Surveillance optimisation to detect poliovirus in the pre-eradication era: a modelling study of England and Wales.

Surveillance for acute flaccid paralysis (AFP) cases are essential for polio eradication. However, as most poliovirus infections are asymptomatic and some regions of the world are inaccessible, additional surveillance tools require development. Within England and Wales, we demonstrate how inclusion of environmental sampling (ENV) improves the sensitivity of detecting both wild and vaccine-derived polioviruses (VDPVs) when compared to current surveillance. Statistical modelling was used to estimate the spatial risk of wild and VDPV importation and circulation in England and Wales. We estimate the sensitivity of each surveillance mode to detect poliovirus and the probability of being free from poliovirus, defined as being below a pre-specified prevalence of infection. Poliovirus risk was higher within local authorities in Manchester, Birmingham, Bradford and London. The sensitivity of detecting wild poliovirus within a given month using AFP and enterovirus surveillance was estimated to be 0.096 (95% CI 0.055-0.134). Inclusion of ENV in the three highest risk local authorities and a site in London increased surveillance sensitivity to 0.192 (95% CI 0.191-0.193). The sensitivity of ENV strategies can be compared using the framework by varying sites and the frequency of sampling. The probability of being free from poliovirus slowly increased from the date of the last case in 1993. ENV within areas thought to have the highest risk improves detection of poliovirus, and has the potential to improve confidence in the polio-free status of England and Wales and detect VDPVs.

Evolving epidemiology of poliovirus serotype 2 following withdrawal of the serotype 2 oral poliovirus vaccine.

Although there have been no cases of serotype 2 wild poliovirus for more than 20 years, transmission of serotype 2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the serotype 2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all serotype 2 poliovirus. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimated the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. A novel OPV2, for which two candidates are currently in clinical trials, is urgently required, together with a contingency strategy if this vaccine does not materialize or perform as anticipated.

A New Method for Estimating the Coverage of Mass Vaccination Campaigns Against Poliomyelitis From Surveillance Data.

Mass vaccination campaigns with the oral poliovirus vaccine targeting children aged <5 years are a critical component of the global poliomyelitis eradication effort. Monitoring the coverage of these campaigns is essential to allow corrective action, but current approaches are limited by their cross-sectional nature, nonrandom sampling, reporting biases, and accessibility issues. We describe a new Bayesian framework using data augmentation and Markov chain Monte Carlo methods to estimate variation in vaccination coverage from children's vaccination histories investigated during surveillance for acute flaccid paralysis. We tested the method using simulated data with at least 200 cases and were able to detect undervaccinated groups if they exceeded 10% of all children and temporal changes in coverage of ±10% with greater than 90% sensitivity. Application of the method to data from Pakistan for 2010-2011 identified undervaccinated groups within the Balochistan/Federally Administered Tribal Areas and Khyber Pakhtunkhwa regions, as well as temporal changes in coverage. The sizes of these groups are consistent with the multiple challenges faced by the program in these regions as a result of conflict and insecurity. Application of this new method to routinely collected data can be a useful tool for identifying poorly performing areas and assisting in eradication efforts.

Improving projections at the country level: the UNAIDS Estimation and Projection Package 2005.

BACKGROUND: UNAIDS has developed the Estimation and Projection Package (EPP) as a tool for national programmes to use for making national estimates and short term projections of HIV prevalence. EPP provides direct input to Spectrum, which produces incidence, deaths, and AIDS impacts. METHODS: The latest version, EPP 2005, includes substantial methodological improvements over the previous version. These include: (1) parallel, but unique, interfaces for generalised and concentrated epidemics; (2) use of maximum likelihood fitting procedures; (3) a new procedure, known as level fits, adjusting for expansion of national surveillance systems into lower prevalence sites; (4) provisions for handling turnover in at-risk populations, including the reassignment of HIV positive former members to lower risk populations; and (5) user-defined calibration to HIV prevalence levels from general population or other epidemiological surveys. RESULTS: Following regional training in mid 2005, this new version has been applied by many national programmes to make their end of 2005 estimates of HIV infections. UNAIDS has combined these national estimates to form the 2005 global HIV and AIDS estimates. CONCLUSION: EPP 2005 is a substantial improvement over previous versions, forming a solid base for the next round of modifications. Proposed modifications for that next version are presented for the reader's information.

Projecting the demographic impact of AIDS and the number of people in need of treatment: updates to the Spectrum projection package.

