Papers by Fulvio Lazzarato
International Journal of Cancer
International variations in the prevalence of HPV infection derive from differences in sexual beh... more International variations in the prevalence of HPV infection derive from differences in sexual behaviors, which are also a key factor of the basic reproductive number (R 0) of HPV infection in different populations. R 0 affects the strength of herd protection and hence the impact of a vaccination program. Similar vaccination programs may therefore generate different levels of impact depending upon the population's pre-vaccination HPV prevalence. We used IARC's transmission model to estimate (i) the overall effectiveness of vaccination versus no vaccination in women aged 15-34 years measured as percent prevalence reduction (%PR) of HPV16 and (ii) the corresponding herd protection in populations with gender-equal or traditional sexual behavior and with different levels of sexual activity, corresponding to pre-vaccination HPV16 prevalence from 1 to 8% as observed worldwide. Between populations with different levels of gender-equal sexual activity, the highest difference in %PR under girls-only vaccination is observed at 40% coverage (91%PR vs. 48%PR for 1% and 8% pre-vaccination prevalence, respectively). HPV16 elimination is obtained with 55 and 97% coverage, respectively. To achieve desirable levels of HPV16 prevalence after vaccination, different levels of coverage are required in populations with different levels of pre-vaccination HPV16 prevalence, for example, in populations with gender-equal sexual behavior a decrease to 1/1000 HPV16 from prevaccination prevalence of 1 and 8% would require coverages of 37 and 96%, respectively. In traditional populations, corresponding coverages would need to be 28 and 93%, respectively. In conclusion, pre-vaccination HPV prevalence strongly influences herd immunity and helps predict the overall effectiveness of HPV vaccination.
The Lancet Public Health
Background Modelling studies have been widely used to inform human papillomavirus (HPV) vaccinati... more Background Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level eff ectiveness and herd eff ects. We did a systematic review and meta-analysis of model predictions of the long-term population-level eff ectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd eff ects, incremental benefi t of vaccinating boys, and potential for HPV-vaccine-type elimination. Methods We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% effi cacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine effi cacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RR prev) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals [UI]). Findings 16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RR prev of HPV 16 among women and men was 0•53 (80% UI 0•46-0•68) and 0•36 (0•28-0•61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RR prev of HPV 16 among women and men was 0•93 (0•90-1•00) and 0•83 (0•75-1•00), respectively. Vaccinating boys in addition to girls increased the RR prev of HPV 16 among women and men by 0•18 (0•13-0•32) and 0•35 (0•27-0•39) for 40% coverage, and 0•07 (0•00-0•10) and 0•16 (0•01-0•25) for 80% coverage, respectively. The RR prev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RR prev of 1•00 for women and men for all four HPV types. Variability in pooled fi ndings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years). Interpretation Although HPV models diff er in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd eff ects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine effi cacy is maintained over time.
The Journal of Infectious Diseases
Background. Human papillomavirus (HPV) vaccination is still not reaching many high-risk populatio... more Background. Human papillomavirus (HPV) vaccination is still not reaching many high-risk populations. HPV16/18 vaccines offer cross-protection against other types, for example, HPV45. Both direct vaccine efficacy and indirect herd protection contribute to vaccination effectiveness. Methods. We used a dynamic transmission model, calibrated to cervical screening data from Italy, to estimate vaccination effectiveness against HPV16 and HPV45 infection, assuming for HPV45 either 95% or lower cross-protection. Results. Basic reproductive number was smaller (2.1 vs 4.0) and hence vaccine effectiveness and herd protection stronger for HPV45 than for HPV16. The largest difference in the reduction of infection prevalence in women <35 years old was found at 70% coverage in girls-only vaccination programs (99% vs 83% for total protection for HPV45 and HPV16, respectively, mainly owing to stronger herd protection, ie, 37% vs 16%). In gender-neutral vaccination, the largest difference was at 40% coverage (herd protection, 54% vs 28% for HPV16 and HPV45, respectively). With ≥80% coverage, even 50% cross-protection would reduce HPV45 by ≥94%. Conclusions. The characteristics of individual high-risk HPV types strongly influence herd protection and determine the level of coverage and cross-protection required to reduce or eliminate the infection through HPV vaccination. HPV16 infection and related cancers are the most difficult to eliminate.
