Meta-analysis of the severe acute respiratory syndrome coronavirus 2 serial intervals and the impact of parameter uncertainty on the coronavirus disease 2019 reproduction number

The serial interval of an infectious disease, commonly interpreted as the time between the onset of symptoms in sequentially infected individuals within a chain of transmission, is a key epidemiological quantity involved in estimating the reproduction number. The serial interval is closely related to other key quantities, including the incubation period, the generation interval (the time between sequential infections), and time delays between infection and the observations associated with monitoring an outbreak such as confirmed cases, hospital admissions, and deaths. Estimates of these quantities are often based on small data sets from early contact tracing and are subject to considerable uncertainty, which is especially true for early coronavirus disease 2019 data. In this paper, we estimate these key quantities in the context of coronavirus disease 2019 for the UK, including a meta-analysis of early estimates of the serial interval. We estimate distributions for the serial interval with a mean of 5.9 (95% CI 5.2; 6.7) and SD 4.1 (95% CI 3.8; 4.7) days (empirical distribution), the generation interval with a mean of 4.9 (95% CI 4.2; 5.5) and SD 2.0 (95% CI 0.5; 3.2) days (fitted gamma distribution), and the incubation period with a mean 5.2 (95% CI 4.9; 5.5) and SD 5.5 (95% CI 5.1; 5.9) days (fitted log-normal distribution). We quantify the impact of the uncertainty surrounding the serial interval, generation interval, incubation period, and time delays, on the subsequent estimation of the reproduction number, when pragmatic and more formal approaches are taken. These estimates place empirical bounds on the estimates of most relevant model parameters and are expected to contribute to modeling coronavirus disease 2019 transmission.

The unmitigated profile of COVID-19 infectiousness

Quantifying the temporal dynamics of infectiousness of individuals infected with SARS-CoV-2 is crucial for understanding the spread of the COVID-19 pandemic and for analyzing the effectiveness of different mitigation strategies. Many studies have tried to use data from the onset of symptoms of infector-infectee pairs to estimate the infectiousness profile of SARS-CoV-2. However, both statistical and epidemiological biases in the data could lead to an underestimation of the duration of infectiousness. We correct for these biases by curating data from the initial outbreak of the pandemic in China (when mitigation steps were still minimal), and find that the infectiousness profile is wider than previously thought. For example, our estimate for the proportion of transmissions occurring 14 days or more after infection is an order of magnitude higher - namely 19% (95% CI 10%-25%). The inferred generation interval distribution is sensitive to the definition of the period of unmitigated transmission, but estimates that rely on later periods are less reliable due to intervention effects. Nonetheless, the results are robust to other factors such as the model, the assumed growth rate and possible bias of the dataset. Knowing the unmitigated infectiousness profile of infected individuals affects estimates of the effectiveness of self-isolation and quarantine of contacts. The framework presented here can help design better quarantine policies in early stages of future epidemics using data from the initial stages of transmission.

Genetic Markers Associated with Milk Production Traits in Dairy Cattle

Increasing milk production is one of the key concerns in animal production. Traditional breeding has gotten limited achievement in the improvement of milk production because of its moderate heritability. Milk production traits are controlled by many genes. Thus, identifying candidate genes associated with milk production traits may provide information that can be used to enhance the accuracy of animal selection for moderately heritable traits like milk production. The genomic selection can enhance the accuracy and intensity of selection and shortening the generation interval. The genetic progress of economically important traits can be doubled with the accuracy of selection and shortening of generation interval. Genome-wide association studies (GWAS) have made possible the screening of several single nucleotide polymorphisms (SNPs) in genes associated with milk production traits in dairy cattle. In addition, RNA-sequencing is another well-established tool used to identify genes associated with milk production in dairy cattle. Although it has been widely accepted that these three methods (GWAS, RNA-seq and DNA sequencing) are considered the first step in the screening of genes, however, the outcomes from GWAS, DNA-sequencing and RNA-seq still need further verification for the establishment of bonafide causal variants via genetic replication as well as functional validation. In the current review, we have highlighted genetic markers identified (2010-to date) for their associations with milk production traits in dairy cattle. The information regarding candidate genes associated with milk production traits provided in the current review could be helpful to select the potential genetic markers for the genetic improvement of milk production traits in dairy cattle.