BACKGROUND: In the Joint United Nations Programme on HIV/AIDS (UNAIDS) approach to HIV and AIDS estimates, estimates of adult prevalence produced by the Estimation and Projection Package (EPP) or the Workbook are transferred to Spectrum to estimate the consequences of the HIV/AIDS epidemic, including the number of people living with HIV by age and sex, new infections, AIDS deaths, AIDS orphans, treatment needs, and the impact of treatment on survival. METHODS: The UNAIDS Reference Group on Estimates, Models and Projections recommends updates to the methodology and assumptions based on the latest research findings and international policy and programme guidelines. The latest update to Spectrum has been used in the 2005 round of global estimates. RESULTS: Several new features have been added to Spectrum in the past two years. New patterns of the age distribution of prevalence over time are based on the latest survey data. A more detailed treatment of mother to child transmission of HIV is now based on information about current breastfeeding practices, treatment options offered to prevent mother to child transmission (PMTCT), infant feeding options, and the percentage or number of pregnant women accessing PMTCT services. A new section on child survival includes the effects of cotrimoxazole and ART on child survival. Projections can now be calibrated with national survey data. A new set of outputs is provided for all adults over the age of 15 in addition to the traditional 15-49 age group. New outputs are now available to show plausibility bounds and regional estimates for key indicators. CONCLUSIONS: The latest update to the Spectrum program is intended to incorporate the latest research findings and provide new outputs needed by national and international planners.

The UNAIDS Estimation and Projection Package: a software package to estimate and project national HIV epidemics.

This paper describes the Estimation and Projection Package (EPP) for estimating and projecting HIV prevalence levels in countries with generalised epidemics. The paper gives an overall summary of the software and interface. It describes the process of defining and modelling a national epidemic in terms of locally relevant sub-epidemics and the four epidemiological parameters used to fit a curve to produce the prevalence trends in the epidemic. It also provides an example of using the EPP in a country with a generalised epidemic. The paper discusses the strengths and weaknesses of the software and its envisaged future developments.

The workbook approach to making estimates and projecting future scenarios of HIV/AIDS in countries with low level and concentrated epidemics.

This paper describes an approach to making estimates and short term projections of future scenarios of HIV/AIDS in countries with low level and concentrated epidemics. This approach focuses on identifying populations which through their behaviour are at higher risk of infection with HIV or who are exposed through the risk behaviour of their sexual partners. Estimates of the size and HIV prevalence of these populations allow the total number of HIV infected people in a country or region to be estimated. Subsequently, assumptions about the possible level and timing of saturation of HIV prevalence among each population can be used to explore future scenarios of HIV prevalence. The basic structure of the software used to make estimates and projections is described. This software includes a set of consistency and audit checks to help exclude unrealistic projections. The paper also discusses the strengths and weakness to this approach to making estimates and projections of HIV/AIDS in countries with low level and concentrated epidemics.

Uncertainty in estimates of HIV/AIDS: the estimation and application of plausibility bounds.

OBJECTIVES: To establish the accuracy of the country specific estimates of HIV prevalence, incidence, and AIDS mortality published every 2 years by UNAIDS and WHO. METHODS: We review sources of error in the data used to generate national HIV/AIDS and where possible estimate their statistical properties. We use numerical and approximate analytic methods to estimate the combined impact of these errors on HIV/AIDS estimates. Heuristic rules are then derived to produce plausible bounds about these estimates for countries with different types of epidemic and different qualities of surveillance system. RESULTS: Although 95% confidence intervals (CIs) can be estimated for some sources of error, the sizes of other sources of error must be based on expert judgment. We therefore produce plausible bounds about HIV/AIDS estimates rather than statistical CIs. The magnitude of these bounds depends on the stage of the epidemic and the quality and coverage of the sentinel HIV surveillance system. The bounds for adult estimates are narrower than those for children, and those for prevalence are narrower than those for new infections. CONCLUSIONS: This paper presents a first attempt at a rigorous description of the errors associated with estimation of global statistics of an infectious disease. The proposed methods work well in countries with generalised epidemics (>1% adult HIV prevalence) where the quality of surveillance is good. Although methods have also been derived for countries with low level or concentrated epidemics, more data on the biases in the estimation process are required.

The effectiveness of HIV prevention and the epidemiological context.

Planning an intervention to prevent infections with the human immunodeficiency virus (HIV) should be guided by local epidemiological and socioeconomic conditions. The socioeconomic setting and existing public service capacity determine whether an intervention can have a significant outcome in terms of a reduction in a defined risk. The epidemiological context determines whether such risk reduction translates into a measurable impact on HIV incidence. Measurement of variables describing the epidemiological context can be used to determine the local suitability of interventions, thereby guiding planners and policy-makers in their choice of intervention. Such measurements also permit the retrospective analysis of the impact of interventions where HIV incidence was not recorded. The epidemiological context is defined for four different categories of intervention, shown to be effective in lower-income countries by randomized controlled trials. Appropriate indicators for the epidemiological context and methodological guidelines for their measurement are proposed. Their use in the transfer of a successful intervention from one context to another and in scaling up the effort to control HIV infection is explored. These indicators should provide a useful resource for those involved in planning HIV prevention interventions.

