False discovery rate for functional data Olsen, Niels Lundtorp; Pini, Alessia; Vantini, Simone
Test (Madrid, Spain),
09/2021, Letnik:
30, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Since Benjamini and Hochberg introduced false discovery rate (FDR) in their seminal paper, this has become a very popular approach to the multiple comparisons problem. An increasingly popular topic ...within functional data analysis is local inference, i.e. the continuous statistical testing of a null hypothesis along the domain. The principal issue in this topic is the infinite amount of tested hypotheses, which can be seen as an extreme case of the multiple comparisons problem. In this paper, we define and discuss the notion of FDR in a very general functional data setting. Moreover, a continuous version of the Benjamini–Hochberg procedure is introduced along with a definition of adjusted
p
value function. Some general conditions are stated, under which the functional Benjamini–Hochberg procedure provides control of the functional FDR. Two different simulation studies are presented; the first study has a one-dimensional domain and a comparison with another state-of-the-art method, and the second study has a planar two-dimensional domain. Finally, the proposed method is applied to satellite measurements of Earth temperature. In detail, we aim at identifying the regions of the planet where temperature has significantly increased in the last decades. After adjustment, large areas are still significant.
In this paper we investigate the changes in the functional connectivity intensity, and some related properties, in healthy people, across the life span and at resting state. For the explicit ...computation of the functional connectivity we exploit a recently proposed model, that bases not only on the correlations data provided by the acquisition equipment, but also on different parameters, such as the anatomical distances between nodes and their degrees. The leading purpose of the paper is to show that the proposed approach is able to recover the main aspects of resting state condition known from the available literature, as well as to suggest new insights, perspectives and speculations from a neurobiological point of view. Our study involves 133 subjects, both males and females of different ages, with no evidence of neurological diseases or systemic disorders. First, we show how the model applies to the sample, where the subjects are grouped into 28 different groups (14 of males and 14 of females), according to their age. This leads to the construction of two graphs (one for males and one for females), that can be realistically interpreted as representative of the neural network during the resting state. Second, following the idea that the brain network is better understood by focusing on specific nodes having a kind of centrality, we refine the two output graphs by introducing a new metric that favours the selection of nodes having higher degrees. As a third step, we extensively comment and discuss the obtained results. In particular, it is remarkable that, despite a great overlapping exists between the outcomes concerning males and females, some intriguing differences appear. This motivates a deeper local investigation, which represents the fourth part of the paper, carried out through a thorough statistical analysis. As a result, we are enabled to support that, for two special age groups, a few links contribute in differentiating the behaviour of males and females. In addition, we performed an average-based comparison between the proposed model and the traditional statistical correlation-based approach, then discussing and commenting the main outlined discrepancies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Endogenous retroviruses (ERVs), the remnants of retroviral infections in the germ line, occupy ~8% and ~10% of the human and mouse genomes, respectively, and affect their structure, evolution, and ...function. Yet we still have a limited understanding of how the genomic landscape influences integration and fixation of ERVs. Here we conducted a genome-wide study of the most recently active ERVs in the human and mouse genome. We investigated 826 fixed and 1,065 in vitro HERV-Ks in human, and 1,624 fixed and 242 polymorphic ETns, as well as 3,964 fixed and 1,986 polymorphic IAPs, in mouse. We quantitated >40 human and mouse genomic features (e.g., non-B DNA structure, recombination rates, and histone modifications) in ±32 kb of these ERVs' integration sites and in control regions, and analyzed them using Functional Data Analysis (FDA) methodology. In one of the first applications of FDA in genomics, we identified genomic scales and locations at which these features display their influence, and how they work in concert, to provide signals essential for integration and fixation of ERVs. The investigation of ERVs of different evolutionary ages (young in vitro and polymorphic ERVs, older fixed ERVs) allowed us to disentangle integration vs. fixation preferences. As a result of these analyses, we built a comprehensive model explaining the uneven distribution of ERVs along the genome. We found that ERVs integrate in late-replicating AT-rich regions with abundant microsatellites, mirror repeats, and repressive histone marks. Regions favoring fixation are depleted of genes and evolutionarily conserved elements, and have low recombination rates, reflecting the effects of purifying selection and ectopic recombination removing ERVs from the genome. In addition to providing these biological insights, our study demonstrates the power of exploiting multiple scales and localization with FDA. These powerful techniques are expected to be applicable to many other genomic investigations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Popliteal artery aneurysms (PAAs) need urgent treatment in case of acute thrombosis, distal embolization, or rupture. Few data are available in the literature about the treatment ...results in these scenarios. The aim of the present study was to evaluate an 11-year multicenter experience in the urgent treatment of PAAs.