Different historical generation intervals in human populations inferred from Neanderthal fragment lengths and mutation signatures

After the main Out-of-Africa event, humans interbred with Neanderthals leaving 1–2% of Neanderthal DNA scattered in small fragments in all non-African genomes today. Here we investigate what can be learned about human demographic processes from the size distribution of these fragments. We observe differences in fragment length across Eurasia with 12% longer fragments in East Asians than West Eurasians. Comparisons between extant populations with ancient samples show that these differences are caused by different rates of decay in length by recombination since the Neanderthal admixture. In concordance, we observe a strong correlation between the average fragment length and the mutation accumulation, similar to what is expected by changing the ages at reproduction as estimated from trio studies. Altogether, our results suggest differences in the generation interval across Eurasia, by up 10–20%, over the past 40,000 years. We use sex-specific mutation signatures to infer whether these changes were driven by shifts in either male or female age at reproduction, or both. We also find that previously reported variation in the mutational spectrum may be largely explained by changes to the generation interval. We conclude that Neanderthal fragment lengths provide unique insight into differences among human populations over recent history.

Correlation between times to SARS-CoV-2 symptom onset and secondary transmission undermines epidemic control efforts

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infections have been associated with substantial presymptomatic transmission, which occurs when the generation interval—the time between infection of an individual with a pathogen and transmission of the pathogen to another individual—is shorter than the incubation period—the time between infection and symptom onset. We collected a dataset of 257 SARS-CoV-2 transmission pairs in Japan and jointly estimated the mean generation interval (3.7–5.1 days) and mean incubation period (4.4–5.7 days) as well as measured their dependence (Kendall’s tau of 0.4–0.6), taking into consideration demographic and epidemiological characteristics of the pairs. The positive correlation between the two parameters demonstrates that reliance on isolation of symptomatic COVID-19 cases as a focal point of control efforts is insufficient to address the challenges posed by SARS-CoV-2 transmission dynamics. Accounting for this dependence within SARS-CoV-2 epidemic models can also improve model estimates.

On realized serial and generation intervals given control measures: The COVID-19 pandemic case

The SARS-CoV-2 pathogen is currently spreading worldwide and its propensity for presymptomatic and asymptomatic transmission makes it difficult to control. The control measures adopted in several countries aim at isolating individuals once diagnosed, limiting their social interactions and consequently their transmission probability. These interventions, which have a strong impact on the disease dynamics, can affect the inference of the epidemiological quantities. We first present a theoretical explanation of the effect caused by non-pharmaceutical intervention measures on the mean serial and generation intervals. Then, in a simulation study, we vary the assumed efficacy of control measures and quantify the effect on the mean and variance of realized generation and serial intervals. The simulation results show that the realized serial and generation intervals both depend on control measures and their values contract according to the efficacy of the intervention strategies. Interestingly, the mean serial interval differs from the mean generation interval. The deviation between these two values depends on two factors. First, the number of undiagnosed infectious individuals. Second, the relationship between infectiousness, symptom onset and timing of isolation. Similarly, the standard deviations of realized serial and generation intervals do not coincide, with the former shorter than the latter on average. The findings of this study are directly relevant to estimates performed for the current COVID-19 pandemic. In particular, the effective reproduction number is often inferred using both daily incidence data and the generation interval. Failing to account for either contraction or mis-specification by using the serial interval could lead to biased estimates of the effective reproduction number. Consequently, this might affect the choices made by decision makers when deciding which control measures to apply based on the value of the quantity thereof.

