What if They Don't Have Tuberculosis? The Consequences and Trade-offs Involved in False-positive Diagnoses of Tuberculosis.

To find the millions of missed tuberculosis (TB) cases, national TB programs are under pressure to expand TB disease screening and to target populations with lower disease prevalence. Together with imperfect performance and application of existing diagnostic tools, including empirical diagnosis, broader screening risks placing individuals without TB on prolonged treatment. These false-positive diagnoses have profound consequences for TB patients and prevention efforts, yet are usually overlooked in policy decision making. In this article we describe the pathways to a false-positive TB diagnosis, including trade-offs involved in the development and application of diagnostic algorithms. We then consider the wide range of potential consequences for individuals, households, health systems, and reliability of surveillance data. Finally, we suggest practical steps that the TB community can take to reduce the frequency and potential harms of false-positive TB diagnosis and to more explicitly assess the trade-offs involved in the screening and diagnostic process.

Investigating the impact of TB case-detection strategies and the consequences of false positive diagnosis through mathematical modelling.

BACKGROUND: Increasing case notifications is one of the top programmatic priorities of National TB Control Programmes (NTPs). To find more cases, NTPs often need to consider expanding TB case-detection activities to populations with increasingly low prevalence of disease. Together with low-specificity diagnostic algorithms, these strategies can lead to an increasingly high number of false positive diagnoses, which has important adverse consequences. METHODS: We apply TIME, a widely-used country-level model, to quantify the expected impact of different case-finding strategies under two scenarios. In the first scenario, we compare the impact of implementing two different diagnostic algorithms (higher sensitivity only versus higher sensitivity and specificity) to reach programmatic screening targets. In the second scenario, we examine the impact of expanding coverage to a population with a lower prevalence of disease. Finally, we explore the implications of modelling without taking into consideration the screening of healthy individuals. Outcomes considered were changes in notifications, the ratio of additional false positive to true positive diagnoses, the positive predictive value (PPV), and incidence. RESULTS: In scenario 1, algorithm A of prolonged cough and GeneXpert yielded fewer additional notifications compared to algorithm B of any symptom and smear microscopy (n = 4.0 K vs 13.8 K), relative to baseline between 2017 and 2025. However, algorithm A resulted in an increase in PPV, averting 2.4 K false positive notifications thus resulting in a more efficient impact on incidence. Scenario 2 demonstrated an absolute decrease of 11% in the PPV as intensified case finding activities expanded into low-prevalence populations without improving diagnostic accuracy, yielding an additional 23 K false positive diagnoses for an additional 1.3 K true positive diagnoses between 2017 and 2025. Modelling the second scenario without taking into account screening amongst healthy individuals overestimated the impact on cases averted by a factor of 6. CONCLUSION: Our findings show that total notifications can be a misleading indicator for TB programme performance, and should be interpreted carefully. When evaluating potential case-finding strategies, NTPs should consider the specificity of diagnostic algorithms and the risk of increasing false-positive diagnoses. Similarly, modelling the impact of case-finding strategies without taking into account potential adverse consequences can overestimate impact and lead to poor strategic decision-making.

Saving Lives at Birth; development of a retrospective theory of change, impact framework and prioritised metrics.

BACKGROUND: Grand Challenges for international health and development initiatives have received substantial funding to tackle unsolved problems; however, evidence of their effectiveness in achieving change is lacking. A theory of change may provide a useful tool to track progress towards desired outcomes. The Saving Lives at Birth partnership aims to address inequities in maternal-newborn survival through the provision of strategic investments for the development, testing and transition-to-scale of ground-breaking prevention and treatment approaches with the potential to leapfrog conventional healthcare approaches in low resource settings. We aimed to develop a theory of change and impact framework with prioritised metrics to map the initiative's contribution towards overall goals, and to measure progress towards improved outcomes around the time of birth. METHODS: A theory of change and impact framework was developed retrospectively, drawing on expertise across the partnership and stakeholders. This included a document and literature review, and wide consultation, with feedback from stakeholders at all stages. Possible indicators were reviewed from global maternal-newborn health-related partner initiatives, priority indicator lists, and project indicators from current innovators. These indicators were scored across five domains to prioritise those most relevant and feasible for Saving Lives at Birth. These results informed the identification of the prioritised metrics for the initiative. RESULTS: The pathway to scale through Saving Lives at Birth is articulated through a theory of change and impact framework, which also highlight the roles of different actors involved in the programme. A prioritised metrics toolkit, including ten core impact indicators and five additional process indicators, complement the theory of change. The retrospective nature of this development enabled structured reflection of the program mechanics, allowing for inclusion of learning from the first four rounds of the program to inform implementation of subsequent rounds. CONCLUSIONS: While theories of change are more traditionally developed before program implementation, retrospective development can still be a useful exercise for multi-round programs like Saving Lives at Birth, where outputs from the development can be used to strengthen subsequent rounds. However, identifying a uniform set of prioritised metrics for use across the portfolio proved more challenging. Lessons learnt from this exercise will be relevant to the development of pathways to change across other Grand Challenges and global health platforms.

