Genomic variants associated with age at diagnosis of childhood-onset type 1 diabetes.

Age at diagnosis (AAD) of Type 1 diabetes (T1D) is determined by the age at onset of the autoimmune attack and by the rate of beta cell destruction that follows. Twin studies found that T1D AAD is strongly influenced by genetics, notably in young children. In young UK, Finnish, Sardinian patients AAD-associated genomic variants were previously identified, which may vary across populations and with time. In 1956 children of European ancestry born in mainland France in 1980-2008 who declared T1D before 15 years, we tested 94 T1D-associated SNPs for their association with AAD using nonparametric Kruskal-Wallis test. While high-risk HLA genotypes were not found to be associated with AAD, fourteen SNPs located in 12 non-HLA loci showed a strong association (2.9 × 10-12 < P < 1.4 × 10-3 after FDR correction). Four of these loci have been associated with AAD in previous cohorts (GSDMB, IL2, TNFAIP3, IL1), supporting a partially shared genetic influence on AAD of T1D in the studied European populations. In contrast, the association of 8 new loci CLEC16A, TYK2, ERBB3, CCR7, FCRL3, DNAH2, FGF3/4, and HPSE2 with AAD is novel. The 12 protein-coding genes located within these loci are involved in major immune pathways or in predisposition to other autoimmune diseases, which suggests a prominent role for these genes in the early immune mechanisms of beta cell destruction.

COVID-19: individual and herd immunity.

Immunity to the SARS-CoV-2 virus ensures protection against reinfection by this virus thanks to the combined action of neutralizing antibodies and T lymphocytes specific to viral proteins, in particular the Spike protein. It must be distinguished from the immune response that ensures healing of the infection following contamination that involves innate immunity, particularly type 1 interferons, and which is followed by adaptive cellular and humoral immunity. The importance of the effect of interferons is highlighted by the occurrence of severe forms of the disease in genetically deficient subjects or in patients with antibodies neutralizing type 1 interferon. Herd immunity is not an individual biological property. It is a mathematical property that qualifies the fact that when the proportion of subjects with individual immunity is high enough, there is little chance that an epidemic can occur. The level of that proportion-the herd immunity of the population can be computed under theoretical, often unrealistic, hypotheses, and is difficult to assess in natural conditions.

L'immunité individuelle contre le virus SARS-CoV-2 assure la protection contre la réinfection par ce virus grâce à l'action conjuguée des anticorps neutralisants et des lymphocytes T spécifiques des protéines virales, notamment la protéine Spike (spicule). Il faut la distinguer de la réponse immunitaire qui assure la guérison de l'infection dans les jours suivant la contamination. Celle-ci fait intervenir l'immunité innée et tout particulièrement les interférons de type 1 puis l'immunité adaptative cellulaire et humorale. L'importance de l'effet des interférons est soulignée par la survenue de formes graves chez des sujets génétiquement déficients dans leur synthèse ou encore des patients présentant des anticorps neutralisant l'interféron de type 1. L'immunité collective caractérise la faible probabilité de développement d'une épidémie dans une population ayant un pourcentage élevé de sujets présentant une immunité individuelle. Le taux d'immunité collective nécessaire pour faire disparaître l'épidémie a été calculé dans des modèles mathématiques supposant la panmixie ; il est difficile à évaluer dans les populations réelles.

Exploring the risk of hypospadias in children born from mothers living close to a vineyard.

Hypospadias (H) is a common birth defect affecting the male urinary tract. It has been suggested that exposure to endocrine disrupting chemicals might increase the risk of H by altering urethral development. However, whether H risk is increased in places heavily exposed to agricultural pesticides, such as vineyards, remains debated and difficult to ascertain. The objective of the work is to test the possible association of H with residential proximity to vineyards. Residential address at birth of 8,766 H cases born 1980-2011 was taken from 17 specialized surgery centers. The geographical distribution of vineyards was obtained from the European Land Parcel Identification System (LPIS) and the distance of address to the nearest vineyard was computed. A first estimate of the variation of H relative risk with distance to vineyards was obtained using as controls 13,105 cryptorchidism (C) cases operated during the same period in the same centers. A separate estimate was obtained from a case-control study using "virtual controls" (VC) defined as points of the map sampled to match the demographic distribution of births within the recruitment territories of the study centers. Non-exposed patients were defined as those with a residence between 5,000 and 10,000 m from the closest vineyard. The residential distance to vineyard was smaller for H than for C cases (p<10-4). We found 42/8766 H cases (0.48%) and 50/13,105 C cases (0.38%) born to mothers living within 20 m of a vineyard. The odds ratios for H were 2.48 (CI: 1.0 to 5.1) and 2.4 (CI: 1.3 to 4.4), vs C or vs VC, respectively, when pregnant mothers lived 10-20 m from a vineyard. In conclusion, our study supports that children born to mothers living close to a vineyard have a two-fold increased risk of H. For environmental research, the use of VC provides an alternative to classical case control technique.

