The purpose of this review is to clarify the concepts of bias, precision and accuracy as they are commonly defined in the biostatistical literature, with our focus on the use of these concepts in ...quantitatively testing the performance of point estimators (specifically species richness estimators). We first describe the general concepts underlying bias, precision and accuracy, and then describe a number of commonly used unscaled and scaled performance measures of bias