QuantiFERON?-TB Gold In-Tube Performance for Diagnosing Active Tuberculosis in Children and Adults in a High Burden Setting

Aim

To determine whether QuantiFERON®-TB Gold In-Tube (QFT) can contribute to the diagnosis of active tuberculosis (TB) in children in a high-burden setting and to assess the performance of QFT and tuberculin skin test (TST) in a prospective cohort of TB suspect children compared to adults with confirmed TB in Tanzania.

Methods

Sensitivity and specificity of QFT and TST for diagnosing active TB as well as indeterminate QFT rates and IFN-γ levels were assessed in 211 TB suspect children in a Tanzanian district hospital and contrasted in 90 adults with confirmed pulmonary TB.

Results

Sensitivity of QFT and TST in children with confirmed TB was 19% (5/27) and 6% (2/31) respectively. In adults sensitivity of QFT and TST was 84% (73/87) and 85% (63/74). The QFT indeterminate rate in children and adults was 27% and 3%. Median levels of IFN-γ were lower in children than adults, particularly children <2 years and HIV infected. An indeterminate result was associated with age <2 years but not malnutrition or HIV status. Overall childhood mortality was 19% and associated with an indeterminate QFT result at baseline.

Conclusion

QFT and TST showed poor performance and a surprisingly low sensitivity in children. In contrast the performance in Tanzanian adults was good and comparable to performance in high-income countries. Indeterminate results in children were associated with young age and increased mortality. Neither test can be recommended for diagnosing active TB in children with immature or impaired immunity in a high-burden setting.     

Mycobacterium Tuberculosis-Specific TNF-α Is a Potential Biomarker for the Rapid Diagnosis of Active Tuberculosis Disease in Chinese Population

Interferon-gamma release assays (IGRAs) have proven to be useful to accurately detect Mycobacterium tuberculosis (Mtb) infection, but they cannot reliably discriminate between active tuberculosis (TB) and latent tuberculosis infection (LTBI). This study aims to test whether Mtb-specific tumor necrosis factor-alpha (TNF-α) could be used as a new tool for the rapid diagnosis of active TB disease. The secretion of TNF-α by Mtb-specific antigen-stimulated peripheral blood mononuclear cells (PBMCs) of sixty seven participants was investigated in the study. Our results showed that the total measurement of TNF-α secretion by Mtb-specific antigen-stimulated PBMCs is not a good biomarker for active TB diagnosis. However, we found that calculation of Mtb-specific TNF-α not only distinguish between active and latent TB infection, but also can differentiate active TB from non-TB patients. Using the cutoff value of 136.9 pg/ml for Mtb-specific TNF-α, we were able to differentiate active TB from LTBI. Sensitivity and specificity were 72% and 90.91%. These data suggest that Mtb-specific TNF-α could be a potential biomarker for the diagnosis of active TB disease.     

Combined Analysis of IFN-γ, IL-2, IL-5, IL-10, IL-1RA and MCP-1 in QFT Supernatant Is Useful for Distinguishing Active Tuberculosis from Latent Infection

The QuantiFERON®-TB Gold In-Tube test (QFT), an interferon-γ release assay, is used to diagnose Mycobacterium tuberculosis, but its inaccuracy in distinguishing active tuberculosis from latent infection is a major concern. There is thus a need for an easy and accurate tool for achieving that goal in daily clinical settings. This study aimed to identify candidate cytokines for specifically differentiating active tuberculosis from latent infection. Our study population consisted of 31 active TB (tuberculosis) patients, 29 LTBI (latent tuberculosis infection) patients and 10 healthy control subjects. We assayed for 27 cytokines in QFT supernatants of both specific antigen-stimulated blood samples (TBAg) and negative-control samples (Nil). We analyzed their specificities and sensitivities by creating receiver operating characteristic (ROC) curves and measuring the area under those curves (AUCs). In TBAg–Nil supernatants, IL-10, IFN-γ, MCP-1 and IL-1RA showed high AUCs of 0.8120, 0.7842, 0.7419 and 0.7375, respectively. Compared with each cytokine alone, combined assay for these top four cytokines showed positive rates in diagnosing active TB, and GDA analysis revealed that MCP-1 and IL-5 are potent in distinguishing active TB from LTBI, with Wilk’s lambda = 0.718 (p < 0.001). Furthermore, utilizing the unique characteristic of IL-2 that its TBAg–Nil supernatant levels are higher in LTBI compared to active TB, the difference between IFN-γ and IL-2 showed a large AUC of 0.8910. In summary, besides IFN-γ, IL-2, IL-5, IL-10, IL-1RA and MCP-1 in QFT supernatants may be useful for distinguishing active TB from LTBI. Those cytokines may also help us understand the difference in pathogenesis between active TB and LTBI.     

