Screening for carbon monoxide exposure in selected patient groups attending rural and urban emergency departments in England: a prospective observational study

Simon Clarke; Catherine Keshishian; Virginia Murray; George Kafatos; Ruth Ruggles; Elizabeth Coultrip; Sam Oetterli; Daniel Earle; Patricia Ward; Stephen Bush; Crispin Porter; for the Carbon Monoxide in Emergency Departments (COED) Working Group

doi:10.1136/bmjopen-2012-000877

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Screening for carbon monoxide exposure in selected patient groups attending rural and urban emergency departments in England: a prospective observational study

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Unpublished methods and results in "Screening for carbon monoxide exposure..."
Simon Clarke, Patricia Ward, Stephen Bush and Joanne Zamani
Published on: 25 January 2019
False and misleading claims in reply of Clarke et al
Alberr H Donnay
Published on: 25 January 2019
Editor's Note
Adrian Aldcroft
Published on: 14 January 2019
Unpublished methods and results in "Screening for carbon monoxide exposure..."
Albert H Donnay
Published on: 20 September 2018
Editor's Note
Adrian Aldcroft
Published on: 31 August 2018

Published on: 25 January 2019
Unpublished methods and results in "Screening for carbon monoxide exposure..."
- Simon Clarke, Consultant Emergency Physician Musgrove Park Hospital
- Other Contributors:
  Patricia Ward, Consultant Emergency Physician
  
  Stephen Bush, Consultant Emergency Physician
  
  Joanne Zamani, Deputy Manager Research and Development
****Please note that BMJ Open received this response on 10 September 2018, but it was not published until 14 January 2019***

We note the letter from Mr Donnay accusing us of committing research fraud in our 2012 paper [1].
First, Mr Donnay states that we incorrectly used both arterial and venous COHb. It is clear from the published human literature that there is no significant clinical difference between arterial and venous COHb levels after 10-15 minutes of exposure due to admixture [2-12], although I acknowledge that this message has not got through to some front-line clinicians [13].
His second point is more pertinent. We became aware of some discrepancies between the non-invasive and venous results. We subsequently became aware of concerns raised by other researchers about the Rad-57 device [14] so we did analyse the data separately in the report to the Department of Health. However, the separate analyses did not alter the fundamental conclusion of our study that a proportion of patients do present to Emergency Departments with higher than expected COHb levels and our hope to raise awareness of possible CO exposure in these people. We stressed that the figures obtained should not be extrapolated more widely and we were careful to avoid confusing higher than expected COHb levels with exposure to non-smoking exogenous sources of CO. We also discussed in depth the limitations of COHb as a biomarker.
On the note of patient safety our definition of...
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****Please note that BMJ Open received this response on 10 September 2018, but it was not published until 14 January 2019***

We note the letter from Mr Donnay accusing us of committing research fraud in our 2012 paper [1].
First, Mr Donnay states that we incorrectly used both arterial and venous COHb. It is clear from the published human literature that there is no significant clinical difference between arterial and venous COHb levels after 10-15 minutes of exposure due to admixture [2-12], although I acknowledge that this message has not got through to some front-line clinicians [13].
His second point is more pertinent. We became aware of some discrepancies between the non-invasive and venous results. We subsequently became aware of concerns raised by other researchers about the Rad-57 device [14] so we did analyse the data separately in the report to the Department of Health. However, the separate analyses did not alter the fundamental conclusion of our study that a proportion of patients do present to Emergency Departments with higher than expected COHb levels and our hope to raise awareness of possible CO exposure in these people. We stressed that the figures obtained should not be extrapolated more widely and we were careful to avoid confusing higher than expected COHb levels with exposure to non-smoking exogenous sources of CO. We also discussed in depth the limitations of COHb as a biomarker.
On the note of patient safety our definition of ‘positive’ and ‘negative’ cases and their respective subgroups was based on a previously published paper (15), clearly described, and agreed by the Barking and Havering Ethics Committee. In addition, all subjects, including those defined as negative, were verbally advised about the availability of domestic CO detectors and the benefits of having their fossil fuel appliances checked annually by appropriately qualified engineers. We highlighted cases where such people defined as negative discovered faulty appliances at home showing our concern for safety and reinforcing the message about the limitations of COHb as a biomarker.
Lastly, we discussed the limitations of the study in both our paper and final report; extreme caution has to be exercised about overanalysing our data, tempting as that may be. We are more than happy for both the BMJ Open and Department of Health to independently scrutinise the study data. We feel that we have nothing to hide.
Simon Clarke
Patricia Ward
Stephen Bush
Joanne Zamani