BMJ open, Jan 19, 2017
The Bhutanese Screening Programme recommends a Pap smear every 3 years for women aged 25-65 years... more The Bhutanese Screening Programme recommends a Pap smear every 3 years for women aged 25-65 years, and coverage ranges from 20% to 60%, being especially challenging in rural settings. The 'REACH-Bhutan' study was conducted to assess the feasibility and outcomes of a novel approach to cervical cancer screening in rural Bhutan. Cross-sectional, population-based study of cervical cancer screening based on the careHPV test on self-collected samples. Women were recruited in rural primary healthcare centres, that is, Basic Health Units (BHU), across Bhutan. Overall, 3648 women aged 30-60 were invited from 15 BHUs differing in accessibility, size and ethnic composition of the population. Participants provided a self-collected cervicovaginal sample and were interviewed. Samples were tested using careHPV in Thimphu (the Bhutanese capital) referral laboratory. Screening participation by geographic area, centre, age and travelling time. Previous screening history and careHPV positivity...
Epidemiologia E Prevenzione, 2010
The investigation of distribution, determinants and transmission of infectious diseases is largel... more The investigation of distribution, determinants and transmission of infectious diseases is largely based on the development of mathematical models of ecological nature suitable to capture the dynamics of infectious diseases epidemiology. In this paper the essential aspects of the dynamic models of infection transmission are described. These models are increasingly being adopted to investigate and control epidemic and endemic infections, but also cancers of infectious aetiology.
BMC infectious diseases, May 24, 2016
Cervical cancer is the most common female cancer in Rwanda that, in 2011, became the first Africa... more Cervical cancer is the most common female cancer in Rwanda that, in 2011, became the first African country to implement a national vaccination programme against human papillomavirus (HPV). To provide a robust baseline for future evaluations of vaccine effectiveness, cervical cell specimens were obtained from 2508 women aged 18-69 years from the general population in Kigali, Rwanda, during 2013/14. 20 % of women were HIV-positive. Samples were used for liquid-based cytology and HPV testing (44 types) with GP5+/6+ PCR. HPV prevalence was 34 %, being highest (54 %) in women ≤19 years and decreasing to 20 % at age ≥50. Prevalence of high risk (HR) HPV and cytological abnormalities was 22 and 11 % respectively (including 2 % with high-grade squamous intraepithelial lesions, HSIL) decreasing with age. Age-standardised prevalence of HR HPV was 22 % (or 19 % among HIV-negative women), and HPV16 was the most common type. Prevalence of HPV and cytological abnormalities were significantly high...
Emerging Infectious Diseases, 2016
Epidemiologia e prevenzione
In recent years, cost-effectiveness analysis has become a frequent component of randomized clinic... more In recent years, cost-effectiveness analysis has become a frequent component of randomized clinical trials. In statistical terms, the major efforts addressed the method for estimating the Incremental Cost Effectiveness Ratio (ICER) and its confidence interval both with parametric and non-parametric methods. The goal of the present work is to briefly present the main non-parametric methods, based on a bootstrap approach. The methods which have been considered were applied to the data of a randomized clinical trial comparing two alternative approaches to treat hepatocellular carcinoma. The example shows that the application of different methods leads to significantly different confidence intervals' estimates, with consequences on the interpretation of the study results.
(3) Dipartimento di Patologia generale, Seconda Università degli Studi di Napoli. alessandro.weis... more (3) Dipartimento di Patologia generale, Seconda Università degli Studi di Napoli. [email protected]
Bioinformatics, 2014
Chimera is a Bioconductor package that organizes, annotates, analyses and validates fusions repor... more Chimera is a Bioconductor package that organizes, annotates, analyses and validates fusions reported by different fusion detection tools; current implementation can deal with output from bellerophontes, chimeraScan, deFuse, fusionCatcher, FusionFinder, FusionHunter, FusionMap, mapSplice, Rsubread, tophat-fusion and STAR. The core of Chimera is a fusion data structure that can store fusion events detected with any of the aforementioned tools. Fusions are then easily manipulated with standard R functions or through the set of functionalities specifically developed in Chimera with the aim of supporting the user in managing fusions and discriminating falsepositive results. Availability and implementation: Chimera is implemented as a Bioconductor package in R. The package and the vignette can be downloaded at bioconductor.org.
BioMed Research International, 2013
Background. Gene fusions arising from chromosomal translocations have been implicated in cancer. ... more Background. Gene fusions arising from chromosomal translocations have been implicated in cancer. RNA-seq has the potential to discover such rearrangements generating functional proteins (chimera/fusion). Recently, many methods for chimeras detection have been published. However, specificity and sensitivity of those tools were not extensively investigated in a comparative way.Results. We tested eight fusion-detection tools (FusionHunter, FusionMap, FusionFinder, MapSplice, deFuse, Bellerophontes, ChimeraScan, and TopHat-fusion) to detect fusion events using synthetic and real datasets encompassing chimeras. The comparison analysis run only on synthetic data could generate misleading results since we found no counterpart on real dataset. Furthermore, most tools report a very high number of false positive chimeras. In particular, the most sensitive tool, ChimeraScan, reports a large number of false positives that we were able to significantly reduce by devising and applying two filters...