Potential Role of M. tuberculosis Specific IFN-γ and IL-2 ELISPOT Assays in Discriminating Children with Active or Latent Tuberculosis

Background

Although currently available IGRA have been reported to be promising markers for TB infection, they cannot distinguish active tuberculosis (TB) from latent infection (LTBI).

Objective

Children with LTBI, active TB disease or uninfected were prospectively evaluated by an in-house ELISPOT assay in order to investigate possible immunological markers for a differential diagnosis between LTBI and active TB.

Methods

Children at risk for TB infection prospectively enrolled in our infectious disease unit were evaluated by in-house IFN-γ and IL-2 based ELISPOT assays using a panel of Mycobacterium tuberculosis antigens.

Results

Twenty-nine children were classified as uninfected, 21 as LTBI and 25 as active TB cases (including 5 definite and 20 probable cases). Significantly higher IFN-γ ELISPOT responses were observed in infected vs. uninfected children for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p = 0.003), and AlaDH (p = 0.001), while differences were not significant considering Ag85B (p = 0.063), PstS1 (p = 0.512), and HspX (16 kDa) (p = 0.139). IL-2 ELISPOT assay responses were different for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p<0.0001), HspX (16 kDa) (p<0.0001), PstS1 (p<0.0001) and AlaDH (p = 0.001); but not for Ag85B (p = 0.063). Comparing results between children with LTBI and those with TB disease differences were significant for IFN-γ ELISPOT only for AlaDH antigen (p = 0.021) and for IL-2 ELISPOT assay for AlaDH (p<0.0001) and TB 10.3 antigen (p = 0.043). ROC analyses demonstrated sensitivity of 100% and specificity of 81% of AlaDH-IL-2 ELISPOT assay in discriminating between latent and active TB using a cut off of 12.5 SCF per million PBMCs.

Conclusion

Our data suggest that IL-2 based ELISPOT with AlaDH antigen may be of help in discriminating children with active from those with latent TB.     

Is IP-10 an Accurate Marker for Detecting M. tuberculosis-Specific Response in HIV-Infected Persons?

Background

The suboptimal sensitivity of Interferon (IFN)-γ-based in-vitro assays, especially in immunocompromised individuals, emphasizes the need for alternative markers for diagnosing tuberculosis (TB). The objective of this study was to evaluate whether interferon-inducible protein (IP)-10, monocyte chemotactic protein (MCP)-2 and interleukin (IL)-2 can be useful biomarkers for evaluating a specific response to RD1 antigens associated to active TB disease in HIV-infected individuals.

Methodology/Principal Findings

The study was carried out in India, the country with the highest TB burden in the world. Sixty-six HIV-infected individuals were prospectively enrolled, 28 with active-pulmonary-TB and 38 without. The whole blood assay based on RD1-selected peptides (experimental test) and QuantiFERON-TB Gold In tube (QFT-IT) was performed. Plasma was harvested at day-1-post-culture and soluble factors were evaluated by ELISA. The results indicate that by detecting IP-10, the sensitivity of the experimental test and QFT-antigen (75% and 85.7% respectively) for active TB was higher compared to the same assays based on IFN-γ (42.9% and 60.7% respectively) and was not influenced by the ability to respond to the mitogen. By detecting IP-10, the specificity of the experimental test and QFT-antigen (57.9% and 13.2% respectively) for active TB was lower than what was reported for the same assays using IFN-γ-detection (78.9% and 68.4% respectively). On the other side, in vitro IL-2 and MCP-2 responses were not significantly associated with active TB.