Error, population structure and the origin of diverse sign systems.

Evolutionary models of communication are used to shed some light on the selective pressures involved in the evolution of simple referential signals, and the constraints hindering the emergence of signs. Error-prone communication results from errors in transmission (in which individuals learn the wrong associations) and communication (in which signs are mistaken for one another). We demonstrate how both classes of errors are required to generate diversity and subsequently impose limits on the sign repertoire within a population. We then explore the influence of geographic structuring of a population on the evolution of a shared sign system and the importance of such structure for the maintenance of sign diversity. Deceit tends to erode conventional signs systems thereby reducing signal diversity, we demonstrate that population structure can act as a hedge against deceit, thereby ensuring the persistence of sign systems.

Population dynamics of HIV-1 inferred from gene sequences.

A method for the estimation of population dynamic history from sequence data is described and used to investigate the past population dynamics of HIV-1 subtypes A and B. Using both gag and env gene alignments the effective population size of each subtype is estimated and found to be surprisingly small. This may be a result of the selective sweep of mutations through the population, or may indicate an important role of genetic drift in the fixation of mutations. The implications of these results for the spread of drug-resistant mutations and transmission dynamics, and also the roles of selection and recombination in shaping HIV-1 genetic diversity, are discussed. A larger estimated effective population size for subtype A may be the result of differences in time of origin, transmission dynamics, and/or population structure. To investigate the importance of population structure a model of population subdivision was fitted to each subtype, although the improvement in likelihood was found to be nonsignificant.

Mortality among human immunodeficiency virus type 2-positive villagers in rural Guinea-Bissau is correlated with viral genotype.

We present the results of a 6-year study of 131 human immunodeficiency virus (HIV) type 2 (HIV-2)-infected individuals from a rural population in Guinea-Bissau. Proviral DNA sequences 1.3 kb in length were obtained from each individual and, together with clinical data, including proviral load and CD4 and CD8 levels, were used to assess whether viral genotype influences clinical outcome. With a phylogenetic model, a correlation was found between viral genotype and mortality; this correlation was not due to confounding factors, such as age-specific viral strains or cohabitation of patients. The data provide strong evidence for the involvement of viral genetic factors in determining HIV disease progression in vivo. The pattern of association found suggests that virulence factors are multiple and scattered throughout the HIV-2 genome and can be rapidly gained or lost by the virus through a combination of mutation and recombination. These findings may lead to the identification of viral determinants of HIV disease progression.

Seq-Gen: an application for the Monte Carlo simulation of DNA sequence evolution along phylogenetic trees.

MOTIVATION: Seq-Gen is a program that will simulate the evolution of nucleotide sequences along a phylogeny, using common models of the substitution process. A range of models of molecular evolution are implemented, including the general reversible model. Nucleotide frequencies and other parameters of the model may be given and site-specific rate heterogeneity can also be incorporated in a number of ways. Any number of trees may be read in and the program will produce any number of data sets for each tree. Thus, large sets of replicate simulations can be easily created. This can be used to test phylogenetic hypotheses using the parametric bootstrap. AVAILABILITY: Seq-Gen can be obtained by WWW from http:/(/)evolve.zoo.ox.ac.uk/Seq-Gen/seq-gen.html++ + or by FTP from ftp:/(/)evolve.zoo.ox.ac.uk/packages/Seq-Gen/. The package includes the source code, manual and example files. An Apple Macintosh version is available from the same sites.

A likelihood method for the detection of selection and recombination using nucleotide sequences.

Different regions along nucleotide sequences are often subject to different evolutionary forces. Recombination will result in regions having different evolutionary histories, while selection can cause regions to evolve at different rates. This paper presents a statistical method based on likelihood for detecting such processes by identifying the regions which do not fit with a single phylogenetic topology and nucleotide substitution process along the entire sequence. Subsequent reanalysis of these anomalous regions may then be possible. The method is tested using simulations, and its application is demonstrated using the primate psi eta-globin pseudogene, the V3 region of the envelope gene of HIV-1, and argF sequences from Neisseria bacteria. Reanalysis of anomalous regions is shown to reveal possible immune selection in HIV-1 and recombination in Neisseria. A computer program which implements the method is available.

Bi-De: an application for simulating phylogenetic processes.

Birth-Death (Bi-De) is an application for the Apple Macintosh which simulates the growth of phylogenetic trees using various models of lineage birth and death. The trees produced are intended to be analogous to those reconstructed from molecular sequence data. The user may define a constant birth rate and death rate or a function describing how these rates vary by time or population size. Instantaneous mass extinctions can also be simulated. The package allows the tree produced to be used as a template for the simulated evolution of molecular sequence data under a range of different transition models.