from this cohort of Canadian HCWs suggest that the prevalence of positivity for LTBI, as measured by either the TST or the QFT, in this population, is low. Furthermore, many HCWs had discordant test results, where the prognosis and treatment recommendations remain unclear.
Infrequent test positivity (using either test) and weak concordance, may suggest that the noise level (or non-specific responses) from these tests in a low TB incidence setting may be such that the true signal (ie: immunological responses indicating LTBI) is difficult to distinguish. Non-specific variation has been shown to occur in both tests, and despite being health care workers, this cohort remains a low risk population 
. One alternative but not mutually exclusive hypothesis suggests these tests may be measuring independent immunological processes. Unfortunately, these hypotheses are difficult to test in the absence of a gold standard for LTBI.
Unlike many IGRA studies in HCWs, QFT did not estimate a lower positivity rate overall compared with the TST in this cohort 
. Comparable positivity rates have been reported from HCW studies in the United States and Italy, and may be more frequent in cohorts with low BCG vaccination 
. The nature and profile of this particular HCW cohort is an important factor; MUHC HCWs with prior positive TST results do not undergo routine screening, and were therefore excluded. This leads to an underestimation of the overall prevalence of positive TST results among MUHC HCWs undergoing regular screening. When restricted to those HCWs who were TST naive, we found a positivity rate two-fold higher using the TST compared with QFT (9.8% vs. 4.9%). Although this did not reach statistical significance, it is consistent with earlier studies from low TB incidence countries 
. Similar results have been reported in other North American HCW cohorts, including a conference abstract by Dorman et al., where they reported on a large multi-center study including 1,313 HCWs from the United States 
. Both IGRAs: the QFT and the TSPOT.TB test were performed, as well as the TST, and positivity rates were 5.3%, 6.9% and 6.8% respectively. Highlighting both the low overall positivity and comparable rates estimated by the IGRAs and the TST among low risk populations.
TST+/QFT− discordant results are often attributed to BCG vaccination. In this cohort, the low level of BCG vaccination (36.1%) may lead to more comparable positivity rates between the two tests. The effect of BCG was evident when restricted to vaccinated HCWs, the TST rate increased by two fold to 12.9% while the QFT rate saw a smaller increase to 9.3%. Rates for both types of discordance remained high, and while TST+/QFT− discordance was associated with non-occupational exposure, years worked in health care, and BCG vaccination, TST−/QFT+ discordance could not be explained by any of the variables we assessed.
from the multivariable analysis assessing the association between LTBI risk factors and TST positivity were consistent with previous studies 
. Given the non-specific nature of the TST, and its known cross-reactivity with BCG vaccinated persons, we are not surprised by the strong association with BCG when vaccination was performed later in life and/or repeated. Similarly, ‘total years worked in health care’ has been shown in several studies in HCWs to be consistently associated with TST positivity 
The association of positive TST results with self-reported non-occupational exposure was unexpected in our low TB incidence setting. However, this effect was strong and consistent across analyses, indicating non-occupational exposure to TB may continue to play an important role. Conversely, known occupational exposure to TB was not significantly associated with positive results for either test. It may be that most potential hospital source cases were appropriately diagnosed and isolated, effectively reducing nosocomial transmission. Non-occupational TB exposure may also imply longer duration plus lack of proper ventilation and infection control measures, resulting in a higher likelihood of transmission. Finally, known occupational exposures may be less likely to result in transmission than are undetected hospital exposures, which neither participants nor Occupational Health & Safety can report. QFT positivity was associated significantly with just one variable: having worked as a HCW in a foreign country, which could be a proxy for high risk exposure to TB. This variable was also significantly associated with concordant positive results, suggesting these cases may be true LTBI and not false positives.
It has been hypothesized that the TST is more likely to remain positive over time compared with the QFT, which may be a more dynamic test and has been shown to have high rates of reversions upon repeat testing 
. It is therefore possible that TST positivity tends to be associated with cumulative TB exposure, while QFT positivity may be more linked to acute exposure, and hence less likely to persist. While it is not possible to test this hypothesis using the cross-sectional data presented here, we plan to investigate this further using future longitudinal data from this cohort.
Many have suggested alternative cut-offs for the QFT might improve reproducibility, reduce subsequent reversions and improve concordance with the TST 
. We evaluated two alternative cut-offs for the QFT test. Using the most stringent cut-off we found lower overall rates of discordance, noticeably a twofold decrease in TST−/QFT+ discordance compared with TST+/QFT− discordance. This result more closely reflects results from other studies which have consistently identified TST+/QFT− as the most frequent type of reported discordance 
Strengths & Limitations
Our study was conducted in a low TB incidence setting, where TB exposure can be more accurately captured. We attempted to capture all potential exposures, both in the non-occupational and in the occupational setting; unprotected exposures to active TB patients were confirmed through occupational health and safety records. It is possible that we have not captured all occupational exposures, while TB exposure is a relatively rare event at the MUHC, and is well documented in Occupational Health and Safety charts, we cannot exclude the possibility that there were unrecognized exposures for which the HCW cannot report nor would there be any note of such an exposure in their OHS charts.
Recent work has shown that IGRAs have a certain within-subject (intra-assay) variability that can be caused by a range of factors, including: variation in sample collection and processing, improper incubation and storage, as well as laboratory factors or host biology 
. To address these concerns we attempted to reduce variability and further standardized sample processing and incubation times. Periodically, the assay was repeated on the same blood to assess reproducibility of results. However, we still cannot eliminate the possibility that some of the QFT results were false positives.
One significant limitation for all studies investigating diagnostic tests for LTBI is the lack of gold standard. While studies have looked at rates of disease progression in HCWs, this is not feasible in our low incidence setting where LTBI treatment is widely used 
Upon one time testing of a cohort of Canadian HCWs, we found test positivity as measured by TST or QFT was low. Of concern is the high frequency of unexplainable test discordance, namely: TST−/QFT+ subjects, and the lack of association of positive tests (especially QFT) with clear-cut recent TB exposure. In settings with low TB incidence, these dynamic tests may result in such high levels of non-specific results compared with the true underlying prevalence of LTBI that more precise tests may be required to correctly identify TB. Without a clear understanding of what underlying processes each test is measuring (ie: acute, dynamic, static), and the long-term prognosis of HCWs with discordant test results, it remains unclear how to implement QFT tests into current HCW screening programs, and what additional value they may offer over the TST.