Nevin Manimala Statistics

Diagnostic Stewardship of Endotracheal Aspirate Cultures in a PICU

Pediatrics. 2021 Apr 7:e20201634. doi: 10.1542/peds.2020-1634. Online ahead of print.


BACKGROUND: Clinicians commonly obtain endotracheal aspirate cultures (EACs) in the evaluation of suspected ventilator-associated infections. However, bacterial growth in EACs does not distinguish bacterial colonization from infection and may lead to overtreatment with antibiotics. We describe the development and impact of a clinical decision support algorithm to standardize the use of EACs from ventilated PICU patients.

METHODS: We monitored EAC use using a statistical process control chart. We compared the rate of EACs using Poisson regression and a quasi-experimental interrupted time series model and assessed clinical outcomes 1 year before and after introduction of the algorithm.

RESULTS: In the preintervention year, there were 557 EACs over 5092 ventilator days; after introduction of the algorithm, there were 234 EACs over 3654 ventilator days (an incident rate of 10.9 vs 6.5 per 100 ventilator days). There was a 41% decrease in the monthly rate of EACs (incidence rate ratio [IRR]: 0.59; 95% confidence interval [CI] 0.51-0.67; P < .001). The interrupted time series model revealed a preexisting 2% decline in the monthly culture rate (IRR: 0.98; 95% CI 0.97-1.0; P = .01), immediate 44% drop (IRR: 0.56; 95% CI 0.45-0.70; P = .02), and stable rate in the postintervention year (IRR: 1.03; 95% CI 0.99-1.07; P = .09). In-hospital mortality, hospital length of stay, 7-day readmissions, and All Patients Refined Diagnosis Related Group severity and mortality scores were stable. The estimated direct cost savings was $26 000 per year.

CONCLUSIONS: A clinical decision support algorithm standardizing EAC obtainment from ventilated PICU patients was associated with a sustained decline in the rate of EACs, without changes in mortality, readmissions, or length of stay.

PMID:33827937 | DOI:10.1542/peds.2020-1634

Nevin Manimala Statistics

Evenness-Richness Scatter Plots: a Visual and Insightful Representation of Shannon Entropy Measurements for Ecological Community Analysis

mSphere. 2021 Apr 7;6(2):e01019-20. doi: 10.1128/mSphere.01019-20.


Shannon’s entropy is a popular alpha diversity metric because it estimates both richness and evenness in a single equation. However, since its value is dependent on both those parameters, there is theoretically an infinite number of richness/evenness value combinations translating into the same index score. By decoupling both components measured by Shannon’s entropy, two communities having identical indices can be differentiated by mapping richness and evenness coordinates on a scatter plot. In such graphs, confidence ellipses would allow testing significant differences between groups of samples. Multivariate statistical tests such as permutational multivariate analysis of variance (PERMANOVA) can be performed on distance matrices calculated from richness and evenness coordinates and detect statistically significant differences that would have remained unforeseen otherwise. Therefore, plotting richness and evenness on two-dimensional (2D) graphs gives a more thorough understanding of how alpha diversity differs between groups of samples.

PMID:33827912 | DOI:10.1128/mSphere.01019-20

Nevin Manimala Statistics

Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

J Immunother Cancer. 2021 Apr;9(4):e002421. doi: 10.1136/jitc-2021-002421.


BACKGROUND: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.

METHODS: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.

RESULTS: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.

CONCLUSION: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

PMID:33827906 | DOI:10.1136/jitc-2021-002421

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Prognostic model to identify and quantify risk factors for mortality among hospitalised patients with COVID-19 in the USA

BMJ Open. 2021 Apr 7;11(4):e047121. doi: 10.1136/bmjopen-2020-047121.


OBJECTIVES: To develop a prognostic model to identify and quantify risk factors for mortality among patients admitted to the hospital with COVID-19.

DESIGN: Retrospective cohort study. Patients were randomly assigned to either training (80%) or test (20%) sets. The training set was used to fit a multivariable logistic regression. Predictors were ranked using variable importance metrics. Models were assessed by C-indices, Brier scores and calibration plots in the test set.

SETTING: Optum de-identified COVID-19 Electronic Health Record dataset including over 700 hospitals and 7000 clinics in the USA.

PARTICIPANTS: 17 086 patients hospitalised with COVID-19 between 20 February 2020 and 5 June 2020.

MAIN OUTCOME MEASURE: All-cause mortality while hospitalised.