Conclusions

HIV infection does not impair RD1-specific response detected by IP-10, while it significantly decreases IFN-γ-mediated responses. At the moment it is unclear whether higher detection is related to higher sensitivity or lower specificity of the assay. Further studies in high and low TB endemic countries are needed to elucidate this.     

Is There a Lag Globally in Overweight Trends for Children Compared with Adults?

Objective: To determine relative trends in prevalence for overweight for adults compared with children across high‐income countries (Australia, United Kingdom, and United States), middle‐income countries (Brazil and Russia), and low‐income countries (China and Indonesia). Research Methods and Procedures: Extant nationally representative survey data from 1971 to the present are used. Prevalence of overweight for adults ≥18.0 years of age and children 6.0 to 17.9 years of age were used. Absolute and relative annual rates of change in prevalence of overweight in children and adults were the key outcomes. Results: Absolute rates of increase in overweight were higher among adults than among children in all studied countries except Australia. However, relative rates of increase in overweight indicate faster increases in overweight among children in Brazil, China, and the three high‐income countries. As a result, the relative excess of overweight among adults, seen initially in all countries, increased in Indonesia and Russia, but it decreased in Australia, Brazil, China, United Kingdom, and United States. In Brazil, time trends indicate an acceleration in the annual rate of change in overweight for children and a deceleration for adults, whereas in the United States, the increase in overweight shows acceleration for both children and adults. Discussion: In absolute terms, overweight increased faster among children than adults only in Australia; however, the relative gap between children and adults is closing in four additional countries, Brazil, China, the United Kingdom, and the United States.     

Serum S100β is a Better Biomarker than Neuron-Specific Enolase for Sepsis-Associated Encephalopathy and Determining Its Prognosis: A Prospective and Observational Study

S100β and neuron-specific enolase (NSE) are brain injury biomarkers, mainly used in brain trauma, cerebral stroke and hypoxic ischemia encephalopathy. The aim of this study was to study the clinical significance of serum S100β and NSE in diagnosing sepsis-associated encephalopathy (SAE) and predicting its prognosis. This was a prospective and observational study. Clinical data of septic patients were collected within 24 h after ICU admission from May 2012 to April 2013. We evaluated the level of consciousness twice per day. SAE was defined as cerebral dysfunction in the presence of sepsis that fulfilled the exclusion criteria. The infection biochemical indicators, Glasgow coma scale (GCS) score, acute physiology and chronic health evaluation score II, serum NSE and S100β were newly measured or evaluated for SAE patients. Finally, hospital mortality, bacteriological categories, length of ICU stay and length of hospital stay were also recorded for all enrolled patients. The data was analyzed with the Chi square test, two-sample t test or Mann–Whitney U test between two groups. The correlation between two factors was analyzed using the Pearson or Spearman analysis. Receiver operating characteristic (ROC) curves were used to determine the ability of S100β and NSE in diagnosing SAE and predicting the hospital mortality. In addition, cut-off points were obtained from the curves to determine the highest sum of sensitivity and specificity. Of 112 enrolled patients, 48 patients were diagnosed with SAE. The serum S100β and NSE concentrations in SAE patients were both significantly higher than in non-SAE patients 0.306 (IQR 0.157–0.880) μg/L vs. 0.095 (IQR 0.066–0.177) μg/L, 24.87 (IQR 31.73–12.73) ng/mL vs. 15.49 (IQR 9.88–21.46) ng/mL, P < 0.01]. GCS scores were related more closely to S100β than NSE (?0.595 vs. ?0.337). S100β levels of 0.131 μg/L diagnosed SAE with 67.2 % specificity and 85.4 % sensitivity in the ROC curve, the area under the curve was 0.824 (95 % confidence interval 0.750–0.898). NSE levels of 24.15 ng/mL diagnosed SAE with 82.8 % specificity and 54.2 % sensitivity, and the area under the curve was 0.664 (95 % confidence interval 0.561–0.767). In addition, the area under the curve for S100β for predicting hospital mortality was larger than for NSE (0.730 vs. 0.590). Serum S100β concentrations in SAE patients were significantly higher than in non-SAE patients. These may be related to the severity of SAE and may predict the outcome of sepsis. The efficacy and sensitivity of serum S100β in diagnosing SAE were high, but it had a low specificity. Moreover, compared to NSE, serum S100β was better for both diagnosing SAE and predicting the outcome of sepsis.     