Methods
All symptomatic PAAs surgically treated in two vascular centers between 2010 and 2021 were retrospectively analyzed. In the postoperative period periodical clinical and Duplex-Ultrasound evaluation were performed. The evaluated endpoint was the outcome of urgent PAAs treatment according to their clinical presentation. Statistical analysis was performed by Kaplan-Meier log-rank evaluation and multivariable Cox regression tests.
Results
Sixty-six PAAs needed an urgent repair. Twelve (18%) patients had a PAA rupture and 54 (82%) had an acute limb ischemia (ALI) due to either distal embolization or acute thrombosis. Patients with ALI underwent bypass surgery in 51 (95%) cases, which was associated with preoperative thrombolysis in 18 (31%) cases. A primary major amputation was performed in 3 (5%) cases. The mean follow-up was 52 ± 21 months with an overall 5-year limb salvage of 83 ± 6%. Limb salvage was influenced only by the number of patent tibial arteries (pTA) 5-years limb salvage 0%, 86 ± 10%, 92 ± 8% and 100% in case of 0, 1, 2 or 3 pTA, respectively (
P
= .001). An independent association of number of pTA and limb loss was found hazard ratio (HR): 0.14 (95% confidence interval (CI) 0.03–0.6),
P
= .001. Overall 5-year survival was 71 ± 7%. Ruptured PAAs were associated with lower 5-year survival compared with the ALI group (48 ± 2% vs. 79 ± 7%,
P
= .001). The number of pTA (33 ± 20%, 65 ± 10%, 84 ± 10% and 80 ± 10% for 0, 1, 2 and 3 pTA, respectively,
P
= .001) and the thrombolysis (94 ± 6% vs. 62 ± 10%,
P
= .03) were associated with higher survival in patients with ALI. There was an independent association of number of pTA and long-term survival HR 0.15 (95% CI 0.03–0.8),
P
= .03.
Conclusions
PAA rupture is the cause of urgent PAA treatment in almost one fifth of cases, and it is associated with lower long-term survival. ALI can benefit from thrombolysis, and long-term limb salvage and survival are associated with the number of pTA.
Three-dimensional human motion analysis provides in-depth understanding in order to optimize sports performance or rehabilitation following disease or injury. Recent developments of statistical ...methods for functional data allow for novel ways to analyze often complex biomechanical data. Even so, for such methods as well as for traditional well-established statistical methods, the interpretations of the results may be influenced by analysis choices made prior to the analysis. We evaluated the consequences of three such choices when comparing one-leg vertical hop (OLVH) performance in individuals who had ruptured their anterior cruciate ligament (ACL), to that of asymptomatic controls, and also athletes. Kinematic data were analyzed using a statistical approach for functional data, targeting entire curve data. This was done not only for one joint at a time but also for multiple lower limb joints and movement planes simultaneously using a multi-aspect methodology, testing for group differences while also accounting for covariates. We present the results of when an individual representative curve out of three available was either: (1) a mean curve (
Mean
), (2) a curve from the highest hop (
Max
), or (3) a curve describing the variability (
Var
), as a representation of performance stability. We also evaluated choice of sample leg comparison; e.g., ACL-injured leg compared to either the dominant or non-dominant leg of asymptomatic groups. Finally, we explored potential outcome effects of different combinations of included joints. There were slightly more pronounced group differences when using
Mean
compared to
Max
, while the specifics of the observed differences depended on the outcome variable. For
Var
there were less significant group differences. Generally, there were more disparities throughout the hop movement when comparing the injured leg to the dominant leg of controls, resulting in e.g., group differences for trunk and ankle kinematics, for both
Mean
and
Max
. When the injured leg was instead compared to the non-dominant leg of controls, there were trunk, hip and knee joint differences. For a more stringent comparison, we suggest considering to compare the injured leg to the non-dominant leg. Finally, the multiple-joint analyses were coherent with the single-joint analyses. The direct effects of analysis choices can be explored interactively by the reader in the
Supplementary Material
. To summarize, the choices definitively have an impact on the interpretation of a hop test results commonly used in rehabilitation following knee injuries. We therefore strongly recommend well-documented methodological analysis choices with regards to comparisons and representative values of the measures of interests.