Impact of social inequalities at birth on the longevity of children born 1914-1916: A cohort study.

BACKGROUND: Testing whether familial socioeconomic status (SES) in childhood is a predictor of mortality has rarely been done on historical cohorts. METHODS: The birth certificates of 4,805 individuals born 1914-1916 in 16 districts of the Paris region were retrieved. The handwritten information provided the occupation of parents, the legitimacy status, life events (e.g. marriage, divorce), and the precise date of death when after 1945 (i.e. age 31 years (y) in the cohort). We used the median age at death (MAD) as a global measure of mortality, then studied separately survival to and after 31 y. Multivariate Imputation by Chained Equations (MICE), Generalized Additive Models (GAMs) and mixed effect Cox models were used. RESULTS: MAD showed large variations according to paternal occupation. The lowest MAD in both sexes was that of workers' children: it was 56.3 y (95% CI: [48.6-62.7]) in men and 67.4 y (95% CI: [60.8-72.7]) in women, respectively (95% CI: 13.4 y [5.7-21.3]) and 12.3 y (95% CI: [4.0-19.2]) below the highest MAD attained. MAD experienced by illegitimate children was 18.9 y (95% CI: [13.3-32.3]) shorter than of legitimate children. The multivariate analysis revealed that in both sexes survival to age 31 y was predicted independently by legitimacy and paternal occupation. Paternal occupation was found significantly associated with mortality after age 31 y in females only: accordingly difference in life expectancy at age 31 y was 4.4 y (95% CI: [1.2-7.6]) between upper class and workers' daughters. CONCLUSIONS: Paternal occupation and legitimacy status were strong predictors of offspring longevity in this one-century historical cohort born during World War One.

Data Science Priorities for a University Hospital-Based Institute of Infectious Diseases: A Viewpoint.

Automation of laboratory tests, bioinformatic analysis of biological sequences, and professional data management are used routinely in a modern university hospital-based infectious diseases institute. This dates back to at least the 1980s. However, the scientific methods of this 21st century are changing with the increased power and speed of computers, with the "big data" revolution having already happened in genomics and environment, and eventually arriving in medical informatics. The research will be increasingly "data driven," and the powerful machine learning methods whose efficiency is demonstrated in daily life will also revolutionize medical research. A university-based institute of infectious diseases must therefore not only gather excellent computer scientists and statisticians (as in the past, and as in any medical discipline), but also fully integrate the biologists and clinicians with these computer scientists, statisticians, and mathematical modelers having a broad culture in machine learning, knowledge representation, and knowledge discovery.

Comparing Inpatient Satisfaction Collected via a Web-Based Questionnaire Self-Completion and Through a Telephone Interview: An Ancillary Study of the SENTIPAT Randomized Controlled Trial.