Can Interferon-Gamma or Interferon-Gamma-Induced-Protein-10 Differentiate Tuberculosis Infection and Disease in Children of High Endemic Areas?

Background

Diagnosis of childhood tuberculosis (TB) is difficult in high TB burden settings. Interferon-gamma-induced protein 10 (IP10) has been suggested as a marker of TB infection and disease, but its ability to differentiate the two conditions remains uncertain.

Objectives

To describe Interferon-gamma (INFγ) and IP10 expression in children with TB infection and disease and controls to assess their potential to differentiate latent and active TB.

Methods

This was a cross sectional study of 322 1–15 years old children with symptoms of TB (28 confirmed, 136 probable and 131 unlikely TB), 335 children in contact with adults with pulmonary TB and 156 community controls in Southern Ethiopia. The Tuberculin Skin Test (TST) and Quantiferon-In-Tube (QFT-IT) were performed. INFγ and IP10 were measured in plasma supernatants.

Results and Interpretation

Children with confirmed and probable TB and contacts were more likely to have TST+ (78.6%, 59.3% and 54.1%, respectively) than children with unlikely TB (28.7%) and controls (12.8%) (p<0.001). Children with confirmed TB (59.3%) and contacts (44.7%) were more likely to have INFγ+ than children with probable (37.6%) or unlikely TB (28.1%) and controls (13.1%) (p<0.001). IP10 concentrations were higher in INFγ+ children independently of TST (p<0.001). There was no difference between IP10 concentrations of children with confirmed TB and contacts (p = 0.8) and children with and without HIV (p>0.1).INFγ and IP10 can identify children with TB infection and disease, but cannot differentiate between the two conditions. HIV status did not affect the expression of IP10.     

Is Rural Residency a Risk Factor for Overweight and Obesity for U.S. Children?

Objective: Despite studies suggesting that there is a higher prevalence of overweight or obese children in rural areas in the U.S., there are no national studies comparing the prevalence levels of overweight or obese rural to metropolitan children. The objective of this research was to examine the hypothesis that living in a rural area is a risk factor for children being overweight or obese. Research Methods and Procedures: Using the National Survey of Children's Heath, the prevalence of overweight and/or obese rural children was compared with that of children in metropolitan settings. Multivariate analyses were performed on the data to detect if differences varied by health services use factors or demographic factors, such as household income, gender, and race. Results: Multivariate analysis revealed that overweight or obese children ≥5 years of age were more likely to live in rural rather than metropolitan areas (odds ratio = 1.252; 95% confidence interval, 1.248, 1.256). Rural overweight U.S. children ≥5 years of age of age were more likely than their metropolitan counterparts to: be white, live in households ≤200% of the federal poverty level, have no health insurance, have not received preventive health care in the past 12 months, be female, use a computer for non‐school work >3 hours a day, and watch television for >3 hours a day. In addition, they were more likely to have comorbidities. Discussion: Living in rural areas is a risk factor for children being overweight or obese.     

