Evaluation of exposure-specific risks from two independent samples: A simulation study

<p>Abstract</p> <p>Background</p> <p>Previous studies have proposed a simple product-based estimator for calculating exposure-specific risks (ESR), but the methodology has not been rigorously evaluated. The goal of our study was to evaluate the existing methodology for calculating the ESR, propose an improved point estimator, and propose variance estimates that will allow the calculation of confidence intervals (CIs).</p> <p>Methods</p> <p>We conducted a simulation study to test the performance of two estimators and their associated confidence intervals: 1) current (simple product-based estimator) and 2) proposed revision (revised product-based estimator). The first method for ESR estimation was based on multiplying a relative risk (RR) of disease given a certain exposure by an overall risk of disease. The second method, which is proposed in this paper, was based on estimates of the risk of disease in the unexposed. We then multiply the updated risk by the RR to get the revised product-based estimator. A log-based variance was calculated for both estimators. Also, a binomial-based variance was calculated for the revised product-based estimator. 95% CIs were calculated based on these variance estimates. Accuracy of point estimators was evaluated by comparing observed relative bias (percent deviation from the true estimate). Interval estimators were evaluated by coverage probabilities and expected length of the 95% CI, given coverage. We evaluated these estimators across a wide range of exposure probabilities, disease probabilities, relative risks, and sample sizes.</p> <p>Results</p> <p>We observed more bias and lower coverage probability when using the existing methodology. The revised product-based point estimator exhibited little observed relative bias (max: 4.0%) compared to the simple product-based estimator (max: 93.9%). Because the simple product-based estimator was biased, 95% CIs around this estimate exhibited small coverage probabilities. The 95% CI around the revised product-based estimator from the log-based variance provided better coverage in most situations.</p> <p>Conclusion</p> <p>The currently accepted simple product-based method was only a reasonable approach when the exposure probability is small (< 0.05) and the RR is ≤ 3.0. The revised product-based estimator provides much improved accuracy.</p

Management of latent Mycobacterium tuberculosis infection:WHO guidelines for low tuberculosis burden countries

ABSTRACT Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of &lt;100 per 100000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing an

Cholera- and Anthrax-Like Toxins Are among Several New ADP-Ribosyltransferases

Chelt, a cholera-like toxin from Vibrio cholerae, and Certhrax, an anthrax-like toxin from Bacillus cereus, are among six new bacterial protein toxins we identified and characterized using in silico and cell-based techniques. We also uncovered medically relevant toxins from Mycobacterium avium and Enterococcus faecalis. We found agriculturally relevant toxins in Photorhabdus luminescens and Vibrio splendidus. These toxins belong to the ADP-ribosyltransferase family that has conserved structure despite low sequence identity. Therefore, our search for new toxins combined fold recognition with rules for filtering sequences – including a primary sequence pattern – to reduce reliance on sequence identity and identify toxins using structure. We used computers to build models and analyzed each new toxin to understand features including: structure, secretion, cell entry, activation, NAD+ substrate binding, intracellular target binding and the reaction mechanism. We confirmed activity using a yeast growth test. In this era where an expanding protein structure library complements abundant protein sequence data – and we need high-throughput validation – our approach provides insight into the newest toxin ADP-ribosyltransferases

Tuberculosis

This article reviews the published literature on tuberculosis from September 2012 to August 2013 and describes important advances in tuberculosis epidemiology, microbiology, pathology, clinical pharmacology, genetics, treatment and prevention

A century of tuberculosis epidemiology in the northern and southern hemisphere: the differential impact of control interventions

BACKGROUND: Cape Town has one of the highest TB burdens of any city in the world. In 1900 the City of Cape Town, New York City and London had high mortality of tuberculosis (TB). Throughout the 20th century contemporaneous public health measures including screening, diagnosis and treatment were implemented in all three settings. Mandatory notification of TB and vital status enabled comparison of disease burden trajectories. METHODS: TB mortality, notification and case fatality rates were calculated from 1912 to 2012 using annual TB notifications, TB death certifications and population estimates. Notification rates were stratified by age and in Cape Town by HIV status (from 2009 onwards). RESULTS: Pre-chemotherapy, TB mortality and notification rates declined steadily in New York and London but remained high in Cape Town. Following introduction of combination chemotherapy, mean annual case fatality dropped from 45-60% to below 10% in all three settings. Mortality and notification rates subsequently declined, although Cape Town notifications did not decline as far as those in New York or London and returned to pre-chemotherapy levels by 1980. The proportional contribution of childhood TB diminished in New York and London but remained high in Cape Town. The advent of the Cape Town HIV-epidemic in the 1990s was associated with a further two-fold increase in incidence. In 2012, notification rates among HIV-negatives remained at pre-chemotherapy levels. CONCLUSIONS: TB control was achieved in New York and London but failed in Cape Town. The TB disease burden trajectories started diverging before the availability of combination chemotherapy in 1952 and further diverged following the HIV epidemic in 1990. Chemotherapy impacted case fatality but not transmission, evidenced by on-going high childhood TB rates. Currently endemic TB results from high on-going transmission, which has been exacerbated by the HIV epidemic. TB control will require reducing transmission, which is inexorably linked to prevailing socio-economic factors

Timeline of implementation of TB control interventions in Cape Town, New York and London.

<p>ART, antiretroviral therapy; BCG, Bacille Calmette-Guérin; M, mandatory; N/A, not applicable; PAS, P-aminosalicylic acid; V, voluntary.</p><p>Data from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref002" target="_blank">2</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref009" target="_blank">9</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref016" target="_blank">16</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref025" target="_blank">25</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref033" target="_blank">33</a>].</p

TB notification rates over time.

<p>The current (2009–2012) HIV-negative rate in Cape Town was 445 per 100,000 population, the HIV-positive rate was 6338 per 100,000 population (not shown). Note. Rates from 1913 to 1965 are for London County Council (current Inner London) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref017" target="_blank">17</a>], thereafter for the Greater London Area (Inner and Outer London) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref023" target="_blank">23</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref024" target="_blank">24</a>]. CT, Cape Town; NY, New York.</p

Age-stratified TB notification rates per decade over time.

<p>Note. Y-axes are on a logarithmic scale (base 10). Age-stratified rates in Cape Town were not available prior to 1930. Cape Town rates for 2002 and 2010 include TB in HIV-infected persons.</p

TB mortality and case fatality rates over time.

<p>A. TB mortality rates over time. B. TB case fatality rates over time. Note. Rates from 1913 to 1965 are for London County Council (current Inner London) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref017" target="_blank">17</a>], thereafter for the Greater London Area (Inner and Outer London)[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref023" target="_blank">23</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135179#pone.0135179.ref024" target="_blank">24</a>]. CT, Cape Town; NY, New York.</p