Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Avenue, Aurora, CO, 80045, USA.
¹⁴ Division of Pulmonary and Critical Care and Sleep Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 601 N. Caroline St, Baltimore, MD, 21287, USA.
¹⁵ Montana Cystic Fibrosis Center, Billings Clinic, 2800 10th Avenue N, Billings, MT, 59101, USA.
¹⁶ Division of Pulmonary and Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO, 80206, USA.
¹⁷ Former: Department of Psychology, University of Miami, Miami, FL, USA.
¹⁸ Present Address: Miami Children's Research Institute, Nicklaus Children's Hospital, 3100 SW 62nd Ave, Miami, FL, 33155, USA.
¹⁹ Division of Pulmonology, Department of Pediatrics, National Jewish Health, 1400 Jackson St, Denver, CO, 80206, USA.
²⁰ Division of Pulmonary Medicine, Department of Pediatrics, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229-3026, USA.
²¹ Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, 90 Lisburn Road, Belfast, BT9 6AG, UK.
²² Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart Lung and Blood Institute, National Institutes of Health, 10 Center Drive MSC1454, Building 10-CRC, Room 1408A, Bethesda, MD, 20892, USA.
²³ Nuffield College, 1 New Rd, Oxford, OX1 1NF, UK.

PMID: 31027503
PMCID: PMC6485181
DOI: 10.1186/s12874-019-0705-0

Observational Study

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis

Theodore G Liou et al. BMC Med Res Methodol. 2019.

. 2019 Apr 26;19(1):88.

doi: 10.1186/s12874-019-0705-0.

Authors

Affiliations

¹ Adult Cystic Fibrosis Center, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah, 26 North Mario Capecchi Drive, Salt Lake City, UT, 84132, USA. ted.liou@utah.edu.
² Intermountain Pediatric Cystic Fibrosis Center, Division of Pediatric Pulmonology, Department of Pediatrics, University of Utah, 81 North Mario Capecchi Drive, Salt Lake City, UT, 84113, USA. ted.liou@utah.edu.
³ Departments of Mathematics, University of Utah, 155 South 1400 east, JWB 233, Salt Lake City, UT, 84112, USA.
⁴ School of Biological Sciences, University of Utah, 257 South 1400 East, Salt Lake City, UT, 84112, USA.
⁵ Cystic Fibrosis Center, Phoenix Children's Hospital, 1919 East Thomas Road, Phoenix, AZ, 85016, USA.
⁶ Intermountain Pediatric Cystic Fibrosis Center, Division of Pediatric Pulmonology, Department of Pediatrics, University of Utah, 81 North Mario Capecchi Drive, Salt Lake City, UT, 84113, USA.
⁷ St. Luke's Cystic Fibrosis Center of Idaho, 610 W. Hays Street, Boise, ID, 83702, USA.
⁸ Division of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, University of Arizona Health Sciences, 1501 N. Campbell Avenue, Room 3301, PO Box 245073, Tucson, AZ, 85724, USA.
⁹ Adult Cystic Fibrosis Center, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah, 26 North Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
¹⁰ Cystic Fibrosis Center, 3006 S. Maryland Pkwy, Suite #315, Las Vegas, NV, 89109, USA.
¹¹ Adult Cystic Fibrosis Program, Division of Pulmonary, Critical Care and Sleep Medicine, DoIM MSC10-5550, 1 University of New Mexico, Albuquerque, NM, 87131, USA.
¹² Department of Medical Statistics, London School of Hygiene and Tropical Medicine, Room G36, Keppel Street, London, WC1E 7HT, UK.
¹³ Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Avenue, Aurora, CO, 80045, USA.
¹⁴ Division of Pulmonary and Critical Care and Sleep Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 601 N. Caroline St, Baltimore, MD, 21287, USA.
¹⁵ Montana Cystic Fibrosis Center, Billings Clinic, 2800 10th Avenue N, Billings, MT, 59101, USA.
¹⁶ Division of Pulmonary and Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO, 80206, USA.
¹⁷ Former: Department of Psychology, University of Miami, Miami, FL, USA.
¹⁸ Present Address: Miami Children's Research Institute, Nicklaus Children's Hospital, 3100 SW 62nd Ave, Miami, FL, 33155, USA.
¹⁹ Division of Pulmonology, Department of Pediatrics, National Jewish Health, 1400 Jackson St, Denver, CO, 80206, USA.
²⁰ Division of Pulmonary Medicine, Department of Pediatrics, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229-3026, USA.
²¹ Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, 90 Lisburn Road, Belfast, BT9 6AG, UK.
²² Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart Lung and Blood Institute, National Institutes of Health, 10 Center Drive MSC1454, Building 10-CRC, Room 1408A, Bethesda, MD, 20892, USA.
²³ Nuffield College, 1 New Rd, Oxford, OX1 1NF, UK.

