Giacomo Plazzotta

Bio: Giacomo Plazzotta is an academic researcher from Imperial College London. The author has contributed to research in topics: K-ary tree & Random binary tree. The author has an hindex of 6, co-authored 15 publications receiving 167 citations.

Phylogenetic Tools for Generalized HIV-1 Epidemics: Findings from the PANGEA-HIV Methods Comparison

Abstract: Viral phylogenetic methods contribute to understanding how HIV spreads in populations, and thereby help guide the design of prevention interventions. So far, most analyses have been applied to well-sampled concentrated HIV-1 epidemics in wealthy countries. To direct the use of phylogenetic tools to where the impact of HIV-1 is greatest, the Phylogenetics And Networks for Generalized HIV Epidemics in Africa (PANGEA-HIV) consortium generates full-genome viral sequences from across sub-Saharan Africa. Analyzing these data presents new challenges, since epidemics are principally driven by heterosexual transmission and a smaller fraction of cases is sampled. Here, we show that viral phylogenetic tools can be adapted and used to estimate epidemiological quantities of central importance to HIV-1 prevention in sub-Saharan Africa. We used a community-wide methods comparison exercise on simulated data, where participants were blinded to the true dynamics they were inferring. Two distinct simulations captured generalized HIV-1 epidemics, before and after a large community-level intervention that reduced infection levels. Five research groups participated. Structured coalescent modeling approaches were most successful: phylogenetic estimates of HIV-1 incidence, incidence reductions, and the proportion of transmissions from individuals in their first 3 months of infection correlated with the true values (Pearson correlation > 90%), with small bias. However, on some simulations, true values were markedly outside reported confidence or credibility intervals. The blinded comparison revealed current limits and strengths in using HIV phylogenetics in challenging settings, provided benchmarks for future methods' development, and supports using the latest generation of phylogenetic tools to advance HIV surveillance and prevention.

A Metric on Phylogenetic Tree Shapes.

Abstract: The shapes of evolutionary trees are influenced by the nature of the evolutionary process but comparisons of trees from different processes are hindered by the challenge of completely describing tree shape. We present a full characterization of the shapes of rooted branching trees in a form that lends itself to natural tree comparisons. We use this characterization to define a metric, in the sense of a true distance function, on tree shapes. The metric distinguishes trees from random models known to produce different tree shapes. It separates trees derived from tropical versus USA influenza A sequences, which reflect the differing epidemiology of tropical and seasonal flu. We describe several metrics based on the same core characterization, and illustrate how to extend the metric to incorporate trees' branch lengths or other features such as overall imbalance. Our approach allows us to construct addition and multiplication on trees, and to create a convex metric on tree shapes which formally allows computation of average tree shapes.

Cost-effectiveness analysis of the nine-valent HPV vaccine in Italy

Abstract: In Italy HPV vaccination with the quadrivalent vaccine (Gardasil®) is offered actively and free of charge to girls aged 12 since 2007. A nine-valent vaccine (Gardasil 9®) received the European market authorization in 2015 to protect, with only 2 doses, against around 90% of all HPV positive cancers, over 80% of high-grade precancerous lesions and 90% of genital warts caused by HPV types 6/11. A dynamic transmission model simulating the natural history of HPV-infections was calibrated to the Italian setting and used to estimate costs and QALYs associated with vaccination strategies. The analyses compared two strategies with the nine-valent vaccine (cervical cancer screening and vaccination in girls only or vaccination in boys and girls) to four alternative strategies (cervical cancer screening and vaccination with quadrialent vaccine in girls only, in both boys and girls, with bivalent vaccine in girls and screening strategy only). The National Health Service perspective was considered. The switch to the nine-valent vaccine in Italy can further reduce the burden associated to cervical cancer and HPV-related diseases and is highly cost-effective. Compared to the current vaccination program with quadrivalent vaccine, the nine-valent vaccine in a programme including girls and boys shows further reductions of 17% in the incidence of cervical cancer, 35 and 14% in anal cancer for males and females, as well as over a million cases of genital warts avoided after 100 years. The new technology is associated with an ICER of 10,463€ per QALY gained in universal vaccination, decreasing to 4483€ when considering the vaccine switch for girls-only.

Asymptotic frequency of shapes in supercritical branching trees

Abstract: The shapes of branching trees have been linked to disease transmission patterns. In this paper we use the general Crump‒Mode‒Jagers branching process to model an outbreak of an infectious disease under mild assumptions. Introducing a new class of characteristic functions, we are able to derive a formula for the limit of the frequency of the occurrences of a given shape in a general tree. The computational challenges concerning the evaluation of this formula are in part overcome using the jumping chronological contour process. We apply the formula to derive the limit of the frequency of cherries, pitchforks, and double cherries in the constant-rate birth‒death model, and the frequency of cherries under a nonconstant death rate.