RESULTS: The full model that included information on demographics, comorbidities, laboratory results, and vital signs had good discrimination (C-index=0.87) and was well calibrated, with some overpredictions for the most at-risk patients. Results were similar on the training and test sets, suggesting that there was little overfitting. Age was the most important risk factor. The performance of models that included all demographics and comorbidities (C-index=0.79) was only slightly better than a model that only included age (C-index=0.76). Across the study period, predicted mortality was 1.3% for patients aged 18 years old, 8.9% for 55 years old and 28.7% for 85 years old. Predicted mortality across all ages declined over the study period from 22.4% by March to 14.0% by May.

CONCLUSION: Age was the most important predictor of all-cause mortality, although vital signs and laboratory results added considerable prognostic information, with oxygen saturation, temperature, respiratory rate, lactate dehydrogenase and white cell count being among the most important predictors. Demographic and comorbidity factors did not improve model performance appreciably. The full model had good discrimination and was reasonably well calibrated, suggesting that it may be useful for assessment of prognosis.

PMID:33827848 | DOI:10.1136/bmjopen-2020-047121

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Multi-stakeholder perspectives in defining health services quality indicators and dimensions: a concept mapping based comparison for cataract care between Singapore and The Netherlands

BMJ Open. 2021 Apr 7;11(4):e046226. doi: 10.1136/bmjopen-2020-046226.


OBJECTIVE: This study aims to advance understanding of globally valid versus country-specific quality dimensions and indicators, as perceived by relevant stakeholders. It specifically addresses patient-level indicators for cataract surgery.

DESIGN: A mixed-methods case study comparing Singapore and The Netherlands SETTING: Singapore (2017-2019) and The Netherlands (2014-2015).

PARTICIPANTS: Stakeholder representatives of cataract care in Singapore and The Netherlands.

INTERVENTION: Based on the previously identified complete set of stakeholders in The Netherlands, we identified stakeholders of cataract care in Singapore. Stakeholder representatives then established a multi-stakeholder perspective on the quality of cataract care using a concept mapping approach. This yielded a multidimensional cluster map based on multivariate statistical analyses. Consensus-based quality dimensions were subsequently defined during a plenary session. Thereafter, Singaporean dimensions were matched with dimensions obtained in The Netherlands to identify commonalities and differences.

MAIN OUTCOME MEASURE: Health-services quality dimensions of cataract care.

RESULTS: 19 Singaporean stakeholders representing patients, general practitioners, ophthalmologists, nurses, care providers, researchers and clinical auditors defined health-services quality of cataract care using the following eight dimensions: clinical outcome, patient outcomes, surgical process, surgical safety, patient experience, access, cost and standards of care. Compared with the Dutch results, 61% of the indicators were allocated to dimensions of comparable names and compositions. Considerable differences also existed in the composition of some dimensions and the importance attached to indicators.

CONCLUSIONS AND RELEVANCE: This study on cataract care in Singapore and The Netherlands shows that cataract care quality measurement instruments can share a common international core. At the same time, it emphasises the importance of taking a country-specific multi-stakeholder approach to quality definition and measurement. Complementing an international core set with country-specific measures is required to ensure that the included dimensions and indicators adequately capture the country-specific quality views.

PMID:33827846 | DOI:10.1136/bmjopen-2020-046226

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Processes of care and survival associated with treatment in specialist teenage and young adult cancer centres: results from the BRIGHTLIGHT cohort study

BMJ Open. 2021 Apr 7;11(4):e044854. doi: 10.1136/bmjopen-2020-044854.


OBJECTIVE: Survival gains in teenagers and young adults (TYA) are reported to be lower than children and adults for some cancers. Place of care is implicated, influencing access to specialist TYA professionals and research.Consequently, age-appropriate specialist cancer care is advocated for TYA although systematic investigation of associated outcomes is lacking. In England, age-appropriate care is delivered through 13 Principal Treatment Centres (TYA-PTC). BRIGHTLIGHT is the national evaluation of TYA cancer services to examine outcomes associated with differing places and levels of care. We aimed to examine the association between exposure to TYA-PTC care, survival and documentation of clinical processes of care.

DESIGN: Prospective cohort study.

SETTING: 109 National Health Service (NHS) hospitals across England.

PARTICIPANTS: 1114 TYA, aged 13-24, newly diagnosed with cancer between 2012 and 2014.