BACKGROUND: Assessing the satisfaction of patients about the health care they have received is relatively common nowadays. In France, the satisfaction questionnaire, I-Satis, is deployed in each institution admitting inpatients. Internet self-completion and telephone interview are the two modes of administration for collecting inpatient satisfaction that have never been compared in a multicenter randomized experiment involving a substantial number of patients. OBJECTIVE: The objective of this study was to compare two modes of survey administration for collecting inpatient satisfaction: Internet self-completion and telephone interview. METHODS: In the multicenter SENTIPAT (acronym for the concept of sentinel patients, ie, patients who would voluntarily report their health evolution on a dedicated website) randomized controlled trial, patients who were discharged from the hospital to home and had an Internet connection at home were enrolled between February 2013 and September 2014. They were randomized to either self-complete a set of questionnaires using a dedicated website or to provide answers to the same questionnaires administered during a telephone interview. As recommended by French authorities, the analysis of I-Satis satisfaction questionnaire involved all inpatients with a length of stay (LOS), including at least two nights. Participation rates, questionnaire consistency (measured using Cronbach alpha coefficient), and satisfaction scores were compared in the two groups. RESULTS: A total of 1680 eligible patients were randomized to the Internet group (n=840) or the telephone group (n=840). The analysis of I-Satis concerned 392 and 389 patients fulfilling the minimum LOS required in the Internet and telephone group, respectively. There were 39.3% (154/392) and 88.4% (344/389) responders in the Internet and telephone group, respectively (P<.001), with similar baseline variables. Internal consistency of the global satisfaction score was higher (P=.03) in the Internet group (Cronbach alpha estimate=.89; 95% CI 0.86-0.91) than in the telephone group (Cronbach alpha estimate=.84; 95% CI 0.79-0.87). The mean global satisfaction score was lower (P=.03) in the Internet group (68.9; 95% CI 66.4-71.4) than in the telephone group (72.1; 95% CI 70.4-74.6), with a corresponding effect size of the difference at -0.253. CONCLUSIONS: The lower response rate issued from Internet administration should be balanced with a likely improved quality in satisfaction estimates, when compared with telephone administration, for which an interviewer effect cannot be excluded. TRIAL REGISTRATION: Clinicaltrials.gov NCT01769261 ; http://clinicaltrials.gov/ct2/show/NCT01769261 (Archived by WebCite at http://www.webcitation.org/6ZDF5lA41).

Comparison of the temperature-mortality relationship in foreign born and native born died in France between 2000 and 2009.

The daily temperature-mortality relationship is typically U shaped. The temperature of minimum mortality (MMT) has been shown to vary in space (higher at lower latitudes) and time (higher in recent periods). This indicates human populations adapt to their local environment. The pace of this adaptation is unknown. The objective of this study was to investigate the differences in the temperature-mortality relationship in continental France between foreign born and natives. Source data were the 5,273,005 death certificates of individuals living in continental France between 2000 and 2009 at the time of their death. Foreign-born deaths (N = 573,384) were matched 1:1 with a native-born death based on date of birth, sex, and place of death. Four regions of France based on similarity of their temperatures profiles were defined by unsupervised clustering. For each of these four regions, variations of all causes mortality with season and temperature of the day were modeled and compared between four groups of foreign born (Maghreb, sub-Saharan Africa, Southern Europe, and Northern Europe) and matched groups of natives. Overall, the temperature-mortality relationship and MMT were close in foreign born and in native born: The only difference between foreign born and native born concerned the attributable mortality to cold, found in several instances larger in foreign born. There are little differences in France between the temperature-mortality relationships in native born and in foreign born. This supports the hypothesis of an adaptation of these populations to the temperature patterns of continental France, which for those born in Africa differ markedly from the climatic pattern of their birth country.

Prenatal loss of father during World War One is predictive of a reduced lifespan in adulthood.

Although early-life stress is known to alter health, its long-term consequences on mortality remain largely unknown. Thanks to unique French legislation established in 1917 for war orphans and children of disabled soldiers, we were able to study the adult mortality of individuals born in 1914-1916 whose fathers were killed during World War 1. Vital information and socio-demographic characteristics were extracted manually from historical civil registers for 5,671 children born between 1 August 1914 and 31 December 1916 who were granted the status of "pupille de la Nation" (orphan of the Nation). We used a database comprising 1.4 million deceased soldiers to identify war orphans and collect information on their fathers and then paired each orphan with a nonorphan from the same birth register matched for date of birth, sex, and mother's age at the infant's birth. Mortality between ages 31 and 99 y was analyzed for 2,365 orphan/nonorphan pairs. The mean loss of adult lifespan of orphans who had lost their father before birth was 2.4 y (95% CI: 0.7, 3.9 y) and was the result of increased mortality before age 65 y. Adult lifespan was not reduced when the father's death occurred after the infant's birth. These results support the notion that intrauterine exposure to a major psychological maternal stress can affect human longevity.

Using spatio-temporal surveillance data to test the infectious environment of children before type 1 diabetes diagnosis.

