The mobile-phone-based iCOTM Smokerlyzer®: Comparison with the piCO+ Smokerlyzer® among smokers undergoing methadone-maintained therapy

INTRODUCTION The mobile-phone-based Bedfont iCOTM Smokerlyzer® is of unknown validity and reproducibility compared to the widely-used piCO+ Smokerlyzer®. We aimed to compare the validity and reproducibility of the iCOTM Smokerlyzer® with the piCO+ Smokerlyzer® among patients reducing or quitting tobacco smoking. METHODS Methadone-maintained therapy (MMT) users from three centers in Malaysia had their exhaled carbon monoxide (eCO) levels recorded via the piCO+ and iCOTM Smokerlyzers®, their nicotine dependence assessed with the Malay version of the Fagerström Test for Nicotine Dependence (FTND-M), and daily tobacco intake measured via the Opiate Treatment Index (OTI) Tobacco Q-score. Pearson partial correlations were used to compare the eCO results of both devices, as well as the corresponding FTND-M scores. RESULTS Among the 146 participants (mean age 47.9 years, 92.5% male, and 73.3% Malay ethnic group) most (55.5%) were moderate smokers (6-19 cigarettes/day). Mean eCO categories were significantly correlated between both devices (r=0.861, p<0.001), and the first and second readings were significantly correlated for each device (r=0.94 for the piCO+ Smokerlyzer®, p<0.001; r=0.91 for the iCOTM Smokerlyzer®, p<0.001). Exhaled CO correlated positively with FTND-M scores for both devices. The post hoc analysis revealed a significantly lower iCOTM Smokerlyzer® reading of 0.82 (95% CI: 0.69–0.94, p<0.001) compared to that of the piCO+ Smokerlyzer®, and a significant intercept of -0.34 (95% CI: -0.61 – -0.07, p=0.016) on linear regression analysis, suggesting that there may be a calibration error in one or more of the iCOTM Smokerlyzer® devices. CONCLUSIONS The iCOTM Smokerlyzer® readings are highly reproducible compared to those of the piCO+ Smokerlyzer®, but calibration guidelines are required for the mobile-phone-based device. Further research is required to assess interchangeability.


INTRODUCTION
Objective smoking measures are useful to verify selfreported smoking status by individuals participating in harm reduction or smoking cessation interventions and studies 1 . Exhaled carbon monoxide (eCO) is widely used for these purposes because it is less expensive and less invasive than other measures, such as serum or urinary cotinine, and provides immediate results that assist in motivating patients to quit 1,2 . The piCO + Smokerlyzer ® is commonly used to measure eCO levels in clinical and research settings 3 because of its high validity and reproducibility in discriminating smokers from non-smokers [4][5][6] .
To date, the validity and reproducibility of the

Study design
Participants from three methadone clinics (University Malaya Medical Center, San Peng, and Chow Kit) in Kuala Lumpur, Malaysia were recruited from December 2017 to January 2018. Participants who were aged ≥18 years, on MMT for two months or more, who had an established therapeutic compliance and were not on marijuana or any other recreational drugs (as determined by routine urinary drug tests), and smoked at least one cigarette daily for the past one month, were approached for consent to take part in the study. Participants who could not understand the device instructions or who were medically unstable were excluded. The Medical Ethical Committee of University Malaya Medical Center approved the study protocol (MECID: 20146-331).

Procedure
Sociodemographic data were obtained and the Malay version of the Fagerström Test for Nicotine Dependence (FTND-M) was administered 10 . This instrument has moderate validity in distinguishing smokers with nicotine dependence from their nonnicotine-dependent counterparts with a cut-off of 2, and positively correlates with piCO + Smokerlyzer ®measured eCO levels 10,11 .
The tobacco Q-score 12 was calculated by dividing by two the total number of cigarettes consumed on the two days before the day of the study, enabling each participant to be categorized as light (≤5 cigarettes/ day), moderate (6-19 cigarettes/day) or heavy smoker (≥20 cigarettes/day) 13,14 .
Both devices were sanitized with anti-bacterial cleaning wipes between participants as per manufacturer recommendations 3,7 , using makeshift single-use mouthpieces for both devices to reduce transmission of fluids between participants; the smartphone Smokerlyzer application was used with the iCO TM Smokerlyzer ® . The instructions for both devices were: to completely exhale, take a deep breath, hold the breath for 15 s, and exhale completely and slowly into each device, which yielded values in parts per million (ppm). Each participant provided four samples with 5-minute intervals between samples, beginning with the piCO + Smokerlyzer ® , and alternating with the iCO TM Smokerlyzer ® .