PMID: 31027503
PMCID: PMC6485181
DOI: 10.1186/s12874-019-0705-0

Abstract

Background: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers.

Methods: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation.

Results: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies.

Conclusions: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

Keywords: Calprotectin; Cystic Fibrosis Foundation patient registry; Cystic fibrosis; HMGB-1; Neutrophil elastase; Randomized observational trial; Sputum inflammation; Study design.

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Conflict of interest statement

Authors’ information

DRC is an Honorary Fellow at Nuffield College. His pioneering work in Statistics includes introduction of the current methods of logistic regression [57] and proportional hazards models [58]. He was awarded the Guy Medal in both Silver and Gold from the Royal Statistical Society, the Kettering Prize and Gold Medal for Cancer Research, the Copley Medal from the Royal Society, and he recently won the first International Prize in Statistics awarded jointly by the American Statistical Association, the International Biometric Society, the Institute of Mathematical Statistics, the International Statistical Institute, and the Royal Statistical Society. His lifelong experience improving the design of experiments [31, 32] was instrumental in the design of the current study.

RK received her DPhil under the supervision of DRC from the University of Oxford. She is now Associate Professor in the Department of Medical Statistics at the London School of Hygiene and Tropical Medicine, is funded by a Medical Research Council Methodology Fellowship, and teaches Master’s level courses in medical statistics. She helped the study greatly by participating in the teaching video (Additional files 1, 2 and 3) with DRC and with our initial study design.

Our non-MWCFC collaborators brought skills and experience not found in the MWCFC. NL is Director of the Adult CF Program and Associate Professor in the Department of Medicine, Division of Pulmonary and Critical Care Medicine at the Johns Hopkins University. He has published in the area of assessment of pain in patients with CF [45] and brings that expertise to our study. ALQ is a behavioral scientist and clinical psychologist at the Miami Children’s Research Institute. She was awarded the inaugural Mattingly Leadership in Mental Health Care Award in 2016 by the US CF Foundation, and she contributed her expertise on quantitative measurements of depression, anxiety and quality of life [59] to the study.

The study benefited greatly from guidance by the external advisory committee. JPC is Professor and Research Director for the Division of Pulmonary Medicine, Department of Pediatrics, at the U of Cincinnati and has been a member or leader of multiple research organizations within the CF Foundation, the European CF Society and the National Institutes of Health in the US (NIH). KNO is Senior Clinician and Chief of the Pulmonary Branch of the National Heart, Lung and Blood Institute (NHLBI) of the NIH and leader of the Chronic Airway Infection Laboratory at the NHLBI. He has led multiple studies of bronchiectasis and infections, especially non-tuberculous Mycobacteria. JSE is Faculty Pro-Vice Chancellor of the School of Medicine, Dentistry and Biomedical Sciences and Faculty in the Institute for Health Sciences and the Centre for Experimental Medicine, Queen's University Belfast, UK. He was President of the European CF Society for 8 years and Trustee, Chair or Member of the Medical Advisory Committee of the CF Trust in the UK since 2002. He received knighthood in 2012 for his work in health care in Northern Ireland. He has been author and driving force for many studies that have improved knowledge and care of patients with CF.