The "hygiene hypothesis" postulates that reduced exposure to infections favours the development of autoimmunity and childhood type 1 diabetes (T1D). But on the other side, viruses, notably enteroviruses, are suspected to trigger T1D. The assessment of the possible relationships between infections and T1D still defies the classical tools of epidemiology. We report the methods and results of a geographical approach that maps the addresses of patients to a communicable diseases surveillance database. We mapped the addresses of patients at birth, infancy and T1D diagnosis to the weekly estimates of the regional incidences of 5 frequent communicable diseases routinely collected since 1984 by the French Sentinel network. The pre-diagnostic infectious environment of 3548 patients with T1D diagnosed between 0.5 and 15 years was compared to those of 100 series of age-matched "virtual controls" drawn randomly on the map. Associations were classified as "suggestive" (summer diarrhea, SD, and varicella, V) when p< 0.05, or "significant" (influenza-like infections, ILI) when they passed the Bonferroni correction for FDR. Exposure to ILI and SD were associated with T1D risk, while V seemed protective. In the subset of 2521 patients for which we had genome wide data, we used a case-only approach to search for interactions between SNPs and the infectious environment as defined by the Sentinel database. Two SNPs, rs116624278 and rs77232854, showed significant interaction with exposure to V between 1 and 3 years of life. The infectious associations found should be taken as possible markers of patients' environment, not as direct causative factors of T1D. They require replication in other populations. The increasing public availability of geographical environmental databases will expand the present approach to map thousands of environmental factors to the lifeline of patients affected by various diseases.

Global epidemiology of type 1 diabetes in young adults and adults: a systematic review.

BACKGROUND: Although type 1 diabetes (T1D) can affect patients of all ages, most epidemiological studies of T1D focus on disease forms with clinical diagnosis during childhood and adolescence. Clinically, adult T1D is difficult to discriminate from certain forms of Type 2 Diabetes (T2D) and from Latent Autoimmune Diabetes in Adults (LADA). METHODS: A systematic review of the literature was performed to retrieve original papers in English, French and Spanish published up to November 6, 2014, reporting the incidence of T1D among individuals aged over 15 years. The study was carried out according to the PRISMA recommendations. RESULTS: We retrieved information reporting incidence of T1D among individuals aged more than 15 years in 35 countries, and published in 70 articles between 1982 and 2014. Specific anti-beta-cell proteins or C-peptide detection were performed in 14 of 70 articles (20%). The most frequent diagnostic criteria used were clinical symptoms and immediate insulin therapy. Country-to-country variations of incidence in those aged >15 years paralleled those of children in all age groups. T1D incidence was larger in males than in females in 44 of the 54 (81%) studies reporting incidence by sex in people >15 years of age. The overall mean male-to-female ratio in the review was 1.47 (95% CI = 1.33-1.60, SD = 0.49, n = 54, p = <0.0001). Overall, T1D incidence decreased in adulthood, after the age of 14 years. CONCLUSIONS: Few studies on epidemiology of T1D in adults are available worldwide, as compared to those reporting on children with T1D. The geographical variations of T1D incidence in adults parallel those reported in children. As opposed to what is known in children, the incidence is generally larger in males than in females. There is an unmet need to evaluate the incidence of autoimmune T1D in adults, using specific autoantibody detection, and to better analyze epidemiological specificities - if any - of adult T1D. PROSPERO REGISTRATION NUMBER: CRD42012002369.

Space-Time Covariation of Mortality with Temperature: A Systematic Study of Deaths in France, 1968-2009.

BACKGROUND: The temperature-mortality relationship has repeatedly been found, mostly in large cities, to be U/J-shaped, with higher minimum mortality temperature (MMT) at low latitudes being interpreted as indicating human adaptation to climate. OBJECTIVES: Our aim was to partition space with a high-resolution grid to assess the temperature-mortality relationship in a territory with wide climate diversity, over a period with notable climate warming. METHODS: The 16,487,668 death certificates of persons > 65 years of age who died of natural causes in continental France (1968-2009) were analyzed. A 30-km × 30-km grid was placed over the map of France. Generalized additive model regression was used to assess the temperature-mortality relationship for each grid square, and extract the MMT and the RM25 and RM25/18 (respectively, the ratios of mortality at 25°C/MMT and 25°C/18°C). Three periods were considered: 1968-1981 (P1), 1982-1995 (P2), and 1996-2009 (P3). RESULTS: All temperature-mortality curves computed over the 42-year period were U/J-shaped. MMT and mean summer temperature were strongly correlated. Mean MMT increased from 17.5°C for P1 to 17.8°C for P2 and to 18.2°C for P3 and paralleled the summer temperature increase observed between P1 and P3. The temporal MMT rise was below that expected from the geographic analysis. The RM25/18 ratio of mortality at 25°C versus that at 18°C declined significantly (p = 5 × 10-5) as warming increased: 18% for P1, 16% for P2, and 15% for P3. CONCLUSIONS: Results of this spatiotemporal analysis indicated some human adaptation to climate change, even in rural areas.