Catastrophic costs potentially averted by tuberculosis control in India and South Africa: a modelling study.

BACKGROUND: The economic burden on households affected by tuberculosis through costs to patients can be catastrophic. WHO's End TB Strategy recognises and aims to eliminate these potentially devastating economic effects. We assessed whether aggressive expansion of tuberculosis services might reduce catastrophic costs. METHODS: We estimated the reduction in tuberculosis-related catastrophic costs with an aggressive expansion of tuberculosis services in India and South Africa from 2016 to 2035, in line with the End TB Strategy. Using modelled incidence and mortality for tuberculosis and patient-incurred cost estimates, we investigated three intervention scenarios: improved treatment of drug-sensitive tuberculosis; improved treatment of multidrug-resistant tuberculosis; and expansion of access to tuberculosis care through intensified case finding (South Africa only). We defined tuberculosis-related catastrophic costs as the sum of direct medical, direct non-medical, and indirect costs to patients exceeding 20% of total annual household income. Intervention effects were quantified as changes in the number of households incurring catastrophic costs and were assessed by quintiles of household income. FINDINGS: In India and South Africa, improvements in treatment for drug-sensitive and multidrug-resistant tuberculosis could reduce the number of households incurring tuberculosis-related catastrophic costs by 6-19%. The benefits would be greatest for the poorest households. In South Africa, expanded access to care could decrease household tuberculosis-related catastrophic costs by 5-20%, but gains would be seen largely after 5-10 years. INTERPRETATION: Aggressive expansion of tuberculosis services in India and South Africa could lessen, although not eliminate, the catastrophic financial burden on affected households. FUNDING: Bill & Melinda Gates Foundation.

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.

BACKGROUND: The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. METHODS: 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. FINDINGS: Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. INTERPRETATION: Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. FUNDING: Bill and Melinda Gates Foundation.

Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models.

BACKGROUND: The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. METHODS: We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice. FINDINGS: Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective. INTERPRETATION: Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary. FUNDING: Bill & Melinda Gates Foundation.

Health-related quality of life and tuberculosis: a longitudinal cohort study.

BACKGROUND: Active tuberculosis (TB) disease can impose substantial morbidity, while treatment for latent TB infection (LTBI) has frequent side effects. We compared health-related quality of life (HRQOL) between persons diagnosed and treated for TB disease, persons treated for LTBI, and persons screened but not treated for TB disease or LTBI, over one year following diagnosis/initial assessment. METHODS: Participants were recruited at two hospitals in Montreal (2008-2011), and completed the Short Form-36 version 2 (SF-36) at baseline, and at 1, 2, 4, 6, 9, and 12 months thereafter. Eight domain scores and physical and mental component summary (PCS and MCS, respectively) scores were calculated from responses. Linear mixed models were used to compare mean scores at each evaluation and changes in scores over consecutive evaluations, among participants treated for TB disease and those treated for LTBI, each compared to the control group. RESULTS: Of the 263 participants, 48 were treated for TB disease, 105 for LTBI, and 110 were control participants. Fifty-four percent were women, mean age was 35 years, and 90% were foreign-born. Participants treated for TB disease reported significantly worse mean scores at baseline compared to control participants (mean PCS scores: 50.0 vs. 50.7; mean MCS scores: 46.4 vs. 51.1), with improvement in mean MCS scores throughout the study period. Scores reported by participants treated for LTBI and control participants were comparable throughout the study. CONCLUSION: TB disease is associated with decrements in HRQOL as measured by the SF-36. This is most pronounced during the weeks after diagnosis and treatment initiation, but is no longer evident after two months.

The impact of tuberculosis on health utility: a longitudinal cohort study.

