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Nevin Manimala Statistics

Haplotype-aware inference of human chromosome abnormalities

Proc Natl Acad Sci U S A. 2021 Nov 16;118(46):e2109307118. doi: 10.1073/pnas.2109307118.

ABSTRACT

Extra or missing chromosomes-a phenomenon termed aneuploidy-frequently arise during human meiosis and embryonic mitosis and are the leading cause of pregnancy loss, including in the context of in vitro fertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing for aneuploidy (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy, may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05 × and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF.

PMID:34772814 | DOI:10.1073/pnas.2109307118

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Nevin Manimala Statistics

Minimal surfaces unveiled from the statistics of turbulent circulation fluctuations

Proc Natl Acad Sci U S A. 2021 Nov 16;118(46):e2117968118. doi: 10.1073/pnas.2117968118.

NO ABSTRACT

PMID:34772821 | DOI:10.1073/pnas.2117968118

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Nevin Manimala Statistics

Taylor’s law of fluctuation scaling for semivariances and higher moments of heavy-tailed data

Proc Natl Acad Sci U S A. 2021 Nov 16;118(46):e2108031118. doi: 10.1073/pnas.2108031118.

ABSTRACT

We generalize Taylor’s law for the variance of light-tailed distributions to many sample statistics of heavy-tailed distributions with tail index α in (0, 1), which have infinite mean. We show that, as the sample size increases, the sample upper and lower semivariances, the sample higher moments, the skewness, and the kurtosis of a random sample from such a law increase asymptotically in direct proportion to a power of the sample mean. Specifically, the lower sample semivariance asymptotically scales in proportion to the sample mean raised to the power 2, while the upper sample semivariance asymptotically scales in proportion to the sample mean raised to the power [Formula: see text] The local upper sample semivariance (counting only observations that exceed the sample mean) asymptotically scales in proportion to the sample mean raised to the power [Formula: see text] These and additional scaling laws characterize the asymptotic behavior of commonly used measures of the risk-adjusted performance of investments, such as the Sortino ratio, the Sharpe ratio, the Omega index, the upside potential ratio, and the Farinelli-Tibiletti ratio, when returns follow a heavy-tailed nonnegative distribution. Such power-law scaling relationships are known in ecology as Taylor’s law and in physics as fluctuation scaling. We find the asymptotic distribution and moments of the number of observations exceeding the sample mean. We propose estimators of α based on these scaling laws and the number of observations exceeding the sample mean and compare these estimators with some prior estimators of α.

PMID:34772810 | DOI:10.1073/pnas.2108031118

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Nevin Manimala Statistics

68Ga-PSMA PET/CT for response assessment and outcome prediction in metastatic prostate cancer patients treated with taxane-based chemotherapy

J Nucl Med. 2021 Nov 12:jnumed.121.263006. doi: 10.2967/jnumed.121.263006. Online ahead of print.

ABSTRACT

Aim: We aimed to evaluate the role of Positron Emission Tomography (PET) targeting the Prostate-Specific Membrane Antigen (PSMA) for response assessment in metastatic prostate cancer (mPCa) patients treated with taxane-based chemotherapy (docetaxel or cabazitaxel) and its predictive value on patient outcome. Methods: We retrospectively evaluated 37 patients with metastatic hormone-sensitive or castration-resistant prostate cancer (mHSPC or mCRPC) who underwent 68Ga-PSMA-11 PET/CT at baseline and after the last cycle of taxane-based chemotherapy (docetaxel or cabazitaxel) without treatment modification between scans. Biochemical response (BR) was defined as an undetectable or decreased prostate-specific antigen (PSA) by ≥50% compared to baseline. Association between BR and different PET parameters were tested. A cut-off of ≥30% change in PSMA total tumor volume (PSMA-TV) was used to define PSMA responders (PSMA-R) vs PSMA non-responders (PSMA-NR). Correlation between PSMA-PET/CT response and BR was evaluated using the Phi coefficient. Association between PET-response and overall survival (OS) was performed using Cox regression and Kaplan-Meier method. Results: Our cohort was composed of 8 (22%) mHSPC and 29 (78%) mCRPC patients. Twenty-one patients received docetaxel, and 16 received cabazitaxel treatment (median: 6 cycles, interquartile (IQR):5-8). BR was found in 18/37 patients. Using PSMA-TV, PSMA-PET/CT response was concordant with BR in 35/37 patients (Phi=0.89, p<0.0001). There were 18/37 PSMA-R (6 complete response and 12 partial response) and 19/37 PSMA-NR (17 progressive disease and 2 stable disease). After a median follow-up of 23 months there was a statistically significant longer overall survival (OS) for PSMA-R compared to PSMA-NR (median OS not reached vs 12 months, respectively, HR 0.10; 95%CI: 0.03-0.39, P = 0.001) for the entire population. Among the mCRPC subgroup, differences in OS were also observed (median 22 vs 12 months respectively, HR 0.22, 95%CI: 0.06-0.82, P = 0.023) with a 12-month OS rate of 100% for PSMA-R and 52% for PSMA-NR (P = 0.011). Conclusion: This retrospective analysis suggests that 68Ga-PSMA-11 PET/CT is a promising imaging modality for assessing response to taxane-based chemotherapy in mPCa. PSMA-expression changes might be used as a predictive biomarker for OS which might help tailor individual therapy and select eligible patients for clinical trials.