We introduce in this work the Interval Testing Procedure (ITP), a novel inferential technique for functional data. The procedure can be used to test different functional hypotheses, e.g., ...distributional equality between two or more functional populations, equality of mean function of a functional population to a reference. ITP involves three steps: (i) the representation of data on a (possibly high-dimensional) functional basis; (ii) the test of each possible set of consecutive basis coefficients; (iii) the computation of the adjusted p-values associated to each basis component, by means of a new strategy here proposed. We define a new type of error control, the interval-wise control of the family wise error rate, particularly suited for functional data. We show that ITP is provided with such a control. A simulation study comparing ITP with other testing procedures is reported. ITP is then applied to the analysis of hemodynamical features involved with cerebral aneurysm pathology. ITP is implemented in the fdatest R package.
Despite interventions, anterior cruciate ligament ruptures can cause long-term deficits. To assist in identifying and treating deficiencies, 3D-motion analysis is used for objectivizing data. ...Conventional statistics are commonly employed to analyze kinematics, reducing continuous data series to discrete variables. Conversely, functional data analysis considers the entire data series.
Here, we employ functional data analysis to examine and compare the entire time-domain of knee-kinematic curves from one-leg hops between and within three groups. All subjects (n=95) were part of a long-term follow-up study involving anterior cruciate ligament ruptures treated ~20years ago conservatively with physiotherapy only or with reconstructive surgery and physiotherapy, and matched knee-healthy controls.
Between-group differences (injured leg, treated groups; non-dominant leg, controls) were identified during the take-off and landing phases, and in the sagittal (flexion/extension) rather than coronal (abduction/adduction) and transverse (internal/external) planes. Overall, surgical and control groups demonstrated comparable knee-kinematic curves. However, compared to controls, the physiotherapy-only group exhibited less flexion during the take-off (0–55% of the normalized phase) and landing (44–73%) phase. Between-leg differences were absent in controls and the surgically treated group, but observed during the flight (4–22%, injured leg>flexion) and the landing (57–85%, injured leg<internal rotation) phases in the physiotherapy-only group.
Functional data analysis identified specific functional knee-joint deviations from controls persisting 20years post anterior cruciate ligament rupture, especially when treated conservatively. This approach is suggested as a means for comprehensively analyzing complex movements, adding to previous analyses.
•Functional ANOVA was used on the entire time-domain of one-leg hop knee kinematics.•Groups were post anterior cruciate ruptures (with and without surgery) and controls.•The family-wise error rate was controlled on any interval of the time-domain.•Deviations vs. controls exist 20years post anterior cruciate injury (without surgery).•Functional data analysis is useful for comprehensive analysis of complex movements.
Chronic limb threatening ischaemia (CLTI) involving the infragenicular arteries is treated by distal angioplasty or pedal bypass; however, this is not always possible, due to chronically occluded ...pedal arteries (no patent pedal artery, N-PPA). This pattern represents a hurdle to successful revascularisation, which must be limited to the proximal arteries. The aim of the study was to analyse the outcome of patients with CLTI and N-PPA after a proximal revascularisation.
All patients with CLTI submitted to revascularisation in a single centre (2019 – 2020) were analysed. All angiograms were reviewed to identify N-PPA, defined as total obstruction of all pedal arteries. Revascularisation was performed with proximal surgical, endovascular, and hybrid procedures. Early and midterm survival, wound healing, limb salvage, and patency rates were compared between N-PPA and patients with one or more patent pedal artery (PPA).