INTERVENTION: Participants were assigned a TYA-PTC category dependent on the proportion of care delivered in a TYA-PTC in the first year after diagnosis: all care in a TYA-PTC (ALL-TYA-PTC, n=270), no care in a TYA-PTC (NO-TYA-PTC, n=359), and some care in a TYA-PTC with additional care in a children’s/adult unit (SOME-TYA-PTC, n=419).

PRIMARY OUTCOME: Data were collected on documented processes indicative of age-appropriate care using clinical report forms, and survival through linkage to NHS databases.

RESULTS: TYA receiving NO-TYA-PTC care were less likely to have documentation of molecular diagnosis, be reviewed by a children’s or TYA multidisciplinary team, be assessed by supportive care services or have a fertility discussion. There was no significant difference in survival according to category of care. There was weak evidence that the association between care category and survival differed by age (p=0.08) with higher HRs for those over 19 receiving ALL or SOME-TYA-PTC compared with NO-TYA-PTC.

CONCLUSION: TYA-PTC care was associated with better documentation of clinical processes associated with age-appropriate care but not improved survival.

PMID:33827838 | DOI:10.1136/bmjopen-2020-044854

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Efficacy of parent-mediated communication-focused treatment in toddlers with autism (PACT) delivered via videoconferencing: a randomised controlled trial study protocol

BMJ Open. 2021 Apr 7;11(4):e044669. doi: 10.1136/bmjopen-2020-044669.


INTRODUCTION: Intervention in the preschool period is currently recommended for autism spectrum disorder. Therapies delivered by parents are particularly suitable for young children. Preschool Autism Communication Trial (PACT) is a parent-mediated therapy that has shown a significant and sustained impact on autism symptom reduction. However, access to such evidence-based therapies for families is limited due to autism centres located in large urban areas. Using videoconferencing to deliver PACT training to parents may improve accessibility for families living in underserved areas.

METHODS AND ANALYSIS: This single-blind randomised controlled trial, involving six sites in France, will investigate the efficacy of a telehealth, videoconferencing-based, parent-mediated PACT therapy on autism symptoms, over a 12-month period. It will compare PACT plus treatment as usual (TAU) against TAU only in a cohort of 238 toddlers (119 per group) aged 18-36 months at inclusion and living with their families more than 40 min away from the specialist centres for autism. Primary outcome will include change of overall autism score on the Autism Diagnostic Observation Scale (ADOS) at 12 months. Secondary outcomes will measure change in child skills, child functioning, impact on parents (stress, health, priorities) and implementation characteristics. Repeated measures analyses will be used to test the effect of PACT intervention on the overall ADOS module 1 score over the 12-month study period. Linear mixed models will be used with time, treatment allocation and the interaction between treatment and time as fixed effects and individual variation as random effect.

ETHICS AND DISSEMINATION: This protocol (V.5, date: 25 October 2019) is approved by the French National Review Board (reference no 2018-A02516-49). The results will be disseminated via peer-reviewed journals TRIAL REGISTRATION NUMBER: NCT04244721.

PMID:33827837 | DOI:10.1136/bmjopen-2020-044669

Nevin Manimala Statistics

Randomised controlled feasibility trial of an active communication education programme plus hearing aid provision versus hearing aid provision alone (ACE To HEAR)

BMJ Open. 2021 Apr 7;11(4):e043364. doi: 10.1136/bmjopen-2020-043364.


OBJECTIVE: To establish the acceptability and feasibility of delivering the Active Communication Education (ACE) programme to increase quality of life through improving communication and hearing aid use in the UK National Health Service.

DESIGN: Randomised controlled, open feasibility trial with embedded economic and process evaluations.

SETTING: Audiology departments in two hospitals in two UK cities.

PARTICIPANTS: Twelve hearing aid users aged 18 years or over who reported moderate or less than moderate benefit from their new hearing aid.

INTERVENTIONS: Consenting participants (along with a significant other) were to be randomised by a remote, centralised randomisation service in groups to ACE plus treatment-as-usual (intervention group) or treatment-as-usual only (control group).

PRIMARY OUTCOME MEASURES: The primary outcomes were related to feasibility: recruitment, retention, treatment adherence and acceptability to participants and fidelity of treatment delivery.

SECONDARY OUTCOME MEASURES: International Outcomes Inventory for Hearing Aids, Self-Assessment of Communication, EQ-5D-5L and Short-Form 36. Blinding of the participants and facilitator was not possible.