PMID:34772793 | DOI:10.2967/jnumed.121.263006

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Nevin Manimala Statistics

Blood Pressure After Endovascular Thrombectomy and Outcomes in Patients With Acute Ischemic Stroke: An Individual Patient Data Meta-analysis

Neurology. 2021 Nov 12:10.1212/WNL.0000000000013049. doi: 10.1212/WNL.0000000000013049. Online ahead of print.

ABSTRACT

OBJECTIVE: To explore the association between blood pressure (BP) levels after endovascular thrombectomy (EVT) and the clinical outcomes of acute ischemic stroke (AIS) patients with large vessel occlusion (LVO).

METHODS: A study was eligible if it enrolled AIS patients older than 18 years, with an LVO treated with either successful or unsuccessful EVT, and provided either individual or mean 24-hour systolic BP values after the end of the EVT procedure. Individual patient data from all studies were analyzed using a generalized linear mixed-effects model.

RESULTS: A total of 5874 patients (mean age: 69±14 years, 50% women, median NIHSS on admission: 16) from 7 published studies were included. Increasing mean systolic BP levels per 10 mm Hg during the first 24 hours after the end of the EVT were associated with a lower odds of functional improvement (unadjusted common OR=0.82, 95%CI:0.80-0.85; adjusted common OR=0.88, 95%CI:0.84-0.93) and modified Ranking Scale score≤2 (unadjusted OR=0.82, 95%CI:0.79-0.85; adjusted OR=0.87, 95%CI:0.82-0.93), and a higher odds of all-cause mortality (unadjusted OR=1.18, 95%CI:1.13-1.24; adjusted OR=1.15, 95%CI:1.06-1.23) at 3 months. Higher 24-hour mean systolic BP levels were also associated with an increased likelihood of early neurological deterioration (unadjusted OR=1.14, 95%CI:1.07-1.21; adjusted OR=1.14, 95%CI:1.03-1.24) and a higher odds of symptomatic intracranial hemorrhage (unadjusted OR=1.20, 95%CI:1.09-1.29; adjusted OR=1.20, 95%CI:1.03-1.38) after EVT.

CONCLUSION: Increased mean systolic BP levels in the first 24 hours after EVT are independently associated with a higher odds of symptomatic intracranial hemorrhage, early neurological deterioration, three-month mortality, and worse three-month functional outcomes.

PMID:34772799 | DOI:10.1212/WNL.0000000000013049

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Nevin Manimala Statistics

Development and validation of multivariable prediction models for adverse COVID-19 outcomes in patients with IBD

BMJ Open. 2021 Nov 12;11(11):e049740. doi: 10.1136/bmjopen-2021-049740.

ABSTRACT

OBJECTIVES: Develop an individualised prognostic risk prediction tool for predicting the probability of adverse COVID-19 outcomes in patients with inflammatory bowel disease (IBD).

DESIGN AND SETTING: This study developed and validated prognostic penalised logistic regression models using reports to the international Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease voluntary registry from March to October 2020. Model development was done using a training data set (85% of cases reported 13 March-15 September 2020), and model validation was conducted using a test data set (the remaining 15% of cases plus all cases reported 16 September-20 October 2020).

PARTICIPANTS: We included 2709 cases from 59 countries (mean age 41.2 years (SD 18), 50.2% male). All submitted cases after removing duplicates were included.