References
1. Clarke S, Keshishian C, Murray V, Kafatos G, Ruggles R, Coultrip E, Oetterli S, Earle D, Ward P, Bush S, and Porter C. Screening for carbon monoxide exposure in selected patient groups attending rural and urban emergency departments in England: a prospective observational study. Br Med J Open. 2012; 2; e000877
2. Benignus VA, Hazucha MJ, Smith MV, and Bromberg PA. Prediction of carboxyhemoglobin formation due to transient exposure to carbon monoxide. J Appl Physiol. 1994; 76; 1739-1745
3. Garvican LA, Burge CM, Cox AJ, Clark SA, Martin DT, and Gore CJ. Carbon monoxide uptake kinetics of arterial, venous and capillary blood during CO rebreathing. 2010; 95; 1156-1166
4. Bruce EN and Bruce MC. A multicompartment model of carboxyhemoglobin and carboxymyoglobin responses to inhalation of carbon monoxide. J Appl Physiol. 2003; 95; 1235-1247
5. Chada KE and Bruce EN. Computational analyses of CO-rebreathing methods for estimating haemoglobin mass in humans. Exp Physiol. 2011; 97; 141–154
6. Touger M, Gallagher EJ and Tyrell J. Relationship between venous and arterial carboxyhemoglobin levels in patients with suspected carbon monoxide poisoning. Ann Emerg Med. 1995; 25; 481-483
7. Yasuda H, Sasaki T, Yamaya M, Ebihara S, Maruyama M, Kanda A, and Sasaki H. Increased arteriovenous carboxyhemoglobin differences in patients with inflammatory pulmonary diseases. Chest. 2004; 125; 2160-2168
8. Eletr D, Reich A, Stubbe HD, Booke M, Daudel F, Erren M, and Westphal M. Arteriovenous carboxyhemoglobin difference is not correlated to TNF-a, IL-6, PCT, CRP and leukocytes in critically ill patients. Clinica Chimica. 2004; 349; 75-80
9. Yasuda H, Yamaya M, Nakayama K, Ebihara S, Sasaki T, Okinaga S, Inoue D, Asada M, Nemoto M, and Sasaki H. Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease. Am J Resp Crit Care Med. 2005; 171; 1246-1251
10. van Staden SR, Groenewald M, Engelbrecht R, Becker PJ, and Hazelhurst LT. Carboxyhaemoglobin levels, health and lifestyle perceptions in smokers converting from tobacco cigarettes to electronic cigarettes. S Afr Med J. 2013; 11; 865-868
11. Ergun D, Ergun R, Ersoy Ortac, E, Ozdemir C, Yuce G, and Ardic S. The measurement of exhaled carbon monoxide and arterial carboxyhemoglobin concentrations in middle-aged and elderly patients with COPD. Turk J Geri. 2014; 17; 223-227
12. Naples R, Laskowski D, McCarthy K, Mattox E, Comhair SAA, and Erzurum SC. Carboxyhemoglobin and methemoglobin in asthma. Lung. 2015; 193; 183-187
13. Bloomer C, Kairam N, Fiesseler F, Riggs R, and Salo D. Are venous carboxyhemoglobin levels being utilized by physicians? Ann Emerg Med. 2009; 54; S115
14. Wilcox SR and Richards JB. Non-invasive carbon monoxide detection: insufficient evidence for broad clinical use. Respir Care. 2012; 58; 376-379
15. Mandal S, Ruggles R, Leonardi G, Goodfellow F, Bradley N and Murray V. Developing best practice response to carbon monoxide incidents: a toolkit for health protection front-line staff. Pub Health. 2011; 125; 148-156
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Conflict of Interest:
None declared.
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Published on: 25 January 2019
False and misleading claims in reply of Clarke et al
- Alberr H Donnay, Consulting Toxicologist Donnay Detoxicology LLC
I am writing to correct false and misleading claims in the reply of Dr. Clarke, two of his co-authors, and Ms. Zamani to my letter of 25 August 2018 documenting evidence of scientific misconduct in their 2012 study of carbon monoxide (CO) poisoning (1).