Covariation of the incidence of type 1 diabetes with country characteristics available in public databases.

BACKGROUND: The incidence of Type 1 Diabetes (T1D) in children varies dramatically between countries. Part of the explanation must be sought in environmental factors. Increasingly, public databases provide information on country-to-country environmental differences. METHODS: Information on the incidence of T1D and country characteristics were searched for in the 194 World Health Organization (WHO) member countries. T1D incidence was extracted from a systematic literature review of all papers published between 1975 and 2014, including the 2013 update from the International Diabetes Federation. The information on country characteristics was searched in public databases. We considered all indicators with a plausible relation with T1D and those previously reported as correlated with T1D, and for which there was less than 5% missing values. This yielded 77 indicators. Four domains were explored: Climate and environment, Demography, Economy, and Health Conditions. Bonferroni correction to correct false discovery rate (FDR) was used in bivariate analyses. Stepwise multiple regressions, served to identify independent predictors of the geographical variation of T1D. FINDINGS: T1D incidence was estimated for 80 WHO countries. Forty-one significant correlations between T1D and the selected indicators were found. Stepwise Multiple Linear Regressions performed in the four explored domains indicated that the percentages of variance explained by the indicators were respectively 35% for Climate and environment, 33% for Demography, 45% for Economy, and 46% for Health conditions, and 51% in the Final model, where all variables selected by domain were considered. Significant environmental predictors of the country-to-country variation of T1D incidence included UV radiation, number of mobile cellular subscriptions in the country, health expenditure per capita, hepatitis B immunization and mean body mass index (BMI). CONCLUSIONS: The increasing availability of public databases providing information in all global environmental domains should allow new analyses to identify further geographical, behavioral, social and economic factors, or indicators that point to latent causal factors of T1D.

Comparison of a French pediatric type 1 diabetes cohort's responders and non-responders to an environmental questionnaire.

BACKGROUND: Type 1 diabetes (T1D) incidence has doubled since the 1980's for children aged <5 years old, potentially relevant environmental factors having thus to be sought early in the patient's life. The identification of environmental factors that can explain the changing epidemiology of T1D requires comprehensive environmental inquiries. However, a limitation is the willingness of patients and families to complete these environmental questionnaires. Our objective was to identify patients' personal and social characteristics predictive of the return, time to the return and completeness of a comprehensive environmental questionnaire. METHODS: The parents of 2832 T1D patients aged <15 years old enrolled in the French Isis cohort were sent a 1379-item environmental questionnaire. A geographic information system was used to collect information on patients' socioeconomic environment. Multivariate statistical analyses were conducted to identify predictors of questionnaire return, time to its return and its completeness. RESULTS: Within 6 months, 867 (30.6%) questionnaires were returned. Socioeconomic environment was strongly associated with the probability of response, with fewer responses from cities with high Townsend deprivation index (p =2 × 10-7), high unemployment (p =0.005), blue-collar workers' rate (p =0.0002) and household overcrowding (p =0.02). Response rates were similar for male and female patients, but were higher for less severely affected patients (p =0.006) and younger patients (p =5 × 10-5). When returned, completeness was high with a mean of 96%. CONCLUSION: Identification of personal or socioeconomic characteristics differing between questionnaire responders and non-responders may help target future environmental investigations on those patients who will more likely return the information, and reduce bias using these variables to stratify the analyses.

An open source software for fast grid-based data-mining in spatial epidemiology (FGBASE).

BACKGROUND: Examining whether disease cases are clustered in space is an important part of epidemiological research. Another important part of spatial epidemiology is testing whether patients suffering from a disease are more, or less, exposed to environmental factors of interest than adequately defined controls. Both approaches involve determining the number of cases and controls (or population at risk) in specific zones. For cluster searches, this often must be done for millions of different zones. Doing this by calculating distances can lead to very lengthy computations. In this work we discuss the computational advantages of geographical grid-based methods, and introduce an open source software (FGBASE) which we have created for this purpose. METHODS: Geographical grids based on the Lambert Azimuthal Equal Area projection are well suited for spatial epidemiology because they preserve area: each cell of the grid has the same area. We describe how data is projected onto such a grid, as well as grid-based algorithms for spatial epidemiological data-mining. The software program (FGBASE), that we have developed, implements these grid-based methods. RESULTS: The grid based algorithms perform extremely fast. This is particularly the case for cluster searches. When applied to a cohort of French Type 1 Diabetes (T1D) patients, as an example, the grid based algorithms detected potential clusters in a few seconds on a modern laptop. This compares very favorably to an equivalent cluster search using distance calculations instead of a grid, which took over 4 hours on the same computer. In the case study we discovered 4 potential clusters of T1D cases near the cities of Le Havre, Dunkerque, Toulouse and Nantes. One example of environmental analysis with our software was to study whether a significant association could be found between distance to vineyards with heavy pesticide. None was found. In both examples, the software facilitates the rapid testing of hypotheses. CONCLUSIONS: Grid-based algorithms for mining spatial epidemiological data provide advantages in terms of computational complexity thus improving the speed of computations. We believe that these methods and this software tool (FGBASE) will lower the computational barriers to entry for those performing epidemiological research.

