The Fragility Index has been introduced as a complement to the P‐value to summarize the statistical strength of evidence for a trial's result. The Fragility Index (FI) is defined in trials with two ...equal treatment group sizes, with a dichotomous or time‐to‐event outcome, and is calculated as the minimum number of conversions from nonevent to event in the treatment group needed to shift the P‐value from Fisher's exact test over the .05 threshold. As the index lacks a well‐defined probability motivation, its interpretation is challenging for consumers. We clarify what the FI may be capturing by separately considering two scenarios: (a) what the FI is capturing mathematically when the probability model is correct and (b) how well the FI captures violations of probability model assumptions. By calculating the posterior probability of a treatment effect, we show that when the probability model is correct, the FI inappropriately penalizes small trials for using fewer events than larger trials to achieve the same significance level. The analysis shows that for experiments conducted without bias, the FI promotes an incorrect intuition of probability, which has not been noted elsewhere and must be dispelled. We illustrate shortcomings of the FI's ability to quantify departures from model assumptions and contextualize the FI concept within current debate around the null hypothesis significance testing paradigm. Altogether, the FI creates more confusion than it resolves and does not promote statistical thinking. We recommend against its use. Instead, sensitivity analyses are recommended to quantify and communicate robustness of trial results.
“Fragility” is defined by the fragility index (FI), calculated as the minimum number of swaps from non-event to event in the treatment arm needed to undo the significance of a trial, with smaller FI ...values representing higher fragility. The smaller trial has a larger effect size, and its confidence interval is farther from the null value of zero. Treatment Sample size Number of events in treated arm Number of events in control arm Relative risk reduction(1-RR) 95% CI P-value Fragility Index A 40 5 14 0.64 0.20, 0.84 0.01 2 B 200 36 55 0.35 0.10, 0.52 0.01 5 Table 1 Two trials with different sample sizes, equal P-values, and different FI values Coin Sample size (number of tosses) Fraction of heads Percent heads 95% CI P-value Fragility Index A 10 10/10 100% 72%, 100% 0.002 2 B 100 66/100 66% 56%, 75% 0.002 6 Table 2 Two coin-toss experiments with different sample sizes, equal P-values, and different FI values
Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness ...of control efforts. Most analyses of contact patterns to date have focused on high-income settings.
Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys, we explored how contact characteristics (number, location, duration, and whether physical) vary across income settings.
Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, with low-income settings characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income strata on the frequency, duration, and type of contacts individuals made.
These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens and the effectiveness of different non-pharmaceutical interventions.
This work is primarily being funded by joint Centre funding from the UK Medical Research Council and DFID (MR/R015600/1).
We present the first analysis of face-to-face contact network data from Niakhar, Senegal. Participants in a cluster-randomized influenza vaccine trial were interviewed about their contact patterns ...when they reported symptoms during their weekly household surveillance visit. We employ a negative binomial model to estimate effects of covariates on contact degree. We estimate the mean contact degree for asymptomatic Niakhar residents to be 16.5 (95% C.I. 14.3, 18.7) in the morning and 14.8 in the afternoon (95% C.I. 12.7, 16.9). We estimate that symptomatic people make 10% fewer contacts than asymptomatic people (95% C.I. 5%, 16%; p = 0.006), and those aged 0-5 make 33% fewer contacts than adults (95% C.I. 29%, 37%; p < 0.001). By explicitly modelling the partial rounding pattern observed in our data, we make inference for both the underlying (true) distribution of contacts as well as for the reported distribution. We created an estimator for homophily by compound (household) membership and estimate that 48% of contacts by symptomatic people are made to their own compound members in the morning (95% CI, 45%, 52%) and 60% in the afternoon/evening (95% CI, 56%, 64%). We did not find a significant effect of symptom status on compound homophily. We compare our findings to those from other countries and make design recommendations for future surveys.
Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion ...reduction in an endpoint due to vaccination and is often calculated as VE
= 1-hazard ratio or VE
= 1-risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VE
, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VE
, the vaccine-induced proportion reduction in mean number of infecting clones per exposure.
Power of VE
and VE
was compared to that of VE
and VE
by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion.
In the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VE
compared to VE
for data like those from RTS,S, but VE
is less powerful than VE
for trials in which the number of clones at first infection is not reduced. VE
was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VE
. The primaquine VE
estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VE
from improving power.
The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis.
NCT00866619, NCT02663700, NCT02143934.
The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naïve adults. Preclinical studies show that T cell-mediated ...immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5-12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya ( NCT02687373 ). Groups of 84 infants each received 4.5 × 10
, 9.0 × 10
or 1.8 × 10
PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 10
dose group = -6.5%, P = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2
Vγ9
T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2
Vγ9
T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group.