For the record, my original letter did not accuse them of “committing research fraud” as they claim. I was open to the possibility that all their misconduct—including not fully reporting their ethics committee approvals, methods, and results—may have been inadvertent or unwitting.

But this seems less likely in light of their reply, which does not address any of my specific concerns while making new false and misleading claims. They say I allege that they “incorrectly used both arterial and venous COHb,” but my complaint was that they incorrectly used one to validate the other. I assumed this was because they mistook the arterial Rad57 measure for venous. However from their reply it appears they recognized the difference but simply ignored it, based on their mistaken belief that “there is no significant clinical difference [emphasis added] between arterial and venous COHb levels after 10-15 minutes of exposure due to admixture [2-12].”

In fact, 8 of the 11 studies they cite for this reported just the opposite, finding both clinically and statistically significant differences, including the only study that, like Clarke et al, compared Rad57 measures with venous COHb (12). Only three reported...
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I am writing to correct false and misleading claims in the reply of Dr. Clarke, two of his co-authors, and Ms. Zamani to my letter of 25 August 2018 documenting evidence of scientific misconduct in their 2012 study of carbon monoxide (CO) poisoning (1).

For the record, my original letter did not accuse them of “committing research fraud” as they claim. I was open to the possibility that all their misconduct—including not fully reporting their ethics committee approvals, methods, and results—may have been inadvertent or unwitting.

But this seems less likely in light of their reply, which does not address any of my specific concerns while making new false and misleading claims. They say I allege that they “incorrectly used both arterial and venous COHb,” but my complaint was that they incorrectly used one to validate the other. I assumed this was because they mistook the arterial Rad57 measure for venous. However from their reply it appears they recognized the difference but simply ignored it, based on their mistaken belief that “there is no significant clinical difference [emphasis added] between arterial and venous COHb levels after 10-15 minutes of exposure due to admixture [2-12].”

In fact, 8 of the 11 studies they cite for this reported just the opposite, finding both clinically and statistically significant differences, including the only study that, like Clarke et al, compared Rad57 measures with venous COHb (12). Only three reported finding no significant difference among mean a-vCOHb differences (6, 9 and 10), but they only tested blood samples; focused only on the statistical significance of the CO difference; and said nothing about the obvious clinical significance of finding either a positive or negative gap. This clearly distinguishes people who are taking up CO from their lungs into tissues (when a>v) from those who are net excreting CO (when v>a), as occurs after any exogenous CO exposure stops until healthy equilibrium is re-established.

Critically, all the studies that Clarke et al now cite published some comparison of their arterial and venous COHb results, including two that reported a-v correlations over 0.91 (6, 10), while Clarke et al withheld from publication the results of their analysis that found a correlation of just 0.03–less than expected by chance—which they only reported to their funder (13).

They also did not disclose their decision to combine rather than contrast their (arterial) Rad57 and (venous) COHb results in their published analyses, which none of these other studies did. They nevertheless reported the “accuracy” of the Rad57 was within +/- 2% of blood COHb, referencing two papers that they only added at the recommendation of their reviewers, without disclosing--except to their funder--that they found differences up to 31%. (13).

In their defence, Clarke et al now claim they “subsequently became aware of concerns raised by other researchers about the Rad-57 device [14], so we did analyse the data separately in the report to the Department of Health,” but this is not possible. The study they cite (14) was only published in 2013, not 2012 as they claim, while their final report to the Department of Health was submitted in 2011 (13).

Also misleading is their claim that “the separate analyses did not alter the fundamental conclusion of our study that a proportion of patients do present to Emergency Departments with higher than expected COHb levels…” The proportion of ED patients they reported with high CO exposure was only 4.3%, while the actual rate—including the 293 cases they mistakenly dismissed as “false positive”—was 21%, which is five-fold higher .

The claim that they “discussed in depth the limitations of COHb as a biomarker” also rings hollow given that their paper did not mention any of these false positives while disclosing just 3 false negatives.

Finally, the authors’ claim that their “definition of ‘positive’ and ‘negative’ cases and their respective subgroups was based on a previously published paper [15], clearly described, and agreed by the Barking and Havering Ethics Committee” is false. The study was granted ethics approval by this committee in 2009 and conducted in 2010, one year before the cited paper [15] was published. Even if this paper was shared with Clarke et al prior to publication (and VM is a co-author of both), it was not submitted until February 2010, one month after the study began testing subjects, and it only specifies one COHb threshold for CO poisoning of 5%, while Clarke et al added a lower threshold of 2.5% for non-smokers.