Two hundred and eighteen procedures were performed. One hundred and forty of 218 (64.2%) patients were male, mean age 73.2 ± 10.6 years. The procedure was surgical in 64/218 (29.4%) cases, endovascular in 138/218 (63.3%), and hybrid in 16/218 (7.3%). N-PPA was present in 60/218 (27.5%) cases. Eleven of 60 (18.3%) cases were treated surgically, 43/60 (71.7%) by endovascular and 6/60 (10%) by hybrid procedures. Technical success was similar in the two groups (N-PPA 85% vs. PPA 82.3%, p = .42). At a mean follow up of 24.5 ± 10.2 months, survival (N-PPA 93.7 ± 3.5% vs. PPA 95.3 ± 2.1%, p = .22) and primary patency (N-PPA 53.1 ± 8.1% vs. PPA 55.2 ± 5%, p = .56) were similar. Limb salvage was significantly lower in N-PPA patients (N-PPA 71.4 ± 6.6% vs. PPA 81.5 ± 3.4%, p = .042); N-PPA was an independent predictor of major amputation (hazard ratio HR 2.02, 1.07 – 3.82, p = .038) together with age > 73 years (HR 2.32, 1.17 – 4.57, p = .012) and haemodialysis (2.84, 1.48 – 5.43, p = .002).
N-PPA is not uncommon in patients with CLTI. This condition does not hamper technical success, primary patency, and midterm survival; however, midterm limb salvage is significantly lower than in patients with PPA. This should be considered in the decision making process.
Machine perfusion is increasingly being tested in clinical transplantation. Despite this, the number of large prospective clinical trials remains limited. The aim of this study was to compare the ...impact of machine perfusion vs. static cold storage (SCS) on outcomes after liver transplantation.
A systematic search of MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted to identify randomized-controlled trials (RCTs) comparing “post-transplant” outcomes following machine perfusion vs. SCS. Data were pooled using random effect models. Risk ratios (RRs) were calculated for relevant outcomes. The quality of evidence was rated using the GRADE-framework.
Seven RCTs were identified (four on hypothermic oxygenated HOPE and three on normothermic machine perfusion NMP), including a total number of 1,017 patients. Both techniques were associated with significantly lower rates of early allograft dysfunction (NMP: n = 41/282, SCS: n = 74/253, RR 0.50, 95% CI 0.30-0.86, p = 0.01, I2 = 39%; HOPE: n = 45/241, SCS: n = 97/241, RR 0.48, 95% CI 0.35-0.65, p < 0.00001, I2 = 5%). The HOPE approach led to a significant reduction in major complications (Clavien Grade ≥IIIb; HOPE: n = 90/241; SCS: n = 117/241, RR 0.76, 95% CI 0.63-0.93, p = 0.006, I2 = 0%), “re-transplantation” (HOPE: n = 1/163; SCS: n = 11/163; RR 0.21, 95% CI 0.04-0.96, p = 0.04; I2 = 0%) and graft loss (HOPE: n = 7/163; SCS: n = 19/163; RR 0.40, 95% CI 0.17-0.95, p = 0.04; I2 = 0%). Both perfusion techniques were found to ‘likely’ reduce overall biliary complications and non-anastomotic strictures.
Although this study provides the highest current evidence on the role of machine perfusion, outcomes remain limited to a 1-year follow-up after liver transplantation. Comparative RCTs and large real-world cohort studies with longer follow-up are required to enhance the robustness of the data further, thereby supporting the introduction of perfusion technologies into routine clinical practice.
CRD42022355252.
For a decade, two dynamic perfusion concepts have increasingly been tested in several transplant centres worldwide. We undertook the first systematic review and meta-analysis and identified seven published RCTs, including 1,017 patients, evaluating the effect of machine perfusion (hypothermic and normothermic perfusion techniques) compared to static cold storage in liver transplantation. Both perfusion techniques were associated with lower rates of early allograft dysfunction in the first week after liver transplantation. Hypothermic oxygenated perfusion led to a reduction in major complications, lower “re-transplantation” rates and better graft survival. Both perfusion strategies were found to ‘likely’ reduce overall biliary complications and non-anastomotic biliary strictures. This study provides the highest current evidence on the role of machine perfusion. Outcomes remain limited to a 1-year post-transplant follow-up. Larger cohort studies with longer follow-up and clinical trials comparing the perfusion techniques are required. This is especially relevant to provide clarity and optimise implementation processes further to support the commissioning of this technology worldwide.
Display omitted
•First systematic review and meta-analysis evaluating the effect of HOPE and NMP compared to SCS in liver transplantation.•HOPE and NMP were associated with lower rates of early allograft dysfunction in the first week after liver transplantation.•HOPE led to a significant reduction in major complications, lower “re-transplantation” rates and better graft survival.•Despite being the highest level of evidence, outcome data on machine perfusion remain limited to 1-year post-transplant follow-up.
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