Different historical generation intervals in human populations inferred from Neanderthal fragment lengths and patterns of mutation accumulation

After the main out-of-Africa event, humans interbred with Neanderthals leaving 1-2% of Neanderthal DNA scattered in small fragments in all non-African genomes today1,2. Here we investigate the size distribution of these fragments in non-African genomes3. We find consistent differences in fragment length distributions across Eurasia with 11% longer fragments in East Asians than in West Eurasians. By comparing extant populations and ancient samples, we show that these differences are due to a different rate of decay in length by recombination since the Neanderthal admixture. In line with this, we observe a strong correlation between the average fragment length and the accumulation of derived mutations, similar to what is expected by changing the ages at reproduction as estimated from trio studies4. Altogether, our results suggest consistent differences in the generation interval across Eurasia, by up to 20% (e.g. 25 versus 30 years), over the past 40,000 years. We use sex-specific accumulations of derived alleles to infer how these changes in generation intervals between geographical regions could have been mainly driven by shifts in either male or female age of reproduction, or both. We also find that previously reported variation in the mutational spectrum5 may be largely explained by changes to the generation interval and not by changes to the underlying mutational mechanism. We conclude that Neanderthal fragment lengths provide unique insight into differences of a key demographic parameter among human populations over the recent history.

Discriminant Canonical Analysis of the Contribution of Spanish and Arabian Purebred Horses to the Genetic Diversity and Population Structure of Hispano-Arabian Horses

Genetic diversity and population structure were analyzed using the historical and current pedigree information of the Arabian (PRá), Spanish Purebred (PRE), and Hispano-Arabian (Há) horse breeds. Genetic diversity parameters were computed and a canonical discriminant analysis was used to determine the contributions of ancestor breeds to the genetic diversity of the Há horse. Pedigree records were available for 207,100 animals born between 1884 and 2019. Nei’s distances and the equivalent subpopulations number indicated the existence of a highly structured, integrated population for the Há breed, which is more closely genetically related to PRá than PRE horses. An increase in the length of the generation interval might be an effective solution to reduce the increase in inbreeding found in the studied breeds (8.44%, 8.50%, and 2.89%, for PRá, PRE, and Há, respectively). Wright’s fixation statistics indicated slight interherd inbreeding. Pedigree completeness suggested genetic parameters were highly reliable. High GCI levels found for number of founders and non-founders and their relationship to the evolution of inbreeding permit controlling potential deleterious negative effects from excessively frequent mating between interrelated individuals. For instance, the use of individuals presenting high GCI may balance founders’ gene contributions and consequently preserve genetic diversity levels (current genetic diversity loss in PRá, PRE, and Há is 6%, 7%, and 4%, respectively).

SELECTION IN HEREFORD CATTLE I. SELECTION INTENSITY, GENERATION INTERVAL AND INDEXES IN RETROSPECT

Selection intensity and generation interval were evaluated in a Hereford cattle herd of 14 inbred lines and 14 linecross groups corresponding to the lines of inbred sire at the San Juan Basin Research Centre, Hesperus, Colorado. Selection indexes practised were calculated in retrospect. The records analysed were weaning weight and postweaning traits in males and females collected from 1946 through 1973. Analyses were performed by line for the inbreds and pooled analyses for the inbred and linecross populations. From records of 1,239 calves weaned, age of sire averaged 3.75 years compared with 4.52 years for age of dam, showing faster generation turnover for sires than for dams. Generation interval determined 98 actual age of midparent was 4.13 years.Selection applied, evaluated as annual selection differentials within inbred lines and then pooled over all lines, averaged .55 standard deviations per generation for sires for weaning weight. Selection of females was much less. Midparent selection differential amounted to .33 standard deviations per generation. Pooled standardized selection differentials per generation over all lines for sires were .49, .46, 40, -.20, -.10, and .69, respectively, for initial weight, final weight, feed consumption, unadjusted feed efficiency, adjusted feed efficiency, and average daily gain. Selection of females for postweaning traits was not intense. Selection Indexes actually practiced in retrospect were: for sires, IS = .4661(WW) -.0092(FE) + .6126(ADG); for inbred dams, ID = .1824(WW) -.0284 (12W) + .0736 (18W) - 1097 (SPW) -.1097 (FAW); for linecross dams, ID= .2693 (WW) - 2960 (12W) + .0147 (18W) + 1185 (SPW) -.0354 (FAW). The corresponding index selection differentials were .818, 203, and .209. Sire index selection differentials represent about 79 percent of the total selection differentials.