Data analysis
Descriptive statistics were used to examine characteristics data. The piCO + Smokerlyzer ® readings were converted into ordinal categories (0-6; 7-10; 11-15; 16-20; 21-25; 26-30; and ≥31 ppm) to be compared with the ordinal categories in the initial results interface obtained from the iCO TM Smokerlyzer ® ; category readings from both devices were averaged for further analyses.
Partial correlations adjusting for covariates of age, tobacco Q-score and FTND-M scores, which were found to significantly influence the correlation between piCO + and iCO TM Smokerlyzer ® readings, were performed using SPSS v25. Additionally, correlations between first and second piCO + and iCO TM Smokerlyzer ® readings and between the iCO TM Smokerlyzer ® readings and FTND-M scores were also performed.

RESULTS
The participants' mean age was 47.9 years ( Table 1). The average daily methadone dose was 69.7 mg, the mean tobacco Q-score was 12.3 cigarettes/day and the mean FTND-M score was 3.9. Most participants were male (92.5%), Malay (73.3%) and moderate smokers (55.5%).
Mean eCO levels were significantly correlated between both devices (r=0.86, p<0.001; Figure 1), after adjusting for covariates of age, tobacco Q-score and FTND-M score. First and second device readings   Additionally, the post hoc analysis finding and subsequent regression analyses with a significant intercept (Figure 1) suggest that one or more of the iCO TM Smokerlyzer ® devices may be consistently yielding underestimates of eCO levels. Therefore, further guidelines are needed to recognize and rectify this calibration error, indicating that routine checks are needed against another calibrated device such as the piCO + Smokerlyzer ® . Finally, the finding that eCO levels of the iCO TM Smokerlyzer ® correlated positively with the FTND-M scores warrants further research on whether reducing smoking in people with high nicotine dependence is a step towards smoking cessation.
This study did not assess raw values of the iCO TM Smokerlyzer ® or abstinence cut-off points, thus restricting further analyses, such as Bland-Altman analysis, and the potential as a clinical utility. A study by Karelitz et al. 15 had demonstrated lack of agreement and differences of 1.5-6.0 ppm between both monitors, thereby suggesting a lack of interchangeability between readings of both monitors. Additionally, the iCO TM Smokerlyzer ® has a cited accuracy of 15% for each 1 ppm 7 , compared to <3% for the piCO + Smokerlyzer ®3 . Consequently, the use of broad categories may indeed be supported, aiming to reduce the differences between devices, and in the process potentially increase interchangeability between readings of both monitors, which would need to be confirmed through further research.
Nevertheless, assessing the iCO TM Smokerlyzer ® against the piCO + Smokerlyzer ® has yielded some results of clinical significance. The piCO + Smokerlyzer ® has been extensively studied and shown to be reproducible and reasonably accurate in determining patients who are abstinent, based on objective scores 4-6 . This study demonstrates that the categories obtained from the iCO TM Smokerlyzer ® correlate with the categorical grouped integers shown on the piCO + Smokerlyzer ® .
As such, there is a possibility for the more economical and user-friendly iCO TM Smokerlyzer ® to be researched in greater detail in order to assess its suitability for use in research and clinical environments.

CONCLUSIONS
The iCO TM Smokerlyzer ® yielded highly reproducible results that are potentially comparable to the piCO + Smokerlyzer ® , pending further calibration guidelines. As a more economical and user-friendly device than the piCO + Smokerlyzer ® , the iCO TM Smokerlyzer ® therefore has potential use in smoking cessation studies. Additionally, many individuals could benefit from using the iCO TM Smokerlyzer ® , to assess the true extent of their cigarette consumption, such that behavioral and pharmacological smoking interventions may be studied and implemented in a timely manner.