EpiBasket: how e-commerce tools can improve epidemiological preparedness.

BACKGROUND: Should an emerging infectious disease outbreak or an environmental disaster occur, the collection of epidemiological data must start as soon as possible after the event's onset. Questionnaires are usually built de novo for each event, resulting in substantially delayed epidemiological responses that are detrimental to the understanding and control of the event considered. Moreover, the public health and/or academic institution databases constructed with responses to different questionnaires are usually difficult to merge, impairing necessary collaborations. We aimed to show that e-commerce concepts and software tools can be readily adapted to enable rapid collection of data after an infectious disease outbreak or environmental disaster. Here, the 'customers' are the epidemiologists, who fill their shopping 'baskets' with standardised questions. METHODS: For each epidemiological field, a catalogue of questions is constituted by identifying the relevant variables based on a review of the published literature on similar circumstances. Each question is tagged with information on its source papers. Epidemiologists can then tailor their own questionnaires by choosing appropriate questions from this catalogue. The software immediately provides them with ready-to-use forms and online questionnaires. All databases constituted by the different EpiBasket users are interoperable, because the corresponding questionnaires are derived from the same corpus of questions. RESULTS: A proof-of-concept prototype was developed for Knowledge, Attitudes and Practice (KAP) surveys, which is one of the fields of the epidemiological investigation frequently explored during, or after, an outbreak or environmental disaster. The catalogue of questions was initiated from a review of the KAP studies conducted during or after the 2003 severe acute respiratory syndrome epidemic. CONCLUSION: Rapid collection of standardised data after an outbreak or environmental disaster can be facilitated by transposing the e-commerce paradigm to epidemiology, taking advantage of the powerful software tools already available.

Age distribution of cases and deaths during the 1889 influenza pandemic.

Using historical data taken from archival records from five European countries and the United States, we evaluate the age distributions of influenza cases and deaths during the 1889 influenza pandemic. We found that the clinical attack rate in 1889 was relatively high and constant between the ages of 1 and 60 years, but was lower outside of the extremes of this age range. By contrast, age-specific influenza-related mortality rates were J-shaped and increased with age beyond 20 years. We conclude that the age-specific attack rates of the 1889 pandemic were most similar to those of the 1968 pandemic and that influenza-related mortality rates did not follow a W-shaped curve as was observed during the 1918 pandemic. Adding 1889 to the short catalogue of influenza pandemics previously studied makes the 1918 pandemic even more exceptional in terms of mortality burden and age distribution of deaths.

Transmission parameters of the A/H1N1 (2009) influenza virus pandemic: a review.

BACKGROUND: The new influenza virus A/H1N1 (2009), identified in mid-2009, rapidly spread over the world. Estimating the transmissibility of this new virus was a public health priority. METHODS: We reviewed all studies presenting estimates of the serial interval or generation time and the reproduction number of the A/H1N1 (2009) virus infection. RESULTS: Thirteen studies documented the serial interval from household or close-contact studies, with overall mean 3 days (95% CI: 2·4, 3·6); taking into account tertiary transmission reduced this estimate to 2·6 days. Model-based estimates were more variable, from 1·9 to 6 days. Twenty-four studies reported reproduction numbers for community-based epidemics at the town or country level. The range was 1·2-3·1, with larger estimates reported at the beginning of the pandemic. Accounting for under-reporting in the early period of the pandemic and limiting variation because of the choice of the generation time interval, the reproduction number was between 1·2 and 2·3 with median 1·5. DISCUSSION: The serial interval of A/H1N1 (2009) flu was typically short, with mean value similar to the seasonal flu. The estimates of the reproduction number were more variable. Compared with past influenza pandemics, the median reproduction number was similar (1968) or slightly smaller (1889, 1918, 1957).