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• W3167454839 abstract "Article Figures and data Abstract Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Recent pertussis resurgence in numerous countries may be driven by asymptomatic infections. Most pertussis surveillance studies are cross-sectional and cannot distinguish asymptomatic from pre-symptomatic infections. Longitudinal surveillance could overcome this barrier, providing more information about the true burden of pertussis at the population level. Here we analyze 17,442 nasopharyngeal samples from a longitudinal cohort of 1320 Zambian mother/infant pairs. Our analysis has two elements. First, we demonstrate that the full range of IS481 qPCR CT values provides insight into pertussis epidemiology, showing concordance of low and high CT results over time, within mother/infant pairs, and in relation to symptomatology. Second, we exploit these full-range qPCR data to demonstrate a high incidence of asymptomatic pertussis, including among infants. Our results demonstrate a wider burden of pertussis infection than we anticipated in this population, and expose key limitations of threshold-based interpretation of qPCR results in infectious disease surveillance. Introduction Bordetella pertussis remains a significant cause of morbidity and mortality among infants and young children around the world (Yeung et al., 2017; Rohani and Scarpino, 2019) and has experienced a resurgence in numerous countries despite long-standing vaccination programs (Jackson and Rohani, 2014; He and Mertsola, 2008; Domenech de Cellès et al., 2016; Rohani and Drake, 2011). Transmission by asymptomatic individuals is a suspected driver of pertussis resurgence (Althouse and Scarpino, 2015; Cherry, 2013) though unequivocal evidence documenting asymptomatic infections in adults and children is lacking. Rapid and reliable molecular diagnosis of pertussis is now possible using quantitative PCR (qPCR), which has supplanted microbiologic culture as the preferred tool for detecting pertussis (Vincart et al., 2007). Yet most pertussis surveillance uses cross-sectional monitoring that only captures a single point in time and thus cannot distinguish asymptomatic from pre-symptomatic infections. In principle, repeated sampling over time could unambiguously identify asymptomatic infections. For example, if one could identify a patient at the moment of pertussis exposure and then regularly monitor them over time, one could anticipate capturing a gradual ‘fade-in/fade-out’ sequence as bacterial load, and thus qPCR signal intensity, varies across the arc of the infection: at initial exposure (where bacterial density is below the assay’s limits of detection), during acute infection (as bacterial density—and signal intensity—rises to a peak), and finally during recovery and convalescence (where an eventual loss of signal indicates pathogen clearance). Indeed, recent human infection trials have borne out this scenario (Chilengi et al., 2020; DeVincenzo et al., 2020). By sampling a single point in time, however, cross-sectional observations lack the historical context necessary to trace this arc of infection. An additional complication arises when diagnostic thresholds are applied to qPCR cycle threshold (CT) values to distinguish positive and negative cases. For example, an IS481 CT <35 has been used as a diagnostic threshold of pertussis (Tatti et al., 2011; Tatti et al., 2008). This process introduces several problems, including calibration (e.g., between labs, machines, or over time) and a poorly examined trade-off between sensitivity and specificity that may also be task-dependent (e.g., clinical diagnosis). Further, this process discards information about qPCR signal intensity, such that borderline or low-intensity signals are summarily discounted as false positives or ‘indeterminate’. These complications become particularly important as we extend the use of qPCR from clinical diagnosis into disease surveillance of populations (Bolotin et al., 2018). Here we present an analysis of 17,442 nasopharyngeal samples (and associated IS481 qPCR assays) collected from 1320 Zambian mother/infant pairs who each provided at least four samples during the study. We begin with a descriptive analysis of eight mother/infant pairs where each symptomatic infant had definitive qPCR-based evidence of pertussis infection. We document the time course of infection in these individuals and observe frequent contemporaneous subclinical infections in the mothers of these infected infants. We then turn our attention to the entire cohort, where we use full-range IS481 CT values to show that qPCR signals of different intensities cluster in time, and we summarize within-subject variations in signal intensity over time. We then quantify the evidence for pertussis infection (EFI) within each individual across the full study. We show that EFI clusters within mother/infant pairs and is associated with clinical