The authors from the Mountain West CF Consortium have been meeting and working collaboratively for over 20 years including a recent publication [52]. The long-standing close relationships between these individuals and teams enhanced the ability to design and perform this complex multicenter study.

Ethics approval and consent to participate

Our project was reviewed and approved by the Investigational Review Board (IRB) of the University of Utah (IRB_00011571), the St. Luke’s Health System IRB (IRB Protocol No.: 13–0547), the IRB of Billings (Study 14.07), the Western IRB (for the Las Vegas CF Center) (STUDY NUM 1146159, WIRB PRO NUM: 20140721, INVEST NUM: 112264, WO NUM: 1–837046-1, Protocol Number 20130530), the National Jewish Health IRB (Study Number: HS-2797), Colorado Multiple IRB (for Children’s Hospital Colorado) (COMIRB Protocol 13–3172), the Phoenix Children’s Hospital IRB (PCH IRB #13–087), the University of Arizona IRB (Protocol Number: 1407394040), and the Human Research Review Committee in the Human Research Protections Office at the University of New Mexico (Study ID 14–085). No patients were enrolled prior to IRB approval. All patients younger than 18 provided assent with informed written consent provided by parents or other legal guardians. Each adult patient gave informed written consent on his or her own behalf.

Consent for publication

Not applicable.

Competing interests

TGL, JAF, JLJ, YL, KAP and JBV received other support from the CFF (CC132-16 AD, LIOU14Y0, LIOU14P0) and the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) (R01 HL125520) and received support during the current study for performing clinical trials from Abbvie, Gilead, Nivalis, Novartis, Proteostasis, Inc., Savara and Vertex. FRA received additional other support from the NHLBI/NIH (R01 HL125520), the National Science Foundation (EMSW21-RTG) and the Margolis Foundation of Utah. PSB received other support from the CFF (Center and TDC grants) and the NHLBI/NIH (U01 HL114623) and received support for a clinical trial from Alcresta. BAC received other support from the CFF (C112–12, C112-TDC09Y, 10063SUB, 41,339,154.s132P010379SUB) and received support for clinical trials from Genentech, Novartis and Vertex. CLD received other support from the CFF (C004–11, C004-TDC09Y, DAINES11Y3) and from the Health Resources and Services Administration (T72MC00012). TH received other support from the CFF (PACE, Center Grant) and received support for clinical trials from Celtaxsys and Vertex. JRH received other support from the NHLBI/NIH (HHSN268200900018C) and the Veterans Administration Healthcare System (I01 BX001533). JL received other support from the CFF (C017-11AF). CN received other support from the CFF (C138–12). PR received other support from the CFF (C003–12, C003-TDC09Y). SDS received other support from the CFF (AQUADEK12K1, SAGEL11CS0, GOAL13K2, NICK13A0, SAGEL14K1, NICK15R0) and the NHLBI/NIH (U54 HL096458) and the NCATS/NIH (Colorado CTSA Grant Number UL1 TR002535). JLT-C received other support from the CFF (TDC) and the NHLBI/NIH (HL103801) and received support for clinical trials from Vertex. KNO is funded by the intramural research program of the NHLBI, NIH.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
Shipping Effects on HMGB-1 Measurements. Overnight shipping of refrigerated unfractionated sputum samples from seven patients was associated with a statistically significant increase in ELISA measurements of HMGB-1, especially for low values. Although the values were correlated with values from samples that were fractionated and frozen prior to shipping (see text), the large and somewhat unpredictable sizes of differences in values and the compressed range of values overall suggested that on-site processing of samples would reduce measurement errors and better enable analyses involving HMGB-1

**Fig. 2**
Patient Enrollment Distribution. The number of patients enrolled varied through the enrollment period of the study. Analyses demonstrated that there were no detectable seasonal biases introduced by differences in enrollments

See this image and copyright information in PMC

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Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis

Affiliations

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis

Authors

Affiliations

Abstract

Conflict of interest statement

Authors’ information

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical