•Currently marginal survival model fits are slow for large data with many clusters.•Bridged-survival models allow for population-average and subject-specific analyses.•Our implementation is 12x ...faster than currently available R software.•Our implementation is 2400x faster than SAS.•Marginal and conditional hazard ratios can be directly estimated.•Marginal and conditional acceleration factors can be directly estimated.
Background and objective: With the recent surge in availability of large biomedical databases mostly derived from electronic health records, the need for the development of scalable marginal survival models with faster implementation cannot be more timely. The presence of clustering renders computational complexity, especially when the number of clusters is high. Marginalizing conditional survival models can violate the proportional hazards assumption for some frailty distributions, disrupting the connection to a conditional model. While theoretical connections between proportional hazard and accelerated failure time models exist, a computational framework to produce both for either marginal or conditional perspectives is lacking. Our objective is to provide fast, scalable bridged-survival models contained in a unified framework from which the effects and standard errors for the conditional hazard ratio, the marginal hazard ratio, the conditional acceleration factor, and the marginal acceleration factor can be estimated, and related to one another in a transparent fashion. Methods We formulate a Weibull parametric frailty likelihood for clustered survival times that can directly estimate the four estimands. Under a nonlinear mixed model specification with positive stable frailties powered by Gaussian quadrature, we put forth a novel closed form of the integrated likelihood that lowered the computational threshold for fitting these models. The method is illustrated on a real dataset generated from electronic health records examining tooth-loss. Results: Our novel closed form of the integrated likelihood significantly lowered the computational threshold for fitting these models by a factor of 12 (36 compared to 3 min) for the R package parfm, and a factor of 2400 for Gaussian Quadrature (4.6 days compared to 3 min) in SAS. Moreover, each of these estimands are connected by simple relationships of the parameters and the proportional hazards assumption is preserved for the marginal model. Our framework provides a flow of analysis enabling the fit of any/all of the 4 perspective-parameterization combinations. Conclusions We see the potential usefulness of our framework of bridged parametric survival models fitted with the Static-Stirling closed form likelihood. Bridged-survival models provide insights on subject-specific and population-level survival effects when their relation is transparent. SAS and R codes, along with implementation details on a pseudo data are provided.
Abstract Malaria transmission-blocking vaccines (TBVs) are potentially helpful tools for malaria eradication. The standard membrane-feeding assay (SMFA) is considered one of the “gold standard” ...assays for TBV development. However, lack of consensus in reporting results from SMFA has made it very challenging to compare results from different studies. Two main readouts, % inhibition in mean oocyst count per mosquito (TRA) and % inhibition in prevalence of infected mosquitoes (TBA), have been used widely. In this study, we statistically modeled the oocyst data in SMFA using data from 105 independent feeding experiments including 9804 mosquitoes. The model was validated using an independent data set that included 10,790 mosquitoes from 110 feeding studies. The model delineates a relationship between TRA, the mean oocyst count in the control mosquitoes ( mo -contl), and TBA. While TRA was independent from mo -contl, TBA values changed depending on mo -contl. Regardless of monoclonal or polyclonal antibodies tested, there were strong concordances between observed TBA and predicted TBA based on the model using mo -contl and observed TRA. Simulations showed that SMFA with lower true control means had increased uncertainty in TRA estimates. The strong linkage between TBA, TRA and mo -contl inspired creation of a standardized TBA, a model-based TBA standardized to a target control mean, which allows comparison across multiple feeds regardless of mo -contl. This is the first study showing that the observed TBA can be reasonably predicted by mo -contl and the TRA of the test antibody using independent experimental data. This study indicates that TRA should be used to compare results from multiple feeds with different levels of mo -contl. If a measure of TBA is desired, it is better to report standardized TBA rather than observed TBA. These recommendations support rational comparisons of results from different studies, thus benefiting future TBV development.
Bloodstream infections (BSIs) acquired in the ICU represent a detrimental yet potentially preventable condition. We determined the prevalence of BSI acquired in the ICU (ICU-onset BSI), pathogen ...profile, and associated risk factors.
Retrospective cohort study.
Eighty-five U.S. hospitals in the Cerner Healthfacts Database.
Adult hospitalizations between January 2009 and December 2015 including a (≥ 3 d) ICU stay.
Prevalence of ICU-onset BSI (between ICU Day 3 and ICU discharge) and associated pathogen and antibiotic resistance distributions were compared with BSI present on (ICU) admission (ICU-BSI POA ); and BSI present on ICU admission day or Day 2. Cox models identified risk factors for ICU-onset BSI among host, care setting, and treatment-related factors. Among 150,948 ICU patients, 5,600 (3.7%) had ICU-BSI POA and 1,306 (0.9%) had ICU-onset BSI. Of those with ICU-BSI POA , 4,359 (77.8%) were admitted to ICU at hospital admission day. Patients with ICU-onset BSI (vs ICU-BSI POA ) displayed higher crude mortality of 37.9% (vs 20.4%) ( p < 0.001) and longer median (interquartile range) length of stay of 13 days (8-23 d) (vs 5 d 3-8 d) ( p < 0.001) (considering all ICU stay). Compared with ICU-BSI POA , ICU-onset BSI displayed more Pseudomonas , Acinetobacter , Enterococcus, Candida , and Coagulase-negative Staphylococcus species, and more methicillin-resistant staphylococci, vancomycin-resistant enterococci, ceftriaxone-resistant Enterobacter , and carbapenem-resistant Enterobacterales and Acinetobacter species, respectively. Being younger, male, Black, Hispanic, having greater comorbidity burden, sepsis, trauma, acute pulmonary or gastrointestinal presentations, and pre-ICU exposure to antibacterial and antifungal agents was associated with greater ICU-onset BSI risk after adjusted analysis. Mixed ICUs (vs medical or surgical ICUs) and urban and small/medium rural hospitals were also associated with greater ICU-onset BSI risk. The associated risk of acquiring ICU-onset BSI manifested with any duration of mechanical ventilation and 7 days after insertion of central venous or arterial catheters.
ICU-onset BSI is a serious condition that displays a unique pathogen and resistance profile compared with ICU-BSI POA . Further scrutiny of modifiable risk factors for ICU-onset BSI may inform control strategies.
In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. ...Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively referred to as 'LS') into the genes encoding the crystallizable fragment domains of the highly potent HIV-specific 3BNC117 and 10-1074 bNAbs to increase their half-lives and evaluated their efficacy in blocking infection following repeated low-dose mucosal challenges of rhesus macaques (Macaca mulatta) with the tier 2 SHIV
. A single intravenous infusion of 10-1074-LS monoclonal antibodies markedly delayed virus acquisition for 18 to 37 weeks (median, 27 weeks), whereas the protective effect of the 3BNC117-LS bNAb was more modest (provided protection for 11-23 weeks; median, 17 weeks). Serum concentrations of the 10-1074-LS monoclonal antibody gradually declined and became undetectable in all recipients between weeks 26 and 41, whereas the 3BNC117-LS bNAb exhibited a shorter half-life. To model immunoprophylaxis against genetically diverse and/or neutralization-resistant HIV-1 strains, a combination of the 3BNC117-LS plus 10-1074-LS monoclonal antibodies was injected into macaques via the more clinically relevant subcutaneous route. Even though the administered mixture contained an amount of each bNAb that was nearly threefold less than the quantity of the single monoclonal antibody in the intravenous injections, the monoclonal antibody combination still protected macaques for a median of 20 weeks. The extended period of protection observed in macaques for the 3BNC117-LS plus 10-1074-LS combination could translate into an effective semiannual or annual immunoprophylaxis regimen for preventing HIV-1 infections in humans.
Background. Shock frequently complicates necrotizing fasciitis (NF) caused by group A Streptococcus (GAS) or Staphylococcus aureus. Intravenous immunoglobulin (IVIG) is sometimes administered for ...presumptive toxic shock syndrome (TSS), but its frequency of use and efficacy are unclear. Methods. Adult patients with NF and vasopressor-dependent shock undergoing surgical debridement from 2010 to 2014 were identified at 130 US hospitals. IVIG cases were propensity-matched and risk-adjusted. The primary outcome was in-hospital mortality and the secondary outcome was median length of stay (LOS). Results. Of 4127 cases of debrided NF with shock at 121 centers, only 164 patients (4%) at 61 centers received IVIG. IVIG subjects were younger with lower comorbidity indices, but higher illness severity. Clindamycin and vasopressor intensity were higher among IVIG cases, as was coding for TSS and GAS. In-hospital mortality did not differ between matched IVIG and non-IVIG groups (crude mortality, 27.3% vs 23.6%; adjusted odds ratio, 1.00 95% confidence interval, .55–1.83; P = .99). Early IVIG (≤2 days) did not alter this effect (P = .99). Among patients coded for TSS, GAS, and/or S. aureus, IVIG use was still unusual (59/868 6.8%) and lacked benefit (P = .63). Median LOS was similar between IVIG and non-IVIG groups (26 13–49 vs 26 11–43; P = .84). Positive predictive values for identifying true NF and debridement among IVIG cases using our algorithms were 97% and 89%, respectively, based on records review at 4 hospitals. Conclusions. Adjunctive IVIG was administered infrequently in NF with shock and had no apparent impact on mortality or hospital LOS beyond that achieved with debridement and antibiotics.
The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize ...the patient in future antibiotic development and potential market entry rewards.
To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics).
Retrospective cohort.
619 U.S. hospitals.
Adult inpatients.
Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections.
Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 2631 episodes of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and
complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage.
Residual confounding.
Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization.
U.S. Food and Drug Administration; NIH Intramural Research Program.
Transmission blocking vaccines for malaria are not designed to directly protect vaccinated people from malaria disease, but to reduce the probability of infecting other people by interfering with the ...growth of the malaria parasite in mosquitoes. Standard membrane-feeding assays compare the growth of parasites in mosquitoes from a test sample (using antibodies from a vaccinated person) compared to a control sample. There is debate about whether to estimate the transmission reducing activity (TRA) which compares the mean number of parasites between test and control samples, or transmission blocking activity (TBA) which compares the proportion of infected mosquitoes. TBA appears biologically more important since each mosquito with any parasites is potentially infective; however, TBA is less reproducible and may be an overly strict criterion for screening vaccine candidates. Through a statistical model, we show that the TBA estimand depends on μ
c
, the mean number of parasites in the control mosquitoes, a parameter not easily experimentally controlled. We develop a standardized TBA estimator based on the model and a given target value for μ
c
which has better mean squared error than alternative methods. We discuss types of statistical inference needed for using these assays for vaccine development. Supplementary materials for this article are available online.
Sleep continuity is commonly assessed with polysomnographic measures such as sleep efficiency, sleep stage percentages, and the arousal index. The aim of this study was to examine whether the ...transition rate between different sleep stages could be used as an index of sleep continuity to predict self-reported sleep quality independent of other commonly used metrics.
Analysis of the Sleep Heart Health Study polysomnographic data.
A community cohort.
Sleep recordings on 5,684 participants were deemed to be of sufficient quality to allow visual scoring of NREM and REM sleep. For each participant, we tabulated the frequency of transitions between wake, NREM sleep, and REM sleep. An overall transition rate was determined as the number of all transitions per hour sleep. Stage-specific transition rates between wake, NREM sleep, and REM sleep were also determined. A 5-point Likert scale was used to assess the subjective experience of restless and light sleep the morning after the sleep study. Multivariable regression models showed that a high overall sleep stage transition rate was associated with restless and light sleep independent of several covariates including total sleep time, percentages of sleep stages, wake time after sleep onset, and the arousal index. Compared to the lowest quartile of the overall transition rate (<7.76 events/h), the odds ratios for restless sleep were 1.27, 1.42, and 1.38, for the second (7.77-10.10 events/h), third (10.11-13.34 events/h), and fourth (≥13.35 events/h) quartiles, respectively. Analysis of stage-specific transition rates showed that transitions between wake and NREM sleep were also independently associated with restless and light sleep.
Assessing overall and stage-specific transition rates provides a complementary approach for assessing sleep continuity. Incorporating such measures, along with conventional metrics, could yield useful insights into the significance of sleep continuity for clinical outcomes.
Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine ...Pfs25-EPA/Alhydrogel in malaria-naive US adults. Here, we compared these vaccines in malaria-experienced Malians.
We did a pilot safety study then double-blind, block-randomised, comparator-controlled main-phase trial in malaria-intense Bancoumana, Mali. 18–50-year-old healthy non-pregnant, non-breastfeeding consenting adult residents were randomly assigned (1:1:1:1) to receive four doses at months 0, 1, 4·5, and 16·5 of either 47 μg Pfs25, 40 μg Pfs230D1 or comparator (Twinrix or Menactra)—all co-administered with normal saline for blinding—or 47 μg Pfs25 plus 40 μg Pfs230D1 co-administered. We documented safety and tolerability (primary endpoint in the as-treated populations) and immunogenicity (secondary endpoint in the as-treated populations: ELISA, standard-membrane-feeding assay, and mosquito direct skin feed assay). This trial is registered at ClinicalTrials.gov, NCT02334462.
Between March 19, and June 2, 2015, we screened 471 individuals. Of 225 enrolled for the pilot and main cohorts, we randomly assigned 25 participants to pilot safety cohort groups of five (20%) to receive a two-dose series of Pfs25-EPA/Alhydrogel (16 μg), Pfs230D1-EPA/Alhydrogel (15 μg) or comparator, followed by Pfs25-EPA/Alhydrogel (16 μg) plus Pfs230D1-EPA/Alhydrogel (15 μg) or comparator plus saline. For the main cohort, we enrolled 200 participants between May 11 and June 2, 2015, to receive a four-dose series of 47 μg Pfs25-EPA/Alhydrogel plus saline (n=50 25%; Pfs25), 40 μg Pfs230D1-EPA/Alhydrogel plus saline (n=49 25%; Pfs230D1), 47 μg Pfs25-EPA/Alhydrogel plus 40 μg Pfs230D1-EPA/Alhydrogel (n=50 25%; Pfs25 plus Pfs230D1), or comparator (Twinrix or Menactra) plus saline (n=51 25%). Vaccinations were well tolerated in the pilot safety and main phases. Most vaccinees became seropositive after two Pfs230D1 or three Pfs25 doses; peak titres increased with each dose thereafter (Pfs230D1 geometric mean: 77·8 95% CI 56·9–106·3, 146·4 108·3–198·0, and 410·2 301·6–558·0; Pfs25 geometric mean 177·7 130·3–242·4 and 315·7 209·9–474·6). Functional activity (mean peak transmission-reducing activity) appeared for Pfs230D1 (74·5% 66·6–82·5) and Pfs25 plus Pfs230D1 (68·6% 57·3–79·8), after the third dose and after the fourth dose (88·9% 81·7–96·2 for Pfs230D1 and 85·0% 78·4–91·5 Pfs25 plus Pfs230D1) but not for Pfs25 (58·2% 49·1–67·3 after the third dose and 58·2% 48·5–67·9 after the fourth dose). Pfs230D1 transmission-reducing activity (73·7% 64·1–83·3) persisted 10 weeks after the fourth dose. Transmission-reducing activity of 80% was estimated at 1659 ELISA units for Pfs25, 218 for Pfs230D1, and 223 for Pfs230D1 plus Pfs25. After 3850 direct skin feed assays, 35 participants (12 Pfs25, eight Pfs230D1, five Pfs25 plus Pfs230D1, and ten comparator) had transmitted parasites at least once. The proportion of positive assays in vaccine groups (Pfs25 33 3% of 982 –0·013 to 0·014, Pfs230D1 22 2% of 954 –0·005 to 0·027, and combination 11 1% of 940 –0·024 to 0·002) did not differ from that of the comparator (22 2% of 974), nor did Pfs230D1 and combination groups differ (–0·024 to 0·001).
Pfs230D1 but not Pfs25 vaccine induces durable serum functional activity in Malian adults. Direct skin feed assays detect parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness.
Intramural Research Program of the National Institute of Allergy and Infectious Diseases and US National Institutes of Health.
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