PLoS ONE, 2013
Infection with high-risk (hr) human papillomavirus (HPV) is considered the necessary cause of cer... more Infection with high-risk (hr) human papillomavirus (HPV) is considered the necessary cause of cervical cancer. Vaccination against HPV16 and 18 types, which are responsible of about 75% of cervical cancer worldwide, is expected to have a major global impact on cervical cancer occurrence. Valid estimates of the parameters that regulate the natural history of hrHPV infections are crucial to draw reliable projections of the impact of vaccination. We devised a mathematical model to estimate the probability of infection transmission, the rate of clearance, and the patterns of immune response following the clearance of infection of 13 hrHPV types. To test the validity of our estimates, we fitted the same transmission model to two large independent datasets from Italy and Sweden and assessed finding consistency. The two populations, both unvaccinated, differed substantially by sexual behaviour, age distribution, and study setting (screening for cervical cancer or Chlamydia trachomatis infection). Estimated transmission probability of hrHPV types (80% for HPV16, 73%-82% for HPV18, and above 50% for most other types); clearance rates decreasing as a function of time since infection; and partial protection against re-infection with the same hrHPV type (approximately 20% for HPV16 and 50% for the other types) were similar in the two countries. The model could accurately predict the HPV16 prevalence observed in Italy among women who were not infected three years before. In conclusion, our models inform on biological parameters that cannot at the moment be measured directly from any empirical data but are essential to forecast the impact of HPV vaccination programmes.
Journal of Epidemiology & Community Health, 2012
Several studies have examined the effects of sample selection on the exposure-outcome association... more Several studies have examined the effects of sample selection on the exposure-outcome association estimates in cohort studies, but the reasons why this selection may induce bias have not been fully explored. To investigate how sample selection of the web-based NINFEA birth cohort may change the confounding patterns present in the source population. The characteristics of the NINFEA participants (n=1105) were compared with those of the wider source population-the Piedmont Birth Registry (PBR)-(n=36 092), and the association of two exposures (parity and educational level) with two outcomes (low birth weight and birth by caesarean section), while controlling for other risk factors, was studied. Specifically the associations among measured risk factors within each dataset were examined and the exposure-outcome estimates compared in terms of relative ORs. The associations of educational level with the other risk factors (alcohol consumption, folic acid intake, maternal age, pregnancy weight gain, previous miscarriages) partly differed between PBR and NINFEA. This was not observed for parity. Overall, the exposure-outcome estimates derived from NINFEA only differed moderately from those obtained in PBR, with relative ORs ranging between 0.74 and 1.03. Sample selection in cohort studies may alter the confounding patterns originally present in the general population. However, this does not necessarily introduce selection bias in the exposure-outcome estimates, as sample selection may reduce some of the residual confounding present in the general population.
International Journal of Cancer, 2013
Human papillomavirus (HPV) vaccination of a birth cohort of girls in the 9-13 age range is recomm... more Human papillomavirus (HPV) vaccination of a birth cohort of girls in the 9-13 age range is recommended as a priority, but decreases in HPV vaccine cost may make catch-up of a few additional cohorts more attractive not only in high-income countries. We assessed the reduction in HPV16 and 18 infections that could be achieved in a medium- (Poland) and a low-income (Guinea) country by adding one-time catch-up of 12- to 19-year-old girls to the vaccination of 11-year-old girls. According to our ad hoc adapted dynamic model of HPV infection transmission, the addition of catch-up was estimated to bring forward the 50% reduction of HPV16/18 prevalence due to vaccination in women ≤35 by as much as 5 years. Catch-up of 12- to 15-year olds reduced the cumulative probability of HPV16/18 infections by age 35 in the relevant cohorts by about 30% in both countries. Catch-up of 16- to 19-year-old girls added little. Regardless of the chosen catch-up strategy, 16 to 20% of HPV16/18 prevention from vaccination was attributable to herd immunity. Assuming a sufficiently low vaccine cost, the addition of a catch-up round is, therefore, worth considering in medium/low-income countries to extend vaccine benefits to less young adolescent girls whose future access to cervical screening is uncertain.