HP1β Is a Biomarker for Breast Cancer Prognosis and PARP Inhibitor Therapy

Members of the heterochromatin protein 1 family (HP1α, β and γ) are mostly associated with heterochromatin and play important roles in gene regulation and DNA damage response. Altered expression of individual HP1 subtype has profound impacts on cell proliferation and tumorigenesis. We analyzed the expression profile of HP1 family by data mining using a published microarray data set coupled with retrospective immunohistochemistry analyses of archived breast cancer biospecimens. We found that the patient group overexpressing HP1β mRNA is associated with poorly differentiated breast tumors and with a significantly lower survival rate. Immunohistochemical staining against HP1α, HP1β and HP1γ shows that respective HP1 expression level is frequently altered in breast cancers. 57.4 - 60.1% of samples examined showed high HP1β expression and 39.9 - 42.6 % of examined tumors showed no or low expression of each HP1 subtype. Interestingly, comparative analysis on HP1 expression profile and breast cancer markers revealed a positive correlation between the respective expression level of all three HP1 subtypes and Ki-67, a cell proliferation and well-known breast cancer marker. To explore the effect of individual HP1 on PARP inhibitor therapy for breast cancer, MCF7 breast cancer cells and individually HP1-depleted MCF7 cells were treated with PARP inhibitor ABT-888 with or without carboplatin. Notably, HP1β-knockdown cells are hypersensitive to the PARP inhibitor ABT-888 alone and its combination with carboplatin. In summary, while increased HP1β expression is associated with the poor prognosis in breast cancer, compromised HP1β abundance may serve as a useful predictive marker for chemotherapy, including PARP inhibitors against breast cancer.     

Is Ultrasound a Better Target than Clinical Disease Activity Scores in Rheumatoid Arthritis with Fibromyalgia? A Case-Control Study

Objectives

Our goal is to study the correlations among gray-scale seven-joint ultrasound score (GS-US7), power Doppler seven-joint ultrasound score (PD-US7), disease activity score-28 joints (DAS28), simplified disease activity index (SDAI) and clinical disease activity index (CDAI) in patients with and without fibromyalgia (FM).

Methods

A matched case-control study included all patients consecutively seen in the Rheumatoid Arthritis (RA) Clinic. Participants were allocated into one of two groups: RA with FM and RA without FM. Ultrasound (US) and clinical scoring were blinded for the presence of FM. Medians and proportions were compared by Mann-Whitney’s test and McNemar’s test, respectively. Spearman’s rank correlation coefficients (r_s) were calculated among clinical and US scores and differences were tested by r-to-z transformation test.

Results

Seventy-two women were included, out of 247 RA patients, mostly white, with median (IQR) age of 57.5 (49.3–66.8) years, with RA symptoms for 13.0 (6.0–19.0) years and FM symptoms for 6.0 (2.0–15.0) years. Disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs and prednisone use was comparable between groups. Objective activity parameters were not different between groups. RA patients with FM had greater DAS28, SDAI and CDAI but similar GS-US7 and PD-US7. GS-US7 correlated with DAS28, SDAI and CDAI in patients with and without FM (r_s = 0.36–0.57), while PD-US7 correlated with clinical scores only in patients without FM (r_s = 0.35–0.38).

Conclusion

To our knowledge, this is the first study to demonstrate that ultrasound synovitis scores are not affected by FM in RA patients. PD-US7 performed better than GS-US7 in long-standing RA patients with DAS28, SDAI or CDAI allegedly overestimated due to FM. Since sonographic synovitis predicts erosion better than swollen joint count, C-reactive protein and erythrocyte sedimentation rate, US should be considered a promising treatment target in RA patients with FM.     