symptomatology and antibiotic use. We use these results to estimate the proportion of mothers and infants with evidence of asymptomatic, minimally symptomatic, and moderately/severely symptomatic pertussis in this cohort. In total, we find that full-range CT values yield valuable insights into pertussis epidemiology in this population. Critically, the burden of pertussis here is substantially underestimated when restricting diagnostic criteria to IS481 CT ≤35. We also demonstrate widespread asymptomatic pertussis infections among mothers and, surprisingly, among young infants. Results Study overview In 2015, we partnered with the Bill and Melinda Gates Foundation to conduct a prospective cohort study in Lusaka, Zambia (Gill et al., 2016). Between April and November 2015, we enrolled 1981 healthy Zambian mother/infant pairs (3962 individuals) shortly after birth and observed them during an additional six clinic visits scheduled at roughly 2–3 week intervals through approximately 14 weeks of age (when the last of the three routine infant DTP vaccine visits occurs). At each visit, we systematically obtained nasopharyngeal (NP) swabs and assessed symptoms and antibiotic use. Of the initial cohort of 1981 pairs, 1497 mother/infant pairs attended at least one post-enrollment clinic visit, and 834 pairs attended all seven scheduled visits (including enrollment, Table 1). In this analysis, we focus on the 1320 pairs with ≥4 NP samples per subject (Figure 1). Baseline cohort demographics are shown in Table 2. Infants were enrolled at a median of 7 days post-partum; 47% were female, with a median gestational age of 40 weeks and birth weight of 3000 g. Mothers’ median age was 25 years; >90% were married, and 17.5% were known to be infected with HIV. Among the HIV-positive mothers, nearly all were on antiretroviral therapy (ART) at the time of enrollment, and half had initiated ART prior to conception. Nearly all mothers received at least one dose of tetanus toxoid during pregnancy, signaling that some antenatal care was received by at least 99.5% of the maternal cohort. The final HIV status of the exposed infants could not be assessed. Table 1 Study profile of cohort enrollment and attendance (bold indicates analysis set). Beyond eligibility and initial screening, the sole cause of cohort attrition was failure to attend one or more scheduled clinic visits. For eligibility and enrollment details, please see Gill et al., 2016. Study PhasephaseMother/Infant PairsRecruitment and screening3033Initial enrollment1981Post-enrollment attendence1497≥4 NP samples per subject1320Attended all seven scheduled visits734 Table 2 Demographic characteristics of participants (interquartile range in parentheses). Only subjects with at least four NP samples were included in subsequent analyses. Study ParticipationParameterEnrolled≥4 NP SamplesNumber Under Study19811320MothersMarried90.2%89.8%HIV+17.5%19.5%Median Age25 (21, 29)25 (22, 30)Median Infants In House (<1 year)1 (1, 1)1 (1, 1)Median Children In House (<5 years)2 (1, 2)2 (1, 2)InfantsBorn at Chawama PHC56.9%56.6%Born at UTH34.8%35.5%Female sex46.9%46.1%Median birth weight (kg)3 (2.8, 3.3)3 (2.8, 3.3) Figure 1 Download asset Open asset Study Attendance. (A) Percent attendance (%) of mother/infant pairs by infant age at last attendance (N = 1320, excluding pairs where subjects had <4 NP samples). Shaded regions show target age windows of DTP doses 1–3. Horizontal lines and text shows number of pairs attending up to marked ages: beginning of study enrollment, and at earliest timely administration of DTP doses 1–3. See Table 1 for study profile. Most pairs (734/1320) attended all seven scheduled visits (including enrollment). (B) NP samples per subject: number of subjects with each sample count (including enrollment and unscheduled visits). Note that, with rare exceptions, each mother has the same number of NP samples as their infant. Descriptive analysis of eight noteworthy mother/infant pairs In contrast to cross-sectional studies, our longitudinal analysis reveals the trajectory of qPCR signal intensity within subjects over time. To avoid confusion, we use the term ‘detecting assay’ throughout to describe a qPCR result with any detectable level of signal; all others are 'non-detecting' (N.D.). All qPCR assays were run for 45 cycles, making CT = 45 our effective limit of detection. Figure 2 provides a detailed timeline of IS481 CT results from the initial group of eight mother/infant pairs, which included all infants with a definitive positive NP sample (IS481 CT <35) during a clinic visit where respiratory symptoms were reported. This figure highlights the experimental design, where pairs were monitored across the infant’s first months of life at regularly spaced clinic visits (e.g., pairs C and E), with additional mother-initiated visits for acute health care (e.g., pairs A and D). Minimal symptoms (cough and/or coryza) were common in both mothers and infants, while moderate to