Fast Tree: Computing Large Minimum-Evolution Trees with Profiles instead of a Distance Matrix

Abstract: Gene families are growing rapidly, but standard methods for inferring phylogenies do not scale to alignments with over 10,000 sequences. We present FastTree, a method for constructing large phylogenies and for estimating their reliability. Instead of storing a distance matrix, FastTree stores sequence profiles of internal nodes in the tree. FastTree uses these profiles to implement neighbor-joining and uses heuristics to quickly identify candidate joins. FastTree then uses nearest-neighbor interchanges to reduce the length of the tree. For an alignment with N sequences, L sites, and a different characters, a distance matrix requires O(N^2) space and O(N^2 L) time, but FastTree requires just O( NLa + N sqrt(N) ) memory and O( N sqrt(N) log(N) L a ) time. To estimate the tree's reliability, FastTree uses local bootstrapping, which gives another 100-fold speedup over a distance matrix. For example, FastTree computed a tree and support values for 158,022 distinct 16S ribosomal RNAs in 17 hours and 2.4 gigabytes of memory. Just computing pairwise Jukes-Cantor distances and storing them, without inferring a tree or bootstrapping, would require 17 hours and 50 gigabytes of memory. In simulations, FastTree was slightly more accurate than neighbor joining, BIONJ, or FastME; on genuine alignments, FastTree's topologies had higher likelihoods. FastTree is available at http://microbesonline.org/fasttree.

Summary of product characteristics

Abstract: 4 CLINICAL PARTICULARS 4.1 Therapeutic Indications Trimetazidine is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies. 4.2 Posology and method of administration Oral administration. Posology The dose is one tablet of 35mg of trimetazidine twice daily during meals. Special populations Renal impairment In patients with moderate renal impairment (creatinine clearance [30-60] ml/min) (see sections 4.4 and 5.2), the recommended dose is 1 tablet of 35mg in the morning during breakfast. Elderly Elderly patients may have increased trimetazidine exposure due to age-related decrease in renal function (see section 5.2). In patients with moderate renal impairment (creatinine clearance [30-60] ml/min), the recommended dose is 1 tablet of 35mg in the morning during breakfast. Dose titration in elderly patients should be exercised with caution (see section 4.4). Health Products Regulatory Authority

Younger Adults' Understanding of Questions for a Service User Experience Survey. Funded/commissioned by: The Health and Social Care Information Centre

Abstract: For some time now councils with social services responsibilities (CSSRs) have been required to conduct surveys of user’s experience of social services. These have taken place nationally in three-yearly cycles. In 2002/03 the survey was for older people, in 2003/04 it was for younger adults with physical and sensory impairments, and in 2004/05 it was for children. 2005/06 marked the beginning of the second wave of the cycle. The mandate for conducting surveys of user’s experiences and satisfaction with services was first given in the white paper Modern Local Government: in Touch with the People (Department for the Environment, Trade and the Regions, 1998). In 2002 the Office of National Statistics (ONS) and SPRU developed a set of questionnaires for this purpose (Qureshi and Rowlands, 2004). Subsequent national surveys have drawn on this work to identify a set of compulsory questions for each round. User experience surveys (UESs) are regarded as an important part of the overall performance framework for social care and, providing councils with information about how they might improve services locally. Local authorities are required to submit their results to government bodies so that the relative performance of the CSSRs can be judged. This report is composed of five sections. The aims and objectives of the report are outlined in the second section and the method used to gather the data is outlined in section 3. In section 4 we report on the findings from the fieldwork and draw some conclusions and recommendations for the national survey in section 5. The topic guides for the focus groups and interviews are included in the appendices along with a brief discussion of the findings from the focus groups and a copy of the final extended questionnaire.

A SARS-CoV-2 vaccine candidate would likely match all currently circulating variants.

Abstract: The magnitude of the COVID-19 pandemic underscores the urgency for a safe and effective vaccine. Many vaccine candidates focus on the Spike protein, as it is targeted by neutralizing antibodies and plays a key role in viral entry. Here we investigate the diversity seen in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences and compare it to the sequence on which most vaccine candidates are based. Using 18,514 sequences, we perform phylogenetic, population genetics, and structural bioinformatics analyses. We find limited diversity across SARS-CoV-2 genomes: Only 11 sites show polymorphisms in >5% of sequences; yet two mutations, including the D614G mutation in Spike, have already become consensus. Because SARS-CoV-2 is being transmitted more rapidly than it evolves, the viral population is becoming more homogeneous, with a median of seven nucleotide substitutions between genomes. There is evidence of purifying selection but little evidence of diversifying selection, with substitution rates comparable across structural versus nonstructural genes. Finally, the Wuhan-Hu-1 reference sequence for the Spike protein, which is the basis for different vaccine candidates, matches optimized vaccine inserts, being identical to an ancestral sequence and one mutation away from the consensus. While the rapid spread of the D614G mutation warrants further study, our results indicate that drift and bottleneck events can explain the minimal diversity found among SARS-CoV-2 sequences. These findings suggest that a single vaccine candidate should be efficacious against currently circulating lineages.