Modelling longitudinal data on respiratory infections to inform health policy

Detecting the start of an outbreak, quantifying its burden, disentangling the contribution of different pathogens and evaluating the effectiveness of an intervention are research questions common to several infectious diseases. The answers to these questions provide the epidemiological understanding to prevent future outbreaks, by informing public health policies such as drug stockpiling, vaccination regimes or non-medical interventions. We investigate the use of statistical models to quantify burden of respiratory disease and evaluate effectiveness of public health interventions, while accounting for the challenges posed by surveillance data. The observational nature of the available information, affected by confounding, makes causal statements difficult. Improvements to routinely employed methodologies are proposed, employing phenomenological models to estimate a counterfactual, i.e. what what would have happened in the absence of a contributing factor or intervention. We apply these methods to different types of studies, to address specific gaps in the literature. S. pneumoniae is the leading cause of respiratory morbidity and mortality globally, especially in young children and in the elderly. To improve the understanding of factors triggering disease progression, we firstly analyse individual-level information about pneumococcal carriage and lower respiratory tract infection with a multi-state model, using data from a cohort study in Thailand. Secondly, we clarify the role of viral coinfection and meteorological conditions in invasive pneumococcal disease (IPD) incidence using English surveillance data. A novel multivariate linear regression model is proposed to estimate the influenza-specific contribution additional to the seasonal IPD burden across age groups. We then quantify the impact of the currently implemented vaccination policy, by estimating the counterfactual of IPD incidence in absence of vaccination. This allows disentangling serotype replacement from the vaccine effect, making use of a synthetic control approach. Finally, an empirical dynamical modelling strategy is employed to quantify the interaction between influenza and pneumococcus. Counterfactual analysis can also be employed to quantify the burden of novel respiratory pathogens. The last application of this approach is to estimate the excess mortality during the the COVID-19 pandemic in England

Estimating age-stratified influenza-associated invasive pneumococcal disease in England: A time-series model based on population surveillance data.

BACKGROUND: Measures of the contribution of influenza to Streptococcus pneumoniae infections, both in the seasonal and pandemic setting, are needed to predict the burden of secondary bacterial infections in future pandemics to inform stockpiling. The magnitude of the interaction between these two pathogens has been difficult to quantify because both infections are mainly clinically diagnosed based on signs and symptoms; a combined viral-bacterial testing is rarely performed in routine clinical practice; and surveillance data suffer from confounding problems common to all ecological studies. We proposed a novel multivariate model for age-stratified disease incidence, incorporating contact patterns and estimating disease transmission within and across groups. METHODS AND FINDINGS: We used surveillance data from England over the years 2009 to 2017. Influenza infections were identified through the virological testing of samples taken from patients diagnosed with influenza-like illness (ILI) within the sentinel scheme run by the Royal College of General Practitioners (RCGP). Invasive pneumococcal disease (IPD) cases were routinely reported to Public Health England (PHE) by all the microbiology laboratories included in the national surveillance system. IPD counts at week t, conditional on the previous time point t-1, were assumed to be negative binomially distributed. Influenza counts were linearly included in the model for the mean IPD counts along with an endemic component describing some seasonal background and an autoregressive component mimicking pneumococcal transmission. Using age-specific counts, Akaike information criterion (AIC)-based model selection suggested that the best fit was obtained when the endemic component was expressed as a function of observed temperature and rainfall. Pneumococcal transmission within the same age group was estimated to explain 33.0% (confidence interval [CI] 24.9%-39.9%) of new cases in the elderly, whereas 50.7% (CI 38.8%-63.2%) of incidence in adults aged 15-44 years was attributed to transmission from another age group. The contribution of influenza on IPD during the 2009 pandemic also appeared to vary greatly across subgroups, being highest in school-age children and adults (18.3%, CI 9.4%-28.2%, and 6.07%, CI 2.83%-9.76%, respectively). Other viral infections, such as respiratory syncytial virus (RSV) and rhinovirus, also seemed to have an impact on IPD: RSV contributed 1.87% (CI 0.89%-3.08%) to pneumococcal infections in the 65+ group, whereas 2.14% (CI 0.87%-3.57%) of cases in the group of 45- to 64-year-olds were attributed to rhinovirus. The validity of this modelling strategy relies on the assumption that viral surveillance adequately represents the true incidence of influenza in the population, whereas the small numbers of IPD cases observed in the younger age groups led to significant uncertainty around some parameter estimates. CONCLUSIONS: Our estimates suggested that a pandemic wave of influenza A/H1N1 with comparable severity to the 2009 pandemic could have a modest impact on school-age children and adults in terms of IPD and a small to negligible impact on infants and the elderly. The seasonal impact of other viruses such as RSV and rhinovirus was instead more important in the older population groups