Is the self always better than a friend? Self-face recognition in Christians and atheists

Early behavioral studies found that human adults responded faster to their own faces than faces of familiar others or strangers, a finding referred to as self-face advantage. Recent research suggests that the self-face advantage is mediated by implicit positive association with the self and is influenced by sociocultural experience. The current study investigated whether and how Christian belief and practice affect the processing of self-face in a Chinese population. Christian and Atheist participants were recruited for an implicit association test (IAT) in Experiment 1 and a face-owner identification task in Experiment 2. Experiment 1 found that atheists responded faster to self-face when it shared the same response key with positive compared to negative trait adjectives. This IAT effect, however, was significantly reduced in Christians. Experiment 2 found that atheists responded faster to self-face compared to a friend's face, but this self-face advantage was significantly reduced in Christians. Hierarchical regression analyses further showed that the IAT effect positively predicted self-face advantage in atheists but not in Christians. Our findings suggest that Christian belief and practice may weaken implicit positive association with the self and thus decrease the advantage of the self over a friend during face recognition in the believers.     

Cost-Effectiveness of Quantiferon?-TB Gold-In-Tube Versus Tuberculin Skin Testing for Contact Screening and Treatment of Latent Tuberculosis Infection in Brazil

Background

Latent tuberculosis infection (LTBI) is a reservoir for new TB cases. Isoniazid preventive therapy (IPT) reduces the risk of active TB by as much as 90%, but LTBI screening has limitations. Unlike tuberculin skin testing (TST), interferon-gamma release assays are not affected by BCG vaccination, and have been reported to be cost-effective in low-burden countries. The goal of this study was to perform a cost-effectiveness analysis from the health system perspective, comparing three strategies for LTBI diagnosis in TB contacts: tuberculin skin testing (TST), QuantiFERON®-TB Gold-in-Tube (QFT-GIT) and TST confirmed by QFT-GIT if positive (TST/QFT-GIT) in Brazil, a middle-income, high-burden country with universal BCG coverage.

Methodology/Principal Findings

Costs for LTBI diagnosis and treatment of a hypothetical cohort of 1,000 adult immunocompetent close contacts were considered. The effectiveness measure employed was the number of averted TB cases in two years. Health system costs were US$ 105,096 for TST, US$ 121,054 for QFT-GIT and US$ 101,948 for TST/QFT-GIT; these strategies averted 6.56, 6.63 and 4.59 TB cases, respectively. The most cost-effective strategy was TST (US$ 16,021/averted case). The incremental cost-effectiveness ratio was US$ 227,977/averted TB case for QFT-GIT. TST/QFT-GIT was dominated.

Conclusions

Unlike previous studies, TST was the most cost-effective strategy for averting new TB cases in the short term. QFT-GIT would be more cost-effective if its costs could be reduced to US$ 26.95, considering a TST specificity of 59% and US$ 18 considering a more realistic TST specificity of 80%. Nevertheless, with TST, 207.4 additional people per 1,000 will be prescribed IPT compared with QFT.     

Is HIV Infection a Risk Factor for Multi-Drug Resistant Tuberculosis? A Systematic Review

Background

Tuberculosis (TB) is an important cause of human suffering and death. Human immunodeficiency virus (HIV), multi-drug resistant TB (MDR-TB), and extensive drug resistant tuberculosis (XDR-TB) have emerged as threats to TB control. The association between MDR-TB and HIV infection has not yet been fully investigated. We conducted a systematic review and meta-analysis to summarize the evidence on the association between HIV infection and MDR-TB.

Methods and Results

Original studies providing Mycobacterium tuberculosis resistance data stratified by HIV status were identified using MEDLINE and ISI Web of Science. Crude MDR-TB prevalence ratios were calculated and analyzed by type of TB (primary or acquired), region and study period. Heterogeneity across studies was assessed, and pooled prevalence ratios were generated if appropriate. No clear association was found between MDR-TB and HIV infection across time and geographic locations. MDR-TB prevalence ratios in the 32 eligible studies, comparing MDR-TB prevalence by HIV status, ranged from 0.21 to 41.45. Assessment by geographical region or study period did not reveal noticeable patterns. The summary prevalence ratios for acquired and primary MDR-TB were 1.17 (95% CI 0.86, 1.6) and 2.72 (95% CI 2.03, 3.66), respectively. Studies eligible for review were few considering the size of the epidemics. Most studies were not adjusted for confounders and the heterogeneity across studies precluded the calculation of a meaningful overall summary measure.