Since the authors now claim they have “nothing to hide” and are “more than happy for both the BMJ Open and Department of Health to independently scrutinize the study data,” I hope they will promptly provide BMJO with both their unpublished final report (13) and an electronic file containing all their individual COHb results.

According to another paper (16) that some of the same authors published in 2012 with different methods and results from the same study; these included at least an initial Rad57 measure taken “at triage,” an arterial COHb taken 2 hours later, and another arterial COHb taken prior to discharge. (see Table 1). Clarke et al also should release their initial and revised protocols so reviewers can take into account whatever changes were introduced when the authors abandoned their original case-control design after just four months.

No such review is needed, however, for BMJ Open to decide whether the authors’ withholding of so much relevant information about their methods and results warrants retraction. Whether this was done deliberately or inadvertently makes no difference to the scientific record.

Albert Donnay

References

1. Clarke S, Keshishian C, Murray V, Kafatos G, Ruggles R, Coultrip E, Oetterli S, Earle D, Ward P, Bush S, and Porter C. Screening for carbon monoxide exposure in selected patient groups attending rural and urban emergency departments in England: a prospective observational study. Br Med J Open. 2012; 2; e000877

2. Benignus VA, Hazucha MJ, Smith MV, and Bromberg PA. Prediction of carboxyhemoglobin formation due to transient exposure to carbon monoxide. J Appl Physiol. 1994; 76; 1739-1745

3. Garvican LA, Burge CM, Cox AJ, Clark SA, Martin DT, and Gore CJ. Carbon monoxide uptake kinetics of arterial, venous and capillary blood during CO rebreathing. 2010; 95; 1156-1166

4. Bruce EN and Bruce MC. A multicompartment model of carboxyhemoglobin and carboxymyoglobin responses to inhalation of carbon monoxide. J Appl Physiol. 2003; 95; 1235-1247

5. Chada KE and Bruce EN. Computational analyses of CO-rebreathing methods for estimating haemoglobin mass in humans. Exp Physiol. 2011; 97; 141–154

6. Touger M, Gallagher EJ and Tyrell J. Relationship between venous and arterial carboxyhemoglobin levels in patients with suspected carbon monoxide poisoning. Ann Emerg Med. 1995; 25; 481-483

7. Yasuda H, Sasaki T, Yamaya M, Ebihara S, Maruyama M, Kanda A, and Sasaki H. Increased arteriovenous carboxyhemoglobin differences in patients with inflammatory pulmonary diseases. Chest. 2004; 125; 2160-2168

8. Eletr D, Reich A, Stubbe HD, Booke M, Daudel F, Erren M, and Westphal M. Arteriovenous carboxyhemoglobin difference is not correlated to TNF-a, IL-6, PCT, CRP and leukocytes in critically ill patients. Clinica Chimica. 2004; 349; 75-80

9. Yasuda H, Yamaya M, Nakayama K, Ebihara S, Sasaki T, Okinaga S, Inoue D, Asada M, Nemoto M, and Sasaki H. Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease. Am J Resp Crit Care Med. 2005; 171; 1246-1251

10. van Staden SR, Groenewald M, Engelbrecht R, Becker PJ, and Hazelhurst LT. Carboxyhaemoglobin levels, health and lifestyle perceptions in smokers converting from tobacco cigarettes to electronic cigarettes. S Afr Med J. 2013; 11; 865-868

11. Ergun D, Ergun R, Ortac E, Ersoy E, Ozdemir C, Yuce G, and Ardic S. The measurement of exhaled carbon monoxide and arterial carboxyhemoglobin concentrations in middle-aged and elderly patients with COPD. Turk J Geri. 2014; 17; 223-227

12. Naples R, Laskowski D, McCarthy K, Mattox E, Comhair SAA, and Erzurum SC. Carboxyhemoglobin and methemoglobin in asthma. Lung. 2015; 193; 183-187