severe symptoms were much rarer, particularly among the mothers. Also rare is ptxS1 corroboration of IS481 results (pair D and infants F-H). This is not surprising, given the high IS481 copy number relative to the single ptxS1 copy, which renders the latter target specific but insensitive for detection of the bacterium (Reischl et al., 2001). Figure 2 Download asset Open asset Timeline of study participation for eight noteworthy mother/infant pairs, showing rounded IS481 CT values (numbers), ptxS1 results (shape), and pertussis symptoms (color) at each clinic visit. Selected pairs include all symptomatic infants with definitive evidence of pertussis infection (IS481 CT <35). Blank cells show NP samples with no detected IS481. Contemporaneous detection of IS481 within pairs is common, as are temporal clusters of IS481 within individuals. Pertussis symptoms are relatively uncommon in mothers: of the seven mothers shown here with detectable IS481, four lacked any observable pertussis symptoms during clinic visits. Of particular note, seven of these eight mothers had at least one detecting assay, while six had multiple detections. However, many of these mothers’ detecting assays showed relatively weak signals (IS481 CT >40, e.g., mothers A, C, and H), with only a few results meeting CDC’s recommended diagnostic criteria for a positive test (Lievano et al., 2002). We note, however, that CDC criteria were designed for application by clinicians when evaluating patients with severe and/or classic pertussis symptoms, and were intended to favor specificity over sensitivity. They were not designed for surveillance of asymptomatic individuals. Moreover, in our data these weak qPCR signals frequently bracketed visits with definitive test results and were observed in all eight infants who met CDC criteria at one or more visit. A clear example of pertussis infection fade-in and fade-out is provided by infant G, including ptxS1 confirmation and severe symptoms that occur after the observed IS481 signal peak. Remarkably, a weak (and asymptomatic) IS481 signal in infant G at age six weeks precedes the acute infection observed around age 8 weeks, while a weak IS481 signal in mother G is observed even earlier, before 4 weeks of age. This example suggests the likely sequence of transmission events within this mother/infant pair and thus influenced our emerging conclusion that weaker IS481 signals should not be automatically discounted. Mother H provides another illustrative example, where seven of nine assays (78%) detect IS481, but none reach the canonical diagnostic threshold of <35, and none had a detectable ptxS1 result. A priori, the probability that all these detections were false positives appears low. In the context of an infected infant, this explanation becomes even less likely. While low sample pathogen density could also reflect clinically uninformative variation in sample collection and processing, the more parsimonious interpretation is that these seven NP samples contained pertussis, albeit at a low density. While all infants in this first analysis were selected based on their presentation of symptomatic pertussis, several of their mothers presented with no respiratory symptoms at clinic visits. Of particular note are mothers G and H, each of whom had multiple detecting assays, strongly suggesting asymptomatic (or minimally symptomatic) pertussis infections. Based on our initial results, we next assessed how frequent low-intensity signals were in our cohort by randomly selecting 500 NP samples from our catalogue of over 9000 maternal samples. None of these samples yielded detectable IS481. Applying the binomial theorem for an expected frequency of just under 1/500 (i.e., assuming that the next sample would have been detecting), the probability that seven of eight mothers of infected infants also had one or more detecting assays occurring by chance was <0.0001. We conclude that random chance is unlikely to account for the high concordance within these pairs, or for their evident tendency to coincide in time. Quantitative analysis of the full cohort The low-intensity IS481 CT values (i.e.,≥35) discussed above would be adjudicated as ‘negative’ or ‘indeterminate’ in a typical cross-sectional study. However, we observed multiple lines of evidence supporting their microbiological and epidemiological significance that compelled us toward a comprehensive analysis of full-range IS481 CT values for the entire cohort. Concordance of qPCR signals over time In Table 3, we summarize IS481 qPCR assays from the full cohort (17,442 NP samples total). Approximately 91% of all tests were non-detecting (N.D.), with 1561 detecting assays, including 818 in mothers and 743 in infants. Only 0.11% and 0.18% of mother and infant samples, respectively, had CT <35 and would have been considered definitive positive samples; all other samples would have been deemed indeterminate or negative based on traditional cut-points. Table 3 