PRIMARY AND SECONDARY OUTCOME MEASURES: COVID-19 related: (1) Hospitalisation+: composite outcome of hospitalisation, ICU admission, mechanical ventilation or death; (2) Intensive Care Unit+ (ICU+): composite outcome of ICU admission, mechanical ventilation or death; (3) Death. We assessed the resulting models’ discrimination using the area under the curve of the receiver operator characteristic curves and reported the corresponding 95% CIs.

RESULTS: Of the submitted cases, a total of 633 (24%) were hospitalised, 137 (5%) were admitted to the ICU or intubated and 69 (3%) died. 2009 patients comprised the training set and 700 the test set. The models demonstrated excellent discrimination, with a test set area under the curve (95% CI) of 0.79 (0.75 to 0.83) for Hospitalisation+, 0.88 (0.82 to 0.95) for ICU+ and 0.94 (0.89 to 0.99) for Death. Age, comorbidities, corticosteroid use and male gender were associated with a higher risk of death, while the use of biological therapies was associated with a lower risk.

CONCLUSIONS: Prognostic models can effectively predict who is at higher risk for COVID-19-related adverse outcomes in a population of patients with IBD. A free online risk calculator (https://covidibd.org/covid-19-risk-calculator/) is available for healthcare providers to facilitate discussion of risks due to COVID-19 with patients with IBD.

PMID:34772750 | DOI:10.1136/bmjopen-2021-049740

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Nevin Manimala Statistics

Current trends in the application of causal inference methods to pooled longitudinal non-randomised data: a protocol for a methodological systematic review

BMJ Open. 2021 Nov 12;11(11):e052969. doi: 10.1136/bmjopen-2021-052969.

ABSTRACT

INTRODUCTION: Causal methods have been adopted and adapted across health disciplines, particularly for the analysis of single studies. However, the sample sizes necessary to best inform decision-making are often not attainable with single studies, making pooled individual-level data analysis invaluable for public health efforts. Researchers commonly implement causal methods prevailing in their home disciplines, and how these are selected, evaluated, implemented and reported may vary widely. To our knowledge, no article has yet evaluated trends in the implementation and reporting of causal methods in studies leveraging individual-level data pooled from several studies. We undertake this review to uncover patterns in the implementation and reporting of causal methods used across disciplines in research focused on health outcomes. We will investigate variations in methods to infer causality used across disciplines, time and geography and identify gaps in reporting of methods to inform the development of reporting standards and the conversation required to effect change.

METHODS AND ANALYSIS: We will search four databases (EBSCO, Embase, PubMed, Web of Science) using a search strategy developed with librarians from three universities (Heidelberg University, Harvard University, and University of California, San Francisco). The search strategy includes terms such as ‘pool*’, ‘harmoniz*’, ‘cohort*’, ‘observational’, variations on ‘individual-level data’. Four reviewers will independently screen articles using Covidence and extract data from included articles. The extracted data will be analysed descriptively in tables and graphically to reveal the pattern in methods implementation and reporting. This protocol has been registered with PROSPERO (CRD42020143148).

ETHICS AND DISSEMINATION: No ethical approval was required as only publicly available data were used. The results will be submitted as a manuscript to a peer-reviewed journal, disseminated in conferences if relevant, and published as part of doctoral dissertations in Global Health at the Heidelberg University Hospital.

PMID:34772754 | DOI:10.1136/bmjopen-2021-052969

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Nevin Manimala Statistics

Protocol for ‘Resilient Caregivers’: a randomised trial of a resilience-based intervention for psychologically distressed partner caregivers of patients with cancer

BMJ Open. 2021 Nov 12;11(11):e048327. doi: 10.1136/bmjopen-2020-048327.

ABSTRACT

INTRODUCTION: Intimate partners of patients with cancer often experience significant distress, but there is a lack of psychological interventions that specifically target this population. ‘Resilient Caregivers’ is a novel resilience-based intervention for distressed partner cancer caregivers. The intervention was developed according to a resilience framework focusing on meta-reflective skills, coping strategies and value clarification. The aim of this study is to evaluate the effectiveness of this intervention in a randomised trial.

METHODS AND ANALYSIS: Eighty participants will be invited through the Oncology Department at Herlev Hospital, Denmark and randomised to either the intervention or usual care. Participants are eligible if they are partners (married or unmarried) of patients diagnosed with cancer and experience distress (>4 on the distress thermometer). ‘Resilient Caregivers’ consists of seven manualised group sessions (2.5 hours each), focusing on resilience in relation to being a partner caregiver of a patient with cancer. The primary outcome is symptoms of anxiety, while secondary outcomes include distress, depression, quality of life, sleep quality and resilience. Data will be collected at baseline, 3, 6 and 12 months follow-up using validated scales, and analysed using mixed models for repeated measures.