RESULTS: Twelve hearing aid users and six significant others consented to take part. Eight hearing aid users were randomised: four to the intervention group; and four to treatment-as-usual only. Four significant others participated alongside the randomised participants. Recruitment to the study was very low and centres only screened 466 hearing aid users over the 15-month recruitment period, compared with the approximately 3500 anticipated. Only one ACE group and one control group were formed. ACE could be delivered and appeared acceptable to participants. We were unable to robustly assess attrition and attendance rates due to the low sample size.

CONCLUSIONS: While ACE appeared acceptable to hearing aid users and feasible to deliver, it was not feasible to identify and recruit participants struggling with their hearing aids at the 3-month posthearing aid fitting point.


PMID:33827834 | DOI:10.1136/bmjopen-2020-043364

Nevin Manimala Statistics

Outcomes of out-of-hospital cardiac arrest in Beijing: a 5-year cross-sectional study

BMJ Open. 2021 Apr 7;11(4):e041917. doi: 10.1136/bmjopen-2020-041917.


OBJECTIVE: The purpose of this study was to assess the trends in outcomes of out-of-hospital cardiac arrest (OHCA) in Beijing over 5 years.

DESIGN: Cross-sectional study.

METHODS: Adult patients with OHCA of all aetiologies who were treated by the Beijing emergency medical service (EMS) between January 2013 and December 2017 were analysed. Data were collected using the Utstein Style. Cases were followed up for 1 year. Descriptive statistics were used to characterise the sample and logistic regression was performed.

RESULTS: Overall, 5016 patients with OHCA underwent attempted resuscitation by the EMS in urban areas of Beijing during the study period. Survival to hospital discharge was 1.2% in 2013 and 1.6% in 2017 (adjusted rate ratio=1.0, p for trend=0.60). Survival to admission and neurological outcome at discharge did not significantly improve from 2013 to 2017. Patient characteristics and the aetiology and location of cardiac arrest were consistent, but there was a decrease in the initial shockable rhythm (from 6.5% to 5.6%) over the 5 years. The rate of bystander cardiopulmonary resuscitation (CPR) increased steadily over the years (from 10.4% to 19.4%).

CONCLUSION: Survival after OHCA in urban areas of Beijing did not improve significantly over 5 years, with long-term survival being unchanged, although the rate of bystander CPR increased steadily, which enhanced the outcomes of patients who underwent bystander CPR.

PMID:33827829 | DOI:10.1136/bmjopen-2020-041917

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Physiotherapist-led treatment for femoroacetabular impingement syndrome (the PhysioFIRST study): a protocol for a participant and assessor-blinded randomised controlled trial

BMJ Open. 2021 Apr 7;11(4):e041742. doi: 10.1136/bmjopen-2020-041742.


INTRODUCTION: This double-blind, randomised controlled trial (RCT) aims to estimate the effect of a physiotherapist-led intervention with targeted strengthening compared with a physiotherapist-led intervention with standardised stretching, on hip-related quality of life (QOL) or perceived improvement at 6 months in people with femoroacetabular impingement (FAI) syndrome. We hypothesise that at 6 months, targeted strengthening physiotherapist-led treatment will be associated with greater improvements in hip-related QOL or greater patient-perceived global improvement when compared with standardised stretching physiotherapist-led treatment.

METHODS AND ANALYSIS: We will recruit 164 participants with FAI syndrome who will be randomised into one of the two intervention groups, both receiving one-on-one treatment with the physiotherapist over 6 months. The targeted strengthening physiotherapist-led treatment group will receive a personalised exercise therapy and education programme. The standardised stretching physiotherapist-led treatment group will receive standardised stretching and personalised education programme. Primary outcomes are change in hip-related QOL using International Hip Outcome Tool-33 and patient-perceived global improvement. Secondary outcomes include cost-effectiveness, muscle strength, range of motion, functional task performance, biomechanics, hip cartilage structure and physical activity levels. Statistical analyses will make comparisons between both treatment groups by intention to treat, with all randomised participants included in analyses, regardless of protocol adherence. Linear mixed models (with baseline value as a covariate and treatment condition as a fixed factor) will be used to evaluate the treatment effect and 95% CI at primary end-point (6 months).

ETHICS AND DISSEMINATION: The study protocol was approved (La Trobe University Human Ethics Committee (HEC17-080)) and prospectively registered with the Australian New Zealand Clinical Trials Registry. The findings of this RCT will be disseminated through peer reviewed scientific journals and conferences. Patients were involved in study development and will receive a short summary following the completion of the RCT.


PMID:33827828 | DOI:10.1136/bmjopen-2020-041742