Frequency of NP samples in each IS481 CT intensity stratum for infants and mothers (not detected: N.D.). IS481 was detected in 1561 (8.95%) samples (743 in infants, 818 in mothers). Very few samples had CT <35: 16 samples (infants) and 10 samples (mothers). CT StrataInfantMotherSum(18,40)99 (1.1%)60 (0.69%)159(40,43)254 (2.9%)276 (3.2%)530(43,45)390 (4.5%)482 (5.5%)872N.D.7980 (91%)7901 (91%)15,881Sum8723 (100%)8719 (100%)17,442 In Figure 3, we show the cohort’s structure and time course. Figure 3A illustrates subject participation over calendar time for several example pairs that were chosen to highlight the cohort’s rolling enrollment across 2015. Figure 3 Download asset Open asset Timeline of study visits, NP samples, and IS481 assays. (A) Timeline of study participation for six mother/infant pairs chosen to illustrate the cohort’s rolling enrollment. Dots show clinic visits; color indicates NP sample IS481 CT strata. Visits included initial enrollment (shortly after birth) followed by (up to) six scheduled visits at 2–3 week intervals, and (in some cases) additional mother-initiated visits. (B) timeline NP samples for the full cohort (N = 17,442), showing the percent of samples with detectable IS481 over time, stratified by signal intensity (lower CT values indicate more IS481, see also Table 3). For each stratum, a generalized additive model estimated the time-varying proportion of all assays contained in that stratum (shading shows 95% CI). Points highlight assays with CT <35. A cluster of detecting assays in all strata peaks in late June/early July. Strong temporal correlation was observed among strata, and is consistent with detection of a pertussis outbreak, but is not consistent with randomly distributed false positive assays. (C) Number of NP samples per week (approx. denominator of B). The dip in Jan 2016 corresponds with the Christmas holiday. If weak qPCR signals (e.g., CT≥40) represent random background noise (i.e., false positives), then we would anticipate random variation in their frequency over time, and no evidence of correlation with stronger signals. To test this hypothesis, we assess the relative frequency over time of detecting assays grouped into three strata of qPCR signal intensities. In Figure 3B, the time-averaged frequency of NP samples in each stratum is shown by a separate curve, expressed as the percent of NP samples collected during that time period. Each of the 1320 study participants was tested repeatedly, and thus could contribute one or more detecting assays to each curve. Of particular note, we find that the mid- and low-intensity strata (e.g., 40≤CT<43 and 43≤CT) both closely mirrored the highest intensity strata (e.g., CT<40) in both mothers and infants, with a peak in June and July and a long tail of decline in September and October. This peak also coincides with a cluster over very high intensity assays (CT<35) that we highlight as points, and a related cluster of definitive infant pertussis cases described in our published 2016 analysis (Gill et al., 2016). We further explore the temporal correlation among CT strata in Figure 4, which provides a detailed view of the weekly percent of NP samples in the high- and mid-intensity strata (CT<40 and 40≤CT<43, respectively). Here, each point represents a single study week in 2015, while color denotes time. Overall, these two strata are highly correlated (infants, ρ=0.68; mothers, ρ=0.71), and they rise and fall in synchrony (maximum cross-correlation at lag=0). However, the mid-intensity stratum is more sensitive to low infection prevalence in both infants and mothers, revealing a pertussis outbreak in April 2015 2–3 weeks prior to the high-intensity strata. Figure 4 Download asset Open asset Phase portraits showing the weekly percent of NP samples in the mid-intensity stratum (X, 40 < CT ≤ 43) versus the high-intensity stratum (Y, CT <40) for infants (left) and mothers (right). Color shows calendar week (for clarity, weeks in 2016 are not shown). These strata are highly correlated: ρ = 0.68 (infants); ρ = 0.71 (mothers). The many weeks with Y = 0 and X > 0 illustrates the relatively low sensitivity of the high-intensity stratum. Indeed, the mid-intensity stratum detects a pertussis outbreak 2–3 weeks before the high-intensity stratum in April 2015 in both infants and mothers. We note that cohort size alone cannot explain these results, as the cohort’s size reached a steady state in June of 2015 that was sustained through the end of December 2015 (Figure 3C). Rather, these results are consistent with a population-level ‘fade-in/fade-out’ dynamic, where multiple overlapping signals from single individuals (e.g., Figure 3A) sum to create these curves. Table 3 also highlights the preponderance of detecting assays with low signal intensity. We note that the range of CT values appeared greater for infants than mothers, with twice as many with CT results below 35 (15 vs 8, RR 0.54 95% CI 0.2–1.3). Impact of infant vaccinations