Infectious Agents and Cancer, 2014
Background: The decrease in human papillomavirus (HPV) vaccine prices may allow upscale already s... more Background: The decrease in human papillomavirus (HPV) vaccine prices may allow upscale already started vaccination programmes but the advantages of different options are unclear. Methods: Using a mathematical model of HPV16 and 18 transmission and data on vaccination coverage from Italy, we compared 3 options to upscale an already started programme targeting 11-year old girls (coverage 65%): a) coverage improvement (from 65% to 90%); b) addition of 11-year-old boys (coverage 65%); or c) 1-year catch-up of older girls (coverage 50%). Results: The reduction of cervical HPV16/18 infection as compared to no vaccination (i.e. effectiveness against HPV16/18) increased from 76% to 98% with coverage improvement in girls and to 90% with the addition of boys. With higher coverage in girls, HPV16/18 infection cumulative probability by age 35 decreased from 25% to 8% with a 38% increase in vaccine number. The addition of boys decreased the cumulative probability to 18% with a 100% increase in the number of vaccinees. For any coverage in girls, the number of vaccinees to prevent 1 woman from being infected by HPV16/18 by age 35 was 1.5, whereas it was 2.7 for the addition of boys. Catch-up of older girls only moved forward the vaccination effectiveness by 2-5 years. Conclusions: Increasing vaccination coverage among girls is the most effective option for decreasing HPV16/18. If not achievable, vaccinating boys is justifiable if vaccine cost has at least halved, because this option would almost double the number of vaccinees.
Diabetes Care, 2008
OBJECTIVE-Hyperglycemia is a common condition in hospitalized patients. The aim of this study was... more OBJECTIVE-Hyperglycemia is a common condition in hospitalized patients. The aim of this study was to investigate the relationships between glycemia upon admission and mortality in a heterogeneous group of adult patients. RESEARCH DESIGN AND METHODS-The 3-year records released from a general hospital were associated with a plasma glucose dataset of its general laboratory. A matched case-control study was implemented (3,338 case-control subject pairs). All-patient refined diagnosis-related groups and the relative risk of death were the matching criteria. A multivariate conditional logistic regression model was used to evaluate the associations between death and glycemia. RESULTS-Higher in-hospital mortality was associated with hyperglycemia or hypoglycemia, whereas lower risk was observed for values between 78 and 101 mg/dl. CONCLUSIONS-Our data confirm the relation between glycemia upon admission and mortality and suggest that slightly increased or decreased plasma glucose can be linked with increased mortality risk.
BMC Bioinformatics, 2013
Background: RNA-seq has the potential to discover genes created by chromosomal rearrangements. Fu... more Background: RNA-seq has the potential to discover genes created by chromosomal rearrangements. Fusion genes, also known as "chimeras", are formed by the breakage and re-joining of two different chromosomes. It is known that chimeras have been implicated in the development of cancer. Few publications in the past showed the presence of fusion events also in normal tissue, but with very limited overlaps between their results. More recently, two fusion genes in normal tissues were detected using both RNA-seq and protein data. Due to heterogeneous results in identifying chimeras in normal tissue, we decided to evaluate the efficacy of state of the art fusion finders in detecting chimeras in RNA-seq data from normal tissues. Results: We compared the performance of six fusion-finder tools: FusionHunter, FusionMap, FusionFinder, MapSplice, deFuse and TopHat-fusion. To evaluate the sensitivity we used a synthetic dataset of fusion-products, called positive dataset; in these experiments FusionMap, FusionFinder, MapSplice, and TopHat-fusion are able to detect more than 78% of fusion genes. All tools were error prone with high variability among the tools, identifying some fusion genes not present in the synthetic dataset. To better investigate the false discovery chimera detection rate, synthetic datasets free of fusion-products, called negative datasets, were used. The negative datasets have different read lengths and quality scores, which allow detecting dependency of the tools on both these features. FusionMap, FusionFinder, mapSplice, deFuse and TopHat-fusion were error-prone. Only FusionHunter results were free of false positive. FusionMap gave the best compromise in terms of specificity in the negative dataset and of sensitivity in the positive dataset.
The investigation of distribution, determinants and transmission of infectious diseases is largel... more The investigation of distribution, determinants and transmission of infectious diseases is largely based on the development of mathematical models of ecological nature suitable to capture the dynamics of infectious diseases epidemiology. In this paper the essential aspects of the dynamic models of infection transmission are described. These models are increasingly being adopted to investigate and control epidemic and endemic infections, but also cancers of infectious aetiology.
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Papers by Fulvio Lazzarato