PURPOSE: To estimate health utility derived from the Short Form-36 (SF-36) questionnaire and Standard Gamble instrument for persons diagnosed and treated for tuberculosis (TB) disease, those diagnosed and treated for latent TB infection (LTBI), and those screened but not treated for TB disease or LTBI over the year following their diagnosis/initial assessment. METHODS: Participants were recruited at two Montreal hospitals (2008-2011) and completed the SF-36 and Standard Gamble at baseline and at follow-up visits 1, 2, 4, 6, 9, and 12 months thereafter. SF-6D health utility scores were derived from SF-36 responses. Linear mixed models were used to compare mean health utility at each evaluation and changes in health utility between participants treated for TB disease, those treated for LTBI, and those in the control group. RESULTS: Of the 263 participants, 48 were treated for TB disease, 105 for LTBI, and 110 were control participants. Fifty-four percent were women, mean age was 35 years, and 90% were foreign-born. Participants treated for TB disease reported worse health utility compared with control participants at the baseline visit (mean SF-6D: 0.69 vs. 0.81; mean Standard Gamble: 0.64 vs. 0.96). They reported successive improvement at months 1 and 2 that was then sustained throughout follow-up. Health utility reported by participants treated for LTBI and control participants was comparable throughout the study. CONCLUSION: Treatment for TB disease had a substantial negative impact on health utility, particularly during the first 2 months of treatment. However, treatment for LTBI did not have a substantial impact.

Every Newborn: progress, priorities, and potential beyond survival.

In this Series paper, we review trends since the 2005 Lancet Series on Neonatal Survival to inform acceleration of progress for newborn health post-2015. On the basis of multicountry analyses and multi-stakeholder consultations, we propose national targets for 2035 of no more than 10 stillbirths per 1000 total births, and no more than 10 neonatal deaths per 1000 livebirths, compatible with the under-5 mortality targets of no more than 20 per 1000 livebirths. We also give targets for 2030. Reduction of neonatal mortality has been slower than that for maternal and child (1-59 months) mortality, slowest in the highest burden countries, especially in Africa, and reduction is even slower for stillbirth rates. Birth is the time of highest risk, when more than 40% of maternal deaths (total about 290,000) and stillbirths or neonatal deaths (5·5 million) occur every year. These deaths happen rapidly, needing a rapid response by health-care workers. The 2·9 million annual neonatal deaths worldwide are attributable to three main causes: infections (0·6 million), intrapartum conditions (0·7 million), and preterm birth complications (1·0 million). Boys have a higher biological risk of neonatal death, but girls often have a higher social risk. Small size at birth--due to preterm birth or small-for-gestational-age (SGA), or both--is the biggest risk factor for more than 80% of neonatal deaths and increases risk of post-neonatal mortality, growth failure, and adult-onset non-communicable diseases. South Asia has the highest SGA rates and sub-Saharan Africa has the highest preterm birth rates. Babies who are term SGA low birthweight (10·4 million in these regions) are at risk of stunting and adult-onset metabolic conditions. 15 million preterm births, especially of those younger than 32 weeks' gestation, are at the highest risk of neonatal death, with ongoing post-neonatal mortality risk, and important risk of long-term neurodevelopmental impairment, stunting, and non-communicable conditions. 4 million neonates annually have other life-threatening or disabling conditions including intrapartum-related brain injury, severe bacterial infections, or pathological jaundice. Half of the world's newborn babies do not get a birth certificate, and most neonatal deaths and almost all stillbirths have no death certificate. To count deaths is crucial to change them. Failure to improve birth outcomes by 2035 will result in an estimated 116 million deaths, 99 million survivors with disability or lost development potential, and millions of adults at increased risk of non-communicable diseases after low birthweight. In the post-2015 era, improvements in child survival, development, and human capital depend on ensuring a healthy start for every newborn baby--the citizens and workforce of the future.

Increased arterial stiffness in obstructive sleep apnea: a systematic review.

Obstructive sleep apnea is a prevalent disease that is associated with significant morbidity and mortality, particularly due to cardiovascular disease. An emerging cardiovascular risk factor, arterial stiffness, may also be involved in the cardiovascular complications of obstructive sleep apnea. The purpose of this review was to summarize the current literature regarding the effect of obstructive sleep apnea on arterial stiffness. We conducted a systematic literature review using PubMed, Embase and the Cochrane Library. We identified 24 studies that met search criteria investigating the effect of obstructive sleep apnea on arterial stiffness. Arterial stiffness was found to be increased in obstructive sleep apnea patients compared with controls or increased in severe compared with mild sleep apnea. In some studies, a positive correlation was identified between the degree of arterial stiffness and sleep apnea severity. In the two randomized, controlled trials and the two nonrandomized trials identified, treatment of obstructive sleep apnea with continuous positive airway pressure led to significant decreases in arterial stiffness. Obstructive sleep apnea appears to have an independent effect on arterial stiffness, which may be one of the mechanisms accounting for sleep apnea-associated cardiovascular risk.