A highly effective malaria vaccine remains elusive despite decades of research.
sporozoite vaccine (PfSPZ Vaccine), a metabolically active, nonreplicating, whole parasite vaccine demonstrated safety ...and vaccine efficacy (VE) against endemic
for 6 months in Malian adults receiving a five-dose regimen. Safety, immunogenicity, and VE of a three-dose regimen were assessed in adults in Balonghin, Burkina Faso in a two-component study: an open-label dose escalation trial with 32 participants followed by a double-blind, randomized, placebo-controlled trial (RCT) with 80 participants randomized to receive three doses of 2.7 × 10
PfSPZ (
= 39) or normal saline (
= 41) just before malaria season. To clear parasitemia, artesunate monotherapy was administered before first and last vaccinations. Thick blood smear microscopy was performed on samples collected during illness and every 4 weeks for 72 weeks after last vaccinations, including two 6-month malaria transmission seasons. Safety outcomes were assessed in all 80 participants who received at least one dose and VE for 79 participants who received three vaccinations. Myalgia was the only symptom that differed between groups. VE (1 - risk ratio; primary VE endpoint) was 38% at 6 months (
= 0.017) and 15% at 18 months (0.078). VE (1 - hazard ratio) was 48% and 46% at 6 and 18 months (
= 0.061 and 0.018). Two weeks after the last dose, antibodies to
circumsporozoite protein and PfSPZ were higher in protected versus unprotected vaccinees. A three-dose regimen of PfSPZ Vaccine demonstrated safety and efficacy against malaria infection in malaria-experienced adults.
The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low ...absolute lymphocyte count ALC, high absolute neutrophil count ANC, and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib.
To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile.
Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579).
Sixty-seven trial sites in 8 countries.
Adults hospitalized with COVID-19 (
= 999; 85% U.S. participants).
Baricitinib+remdesivir versus placebo+remdesivir.
Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories.
In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio HR, 0.38 95% CI, 0.16 to 0.86;
= 0.020), decreased progression to IMV or death (HR, 0.57 CI, 0.35 to 0.93;
= 0.024), and improved recovery rate (HR, 1.53 CI, 1.16 to 2.02;
= 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile.
Secondary analysis of data collected before circulation of current SARS-CoV-2 variants.
The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19.
National Institute of Allergy and Infectious Diseases.
Sulfadoxine-pyrimethamine resistance threatens efficacy of intermittent preventive treatment of malaria during pregnancy, and alternative regimens need to be identified. With the return of ...chloroquine efficacy in southern Africa, we postulated that chloroquine either as an intermittent therapy or as weekly chemoprophylaxis would be more efficacious than intermittent sulfadoxine-pyrimethamine for prevention of malaria in pregnancy and associated maternal and newborn adverse outcomes.
We did an open-label, single-centre, randomised controlled trial at Ndirande Health Centre, Blantyre, in southern Malawi. We enrolled pregnant women (first or second pregnancy) at 20–28 weeks' gestation who were HIV negative. Participants were randomly assigned in a 1:1:1 ratio using a computer-generated list to either intermittent sulfadoxine-pyrimethamine (two doses of 1500 mg sulfadoxine and 75 mg pyrimethamine, 4 weeks apart), intermittent chloroquine (two doses of 600 mg on day 1, 600 mg on day 2, and 300 mg on day 3), or chloroquine prophylaxis (600 mg on day 1 then 300 mg every week). The primary endpoint was placental malaria in the modified intent-to-treat population, which consisted of participants who contributed placental histopathology data at birth. Secondary outcomes included clinical malaria, maternal anaemia, low birthweight, and safety. This trial is registered with ClinicalTrials.gov, number NCT01443130.
Between February, 2012, and May, 2014, we enrolled and randomly allocated 900 women, of whom 765 contributed histopathological data and were included in the primary analysis. 108 (14%) women had placental malaria, which was lower than the anticipated prevalence of placental malaria infection. Protection from placental malaria was not improved by chloroquine as either prophylaxis (30 12% of 259 had positive histopathology; relative risk RR 0·75, 95% CI 0·48–1·17) or intermittent therapy (39 15% of 253; RR 1·00, 0·67–1·50) compared with intermittent sulfadoxine-pyrimethamine (39 15% of 253). In protocol-specified analyses adjusted for maternal age, gestational age at enrolment, bednet use the night before enrolment, anaemia at enrolment, and malaria infection at enrolment, women taking chloroquine as prophylaxis had 34% lower placental infections than did those allocated intermittent sulfadoxine-pyrimethamine (RR 0·66, 95% CI 0·46–0·95). Clinical malaria was reported in nine women assigned intermittent sulfadoxine-pyrimethamine, four allocated intermittent chloroquine (p=0·26), and two allocated chloroquine prophylaxis (p=0·063). Maternal anaemia was noted in five women assigned intermittent sulfadoxine-pyrimethamine, 15 allocated intermittent chloroquine (p=0·038), and six assigned chloroquine prophylaxis (p>0·99). Low birthweight was recorded for 31 babies born to women allocated intermittent sulfadoxine-pyrimethamine, 29 assigned intermittent chloroquine (p=0·78), and 41 allocated chloroquine prophylaxis (p=0·28). Four women assigned intermittent sulfadoxine-pyrimethamine had adverse events possibly related to study product compared with 94 women allocated intermittent chloroquine (p<0·0001) and 26 allocated chloroquine prophylaxis (p<0·0001). Three women had severe or life-threatening adverse events related to study product, of whom all were assigned intermittent chloroquine (p=0·25).
Chloroquine administered as intermittent therapy did not provide better protection from malaria and related adverse effects compared with intermittent sulfadoxine-pyrimethamine in a setting of high resistance to sulfadoxine-pyrimethamine. Chloroquine chemoprophylaxis might provide benefit in protecting against malaria during pregnancy, but studies with larger sample sizes are needed to confirm these results.
US National Institutes of Health.
The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time "liquid biopsy" for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. ...We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.
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