13. Clarke et al. (co-authors are not specified but second page lists contributors by type starting with [Chief Investigator] Clarke S; [Study Site Researchers] Coultrip E, Oetterli S, Earle D; [Project Management Group] Keshishian C, Murray V, Ruggles R, Ward P, Bush S, Zamani J, Mason A; [Statistical Support] Kafatos G; [Advisory Group] Harrison P, Bielby C, Edwards N, Karalliedde L; [Consulted] Baker D, Leonardi G, Volans G, Croxford B, Griffiths L. [Names in italics are also co-authors of Clarke et al 2012, along with Porter C, who is not listed here]. Non-invasive screening for carbon monoxide exposure in selected patient groups attending rural and urban emergency departments in England. Final Report Revised 30 June 2011. Department of Health, Policy Research Programme, Carbon Monoxide, PR-CO-0907-10003. https://www.coportal.org/wp-content/uploads/gst_attachments/26a118120deb... [accessed August 2018; backup archived at https://www.dropbox.com/s/b5cs338h2k96z72/24122014100805-Dept%20of%20Hea...

14. Wilcox SR and Richards JB. Non-invasive carbon monoxide detection: insufficient evidence for broad clinical use. Respir Care. 2013; 58; 376-379

15. Mandal S, Ruggles R, Leonardi G, Goodfellow F, Bradley N and Murray V. Developing best practice response to carbon monoxide incidents: a toolkit for health protection front-line staff. Pub Health. 2011; 125; 148-156

16. Clarke S, Stephens C, Farhan M, Ward P, Keshishian C, Murray V, and Zenner D. Multiple patients with carbon monoxide toxicity from water-pipe smoking. Prehospital and Disaster Medicine, 2012; 27; 612-614.
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Conflict of Interest:
None declared.
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Published on: 14 January 2019
Editor's Note
- Adrian Aldcroft, Editor in Chief, BMJ Open BMJ Publishing Group
This is a note to indicate that BMJ Open is still looking into the disagreement between Albert Donnay and the authors of the paper.

We will post further updates on the article in due course.

Conflict of Interest:
None declared.
- Back to top
Published on: 20 September 2018
Unpublished methods and results in "Screening for carbon monoxide exposure..."
- Albert H Donnay, Consulting Toxicologist Donnay Detoxicology LLC
In “Screening for carbon monoxide poisoning…in England: a prospective observational study,”(1) Clarke et al mischaracterize Masimo's Rad57 pulse CO-oximeter as a measure of venous carboxyhaemoglobin. As noted in one of their references(2) and the Rad57 Operator’s Manual,(3) Masimo’s trademarked “SpCO” measures arterial carboxyhaemoglobin. Based on this misunderstanding, the authors checked their [arterial] Rad57 ([a]Rad57) results against [venous] carboxyhaemoglobin ([v]COHb) measured by unspecified “point-of-care blood analyzers.”(4)

Instead of publishing these results separately, however, the authors simply combined them—by which 76 of 1758 patients were “positive” for CO poisoning (COp).(1) Only in an unpublished report to their funder did they disclose the R2 correlation among 608 paired [a]Rad57 and [v]COHb measurements was just 0.03.(4) Without any other testing, they assumed [v]COHb was more accurate and used this whenever available, even when [a]Rad57 was higher. By this method, they classified 293 with high [a]Rad57 but normal [v]COHb as false positives—and discharged them without the COp treatment and home inspection given 60 cases confirmed by high [v]COHb.(4)

Also disclosed only to the funder: the authors’ original protocol was “non-invasive” with a nested case-control design.(4) Blood CO-oximetry was only added after the controls—three per case—were dropped because “a number [unspecified] had high COHb readings [unspecified] on the...
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In “Screening for carbon monoxide poisoning…in England: a prospective observational study,”(1) Clarke et al mischaracterize Masimo's Rad57 pulse CO-oximeter as a measure of venous carboxyhaemoglobin. As noted in one of their references(2) and the Rad57 Operator’s Manual,(3) Masimo’s trademarked “SpCO” measures arterial carboxyhaemoglobin. Based on this misunderstanding, the authors checked their [arterial] Rad57 ([a]Rad57) results against [venous] carboxyhaemoglobin ([v]COHb) measured by unspecified “point-of-care blood analyzers.”(4)

Instead of publishing these results separately, however, the authors simply combined them—by which 76 of 1758 patients were “positive” for CO poisoning (COp).(1) Only in an unpublished report to their funder did they disclose the R2 correlation among 608 paired [a]Rad57 and [v]COHb measurements was just 0.03.(4) Without any other testing, they assumed [v]COHb was more accurate and used this whenever available, even when [a]Rad57 was higher. By this method, they classified 293 with high [a]Rad57 but normal [v]COHb as false positives—and discharged them without the COp treatment and home inspection given 60 cases confirmed by high [v]COHb.(4)

Also disclosed only to the funder: the authors’ original protocol was “non-invasive” with a nested case-control design.(4) Blood CO-oximetry was only added after the controls—three per case—were dropped because “a number [unspecified] had high COHb readings [unspecified] on the pulse CO-oximeter without displaying symptoms of CO poisoning.”(4)

Unreported even to the funder was a protocol amendment approved in April 2010—four months after testing started—by the London-Surrey Research Ethics Committee (personal communication).