During our study, infants received routine whole-cell pertussis (wP) vaccinations according to the Zambian schedule at approximately 6, 10, and 14 weeks of age (see also Gunning et al., 2020). In Figure 5, we explore the impact of prior vaccination (i.e., number of doses administered at least 14 days prior to NP sample collection, Figure 5A) on detecting assays (Figure 5B). Here we see a gradual increase in the percent of infant assays that are detecting with increasing infant age, though no such pattern is evident in mothers. We interpret this increase in detections as cumulative ongoing exposure to pertussis in infants in the early weeks of life that achieves an steady state at ~age 8–10 weeks. While it is tempting to ascribe the flattening of this prevalence curve as possible evidence for a vaccine effect, we find no statistical evidence of an effect of prior vaccine dose beyond the (correlated) effect of infant age (Figure 5B). We also note that the steady state of approximately 10% detecting assays reached by infants at age 8–10 weeks approximately equals that of mothers. Critically, we note that the ideal study to identify any such interaction between prior vaccine dose and pertussis detection would be a randomized controlled trial and that, in this observational study, our data leave this question largely unanswered. Figure 5 Download asset Open asset IS481 detections by infant age, showing wP vaccination schedule. (A) number of infant NP samples per week. Shading shows the number of wP doses received at least 14 days prior to sample collection. With rare exceptions, each infant sample is accompanied by a corresponding mother’s sample. In most cases, the third wP dose was administered on the final study visit. (B) percent of NP samples with detectable IS481 over time with 95% CI (shading), estimated from generalized additive models (one each for mothers and infants). Infant age was a significant predictor of percent detection in infants only, while prior wP dose had no observable impact on percent detection in either infants or mothers. Transitions of qPCR signals over time We next explore the time-course of IS481 assays within individual subjects. If qPCR signals track the course of pertussis infection then, accepting the presence of random variation due to NP sample collection and handling and/or qPCR testing processes, we would nonetheless anticipate that adjacent samples would be more similar than dissimilar. For example, if a subject’s first NP sample had CT = 44 (e.g., captured early in the infection process) then we would expect the next NP sample collected from this subject to be more similar (e.g., CT = 42) than different (e.g., CT <35.). Likewise, we expect fewer transitions from CT <40 to N.D. than from CT <40 to CT = 42. To explore this hypothesis, we conducted an analysis of pairwise transitions within individuals over time. In Figure 6, we summarize the relative frequency of transitions between qPCR signal intensity across adjacent NP samples (separated by no more than 25 days), where color shows the departure from expected frequency (assuming independence). Consistent with our hypothesis, we find that pairwise transitions tend to be cluster, with orderly transitions over time. In particular, transitions from detecting to detecting are much more common than expected by chance alone (red, lower left), while transitions from detecting to non-detecting are much less common (blue, right column) than expected. These results again demonstrate that full-range CT values contain epidemiologically relevant information consistent with an underlying biologic process. Figure 6 Download asset Open asset Transition frequency between IS481 CT strata over adjacent pairs of assays (within subjects) for infants (left) and mothers (right). Assay pairs separated by more than 25 days are omitted. N shows total transitions from each CT stratum (row); text shows percent of row total (N) within each cell. Assays were bootstrap resampled to generate a null distribution (1000 draws). Color shows standardized residuals: the difference between observed and expected frequency divided by the standard error of the difference. Transitions from detecting to detecting are more common than expected by chance alone (red), while transitions from detecting to non-detecting are much less frequent than expected (blue). See Table 3 for marginal frequencies in each CT stratum. Quantifying evidence for pertussis infection Our next analysis combines the contextual information provided by repeated sampling with that of full-range IS481 CT values to quantify the evidence for pertussis infection within individuals. As before, we focus on the 1320 mother/infant pairs where four or more NP samples (and associated IS481 assays) were available for each subject (see also Figure 1B). We first summarize CT values across the study: we compute the reverse cumulative distribution (RCD) plots for CT values for mothers and infants