Personal risk or societal benefit? Investigating adults’ support for COVID-19 childhood vaccination

Parental hesitancy poses a serious threat to the success of the COVID-19 childhood vaccination campaign. We investigate whether adults' opinions on childhood vaccination can be influenced via two survey experiments in Italy (n = 3,633 participants) and the UK (n = 3,314 participants). Respondents were randomly assigned to: a “risk treatment” that highlighted the potential risks of COVID-19 to a child, a “herd immunity treatment” that emphasized the community benefits of pediatric vaccination, or a control message. Participants’ probability of supporting COVID-19 childhood vaccination was then assessed on a 0–100 scale. We find that the “risk treatment” reduced the proportion of Italian parents strongly against vaccination by up to 29.6 %, while increasing the proportion of neutral parents by up to 45.0 %. The “herd immunity treatment”, instead, was only effective among non-parents, resulting in a lower proportion of individuals against pediatric vaccination and a higher proportion of individuals in favor (both shifted by around 20 %)

Postmenopausal hormone therapy and risk of stroke : A pooled analysis of data from population-based cohort studies

Background: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT. Methods and findings: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out. Conclusions: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk

HIV pre exposure prophylaxis and its implementation in the PrEP Impact Trial in England: a pragmatic health technology assessment

BackgroundHIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV acquisition. To enable routine commissioning of PrEP in England, we aimed to determine population need, duration of need, PrEP uptake, and duration of use in SHS attendees in England.MethodsThe Impact Trial was a prospective, open-label, single-arm, multi-centre trial conducted at 157 sexual health services (SHS) across England, between 13/10/2017 and 12/07/2020. Clinicians assessed HIV negative attendees for their risk of HIV acquisition to identify those who were eligible to participate and receive either daily or event-based oral PrEP (tenofovir disoproxil with emtricitabine), as appropriate. The main outcomes assessed were PrEP need, uptake, and use, and HIV and STI incidence. Data are presented to 29/02/2020, prior to the introduction of COVID-19 control measures.FindingsWe include 21,356/24,268 participants enrolled before 29/02/2020 in this analysis. Most participants were men who have sex with men (MSM) (95·5%, 20,403). Uptake of PrEP among SHS attendees clinically assessed and coded as eligible was 57·1% (21,292/37,289). Trial participants with at least one post-enrolment visit (n=18,499) had a median of 361 days of follow-up (Interquartile range [IQR]: 143 to 638 days); of these participants, 75·9% (14,039/18,499) had enough PrEP prescribed to provide protection for 75% of their follow-up time. Among MSM, HIV incidence was 0·13 (95% CI 0·08-0·19) and 0·95 (95% CI 0·88-1·03) per 100 person-years in trial participants (27 seroconversions) and non-trial attendees (587 seroconversions), respectively (proportionate reduction 86·8% (95% CI 80·2-91·6)). Bacterial STI incidence was 68·1 per 100 person-years in MSM trial participants (18,607 STI diagnoses). 24·4% of MSM participants were diagnosed with two or more STIs, accounting for approximately 80% of all diagnoses. InterpretationPrEP need was higher than initially estimated by an expert stakeholder group. The high proportion of follow-up time protected by PrEP suggests that the need for protection persisted throughout trial participation for most participants. HIV incidence among MSM trial participants was low. The large unmet need for PrEP suggests that greater provision is required to maximise the potential of a national programme. The high incidence of bacterial STIs among participants, concentrated within a subgroup of PrEP users, presents an opportunity for tailored STI control measures

Baseline characteristics of the postmenopausal women included in the present study of the Combined cohorts of menopausal women—Studies of register-based health outcomes in relation to hormonal drugs (COMPREHEND) material.

<p>Baseline characteristics of the postmenopausal women included in the present study of the Combined cohorts of menopausal women—Studies of register-based health outcomes in relation to hormonal drugs (COMPREHEND) material.</p