Had the authors realized Rad57 results were arterial, they might have published their controls’ results and some comparison with venous COHb, as this asthma study did.(5) Their unpublished report(4) shows the absolute [a]Rad57-[v]COHb difference was:

1) abnormal in 60% of 608 pairs, with 28% differing by 1-3%, 18% by 3-5%, and 14% by 5-31.7%, while only 40% differed by the 0-1% considered healthy;(5)

2) positive only in the seizure group, which had highest rate of COp detection by [a]Rad57 (5.0%), although the authors only published that it had the lowest rate by [v]COHb (2.1%).

Clearly, the [a]Rad57-[v]COHb difference is not due to instrument error. It varies by disorder in both direction and magnitude, with [a]Rad57>[v]COHb whenever free CO is diffusing from lungs and blood into other tissues, and vice-versa.

Unfortunately, the authors’ withholding of all this information from their paper meets BMJ’s definition of research misconduct and warrants retraction.(6)

References

1. Clarke S, Keshishian C, Murray V, et al. for the Carbon Monoxide in Emergency Departments (COED) Working Group. Screening for carbon monoxide exposure in selected patient groups attending rural and urban emergency departments in England: a prospective observational study. BMJ Open 2012;2:e000877

2. Barker SJ, Curry J, Redford D, et al. Measurement of carboxyhaemoglobin and methemoglobin by pulse oximetry. Anesthesiol 2006;105:892–7

3. Masimo Corporation. Rad-57 Signal Extraction Pulse CO-Oximeter Operator’s Manual. 2005. Irvine CA. http://www.infiniti.no/upload/Bruksanvisningar/Masimo/UM_EN_Rad57_070126... [accessed 20 August 2018]

4. Clarke S, Coultrip E, Oetterli S, et al. Earle D, Keshishian C, Murray V, Ruggles R, Ward P, Bush S. Non-invasive screening for carbon monoxide exposure in selected patient groups attending rural and urban emergency departments in England. Report to the Department of Health, PRP:002/0030. Final Report, Second Revision, August 2011. Released 17 August 2018 by the UK NIHR Central Commissioning Facility in WORD format and archived by AD in PDF format at
https://www.dropbox.com/s/ww11hzuv9gsngqi/Clarke%202011%202nd%20revision... [accessed 21 August 2018]

[AD note: A later 2012 version of this Final Report is referenced in an unrelated 2017 report entitled “Carbon Monoxide Pre-Hospital Screening Study,” by Foster T, Scott T, and Prothero L. https://www.coportal.org/wp-content/uploads/gst_attachments/b85a312fdeba... [accessed 20 August 2018].
The 2012 version has the same title and nine authors as Clarke et al 2011(4), but eight are re-ordered. Clarke is still first but Keshishian is moved from fifth to second, Murray from sixth to third, Coultrip from second to fourth, Oetterli from third to fifth, Earle from fourth to sixth, Ward from eighth to seventh, Bush from ninth to eighth and Ruggles from seventh to ninth. The list of authors was changed again in the manuscript submitted to BMJ Open on 17 February 2012, when two authors were added for the first time--Kafatos third and Porter eleventh—and Ruggles was moved from last to fourth(1). ]

5. Naples R, Laskowski D, McCarthy K, et al. Carboxyhemoglobin and methemoglobin in asthma. Lung. 2015 Apr;193(2):183-7

6. Anonymous. Analysis: A consensus statement on research misconduct in the UK. BMJ 2012;344:e1111
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Conflict of Interest:
None declared.
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Published on: 31 August 2018
Editor's Note
- Adrian Aldcroft, Editor in Chief, BMJ Open BMJ Publishing Group
The Editor of BMJ Open has received the comments from Albert Donnay on this paper. The authors of the paper have been contacted and have been asked to provide a response.

Conflict of Interest:
None declared.
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