separately (Figure 7A). We then use these RCDs to compute, for each subject, a summary statistic that we term the 'evidence for infection' (EFI): one minus the geometric mean RCD probability. Here, EFI=0 indicates no evidence (no detecting assays), while an EFI approaching 1 indicates very strong evidence arising from more detecting assays and/or stronger signals. We note that by averaging across time EFI provides no information about when infection occurred within the study. In Figure 7B, we show the distribution of EFI in mothers and infants stratified by the number of detecting assays. Under the premise that many false positives would be highly unlikely regardless of signal intensity, we categorize individuals with three or more detecting assays as having strong EFI, as well as other individual within this EFI range (dotted line, EFI≥0.52). Individuals with intermediate evidence (0<EFI<0.52) are categorized as having weak EFI. Figure 7 with 1 supplement see all Download asset Open asset Quantifying evidence for pertussis infection, and concordance of evidence within mother/infant pairs. (A) Reverse cumulative distribution (RCD) curves of IS481 CT values for mothers and infants. (B) Boxplot summarizing evidence for infection (EFI), stratified by number of detecting assays per subject (x-axis). For each subject, EFI equals one minus the geometric mean RCD proportions (as in A). In general, EFI increases with lower CT values (A) and more detecting assays. The dashed line delineates strong evidence (defined to include all subjects with ≥3 detecting assays, 0.52 ≤ EFI < 1) from weak evidence (0 < EFI < 0.52); dotted line delineates no evidence (EFI = 0). (C) EFI in mother/infant pairs. Dotted and dashed lines as in B for mothers (vertical) and infants (horizontal). (D) Association of EFI strength (from C) between mothers and infants, showing very strong concordance (red) and rare discordance (blue) within pairs, particularly for pairs exhibiting strong EFI. Bar widths are proportional to expected counts; bar height and color show Pearson residuals (scaled difference between observed and expected counts). p-Value and residuals are relative to independent association. See also Figure 7—figure supplement 1. Concordance of evidence within mother/infant pairs Multiple prior studies have reported that mothers and close family contacts of infected infants are very likely to also be infected (Kara et al., 2017; Fedele et al., 2017; Skoff et al., 2015), as consistent with our results in Figure 2. Here we use EFI to assess concordance of infection status within mother/infant pairs across the study. In Figure 7C, we show the intersection of EFI scores in each mother/infant pair as a single point. We use dotted and dashed lines (EFI > 0 and EFI > 0.52, respectively) to delineate possible EFI combinations for each mother/infant pair, for example mother-weak/infant-none or mother-strong/infant-strong. Figure 7D highlights the strong association of EFI category within mother/infant pairs. This association plot shows the frequency of concordance relative to expectation (assuming independent assortment), plotted as Pearson residuals. We find that when infants have no EFI, the corresponding mothers’ EFI is also likely to be absent. Conversely, when infants display strong EFI, evidence in mothers also tends to be strong. We also repeat this analysis by varying the threshold defining a strong EFI score (using either two and four detecting assays, respectively), and find consistent results throughout (Figure 7—figure supplement 1). While this analysis does not provide evidence of contemporaneous infection within pairs, these results offer strong evidence of transmission within the mother/infant pair. Concordance of evidence with symptoms We expect a positive correlation between observed CT values and bacterial burden, and between bacterial burden and the presence and intensity of symptoms. Indeed, such a relationship has been shown for Streptococcus pneumoniae, where NP carriage density was much higher in children with pneumococcal pneumonia compared with asymptomatic carriers (Piralam et al., 2020; Deloria Knoll et al., 2017). As defined, our EFI uses each subject’s full set of NP samples to provide an aggregate measure of the evidence for pertussis infection in that subject, and incorporates information regarding both the number of detecting assays and the CT values for each result. With this in mind, we tested whether EFI category was associated with cough and/or coryza (minimal symptoms), or additional pertussis symptoms (moderate to severe symptoms). In Table 4, we tabulate the frequency of EFI category stratified by symptoms for mothers and infan" @default.
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• W3167454839 title "Author response: Asymptomatic Bordetella pertussis infections in a longitudinal cohort of young African infants and their mothers" @default.
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