ETHICS AND DISSEMINATION: This study will follow the ethical principles in the Declaration of Helsinki and has been reviewed by the Ethics Committee of the Capital Region of Denmark (Journal no. 18055373). Written informed consent will be obtained from all participants. Results will be reported through scientific peer-reviewed journals and relevant conferences.

TRIAL REGISTRATION NUMBER: NCT04610034.

PMID:34772747 | DOI:10.1136/bmjopen-2020-048327

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Nevin Manimala Statistics

Acupuncture for retinitis pigmentosa: study protocol for a randomised, sham-controlled trial

BMJ Open. 2021 Nov 12;11(11):e049245. doi: 10.1136/bmjopen-2021-049245.

ABSTRACT

INTRODUCTION: Primary retinitis pigmentosa (RP) is a common hereditary retinal disease in ophthalmology that has a considerable impact on quality of life, but there are few effective therapeutic strategies. This trial aims to determine the efficacy and safety of acupuncture versus sham acupuncture (SA) for RP.

METHODS AND ANALYSIS: This is a study protocol for a randomised, participant-blind, sham-controlled trial. 64 eligible patients with RP will randomly be divided into acupuncture group and SA group. All groups will receive 48 sessions over 3 months. Participants will complete the trial by visiting the research centre in month 6/9 for a follow-up assessment. The primary outcome is visual field mean sensitivity and visual field mean deviation at month 3/6/9 compared with baseline. Secondary outcomes include the best-corrected visual acuity, central macular thickness, subfoveal choroidal thicknes, traditional Chinese medicine syndrome score and the scale of life quality for diseases with visual impairment at month 3/6/9 compared with baseline. Adverse events and safety indexes will be recorded throughout the study. SPSS V.25.0 statistical software was used for analysis, and measurement data were expressed as mean±SD.

ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the Chinese Clinical Trial Registry (approval no: ChiECRCT20200460). The results of this study will be published in a peer-reviewed journal, and trial participants will be informed via email and/or phone calls.

TRIAL REGISTRATION NUMBER: ChiCTR2000041090.

PMID:34772749 | DOI:10.1136/bmjopen-2021-049245

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Nevin Manimala Statistics

Nocturnal Dipping and Left Ventricular Mass Index in the Chronic Kidney Disease in Children Cohort

Clin J Am Soc Nephrol. 2021 Nov 12:CJN.09810721. doi: 10.2215/CJN.09810721. Online ahead of print.

ABSTRACT

Background and objectives: The physiological nocturnal blood pressure decline is often blunted in patients with chronic kidney disease (CKD); however, the consequences of blood pressure non-dipping in children are largely unknown. Our objective was to determine risk factors for non-dipping and to investigate if non-dipping is associated with higher left ventricular mass index (LVMI) in children with CKD. Design, setting, participants, and measurements: We conducted a cross-sectional analysis of ambulatory blood pressure monitoring and echocardiographic data in participants of the Chronic Kidney Disease in Children study. Multivariable linear and spline regression analyses were used to evaluate the relationship of risk factors with dipping, and of dipping with LVMI. Results: Within 552 participants, mean age was 11 (± 4) years, mean eGFR was 53 (± 20) ml/min/1.73m2, and 41% were classified as non-dippers. In subjects with non-glomerular CKD, female sex and higher sodium intake were significantly associated with less systolic and diastolic dipping (p≤ 0.05). In those with glomerular CKD, African American race and greater proteinuria were significantly associated with less systolic and diastolic dipping (p≤ 0.05). Systolic and diastolic dipping were not significantly associated with LVMI; however, in spline regression plots, diastolic dipping appeared to have a non-linear relationship with LVMI. As compared to diastolic dipping of 20-25%, dipping of < 20% was associated with 1.41 g/m2.7 higher LVMI (95% CI -0.47, 3.29), and dipping of > 25% was associated with 1.98 g/m2.7 higher LVMI (95% CI -0.77, 4.73), though these relationships did not achieve statistical significance. Conclusion: African American race, female sex, and greater proteinuria and sodium intake were significantly associated with blunted dipping in children with CKD. We did not find a statistically significant association between dipping and LVMI.

PMID:34772729 | DOI:10.2215/CJN.09810721