Conclusions

We could not demonstrate an overall association between MDR-TB and HIV or acquired MDR-TB and HIV, but our results suggest that HIV infection is associated with primary MDR-TB. Future well-designed studies and surveillance in all regions of the world are needed to better clarify the relationship between HIV infection and MDR-TB.     

Is Scale-Up Worth It? Challenges in Economic Analysis of Diagnostic Tests for Tuberculosis

David Dowdy and colleagues discuss the complexities of costing new TB diagnostic tests, including GeneXpert, and argue that flexible analytic tools are needed for decision-makers to adapt large-sample cost-effectiveness data to local conditions.     

Costs and Consequences of Using Interferon-γ Release Assays for the Diagnosis of Active Tuberculosis in India

Background

There is growing concern that interferon-γ release assays (IGRAs) are being used off-label for the diagnosis of active tuberculosis (TB) disease in many high-burden settings, including India, where the background prevalence of latent TB infection is high. We analyzed the costs and consequences of using IGRAs for the diagnosis of active TB in India from the perspective of the Indian TB control sector.

Methods and Findings

We constructed a decision analytic model to estimate the incremental cost and effectiveness of IGRAs for the diagnosis of active TB in India. We compared a reference scenario of clinical examination and non-microbiological tests against scenarios in which clinical diagnosis was augmented by the addition of either sputum smear microscopy, IGRA, or Xpert MTB/RIF. We examined costs (in 2013 US dollars) and consequences from the perspective of the Indian healthcare sector. Relative to sputum smear microscopy, use of IGRA for active TB resulted in 23,700 (95% uncertainty range, UR: 3,800 – 38,300) additional true-positive diagnoses, but at the expense of 315,700 (95% UR: 118,300 – 388,400) additional false-positive diagnoses and an incremental cost of US$49.3 million (95% UR: $34.9 – $58.0 million) (2.9 billion Indian Rupees). Relative to Xpert MTB/RIF (including the cost of treatment for drug resistant TB), use of IGRA led to 400 additional TB cases treated (95% UR: [-8,000] – 16,200), 370,600 (95% UR: 252,200 – 441,700) more false-positive diagnoses, 70,400 (95% UR: [-7,900] – 247,200) fewer disability-adjusted life years averted, and US$14.6 million (95%UR: [-$7.2] – $28.7 million) (854 million Indian Rupees) in additional costs.

Conclusion

Using IGRAs for diagnosis of active TB in a setting like India results in tremendous overtreatment of people without TB, and substantial incremental cost with little gain in health. These results support the policies by WHO and Standards for TB Care in India, which discourage the use of IGRAs for the diagnosis of active TB in India and similar settings.     

Is the Exact Test Better than the Asymptotic Test for Testing Marginal Homogeneity in 2 × 2 Tables?

McNemar test is commonly used to test for the marginal homogeneity in 2 × 2 contingency tables. McNemar test is an asymptotic test based either on standard normal distribution or on the chi‐square distribution. When the total sample size is small, an exact version of McNemar test is available based on the binomial probabilities. The example in the paper came from a clinical study to investigate the effect of epidermal growth factor for children who had microvillus inclusion diseases. There were only six observations available. The test results differ between the exact test and the asymptotic test. It is a common belief that with this small sample size the exact test be used. However, we claim that McNemar test performs better than the exact test even when the sample size is small. In order to investigate the performances of McNemar test and the exact test, we identify the parameters that affect the test results and then perform sensitivity analysis. In addition, through Monte Carlo simulation studies we compare the empirical sizes and powers of these tests as well as other asymptotic tests such as Wald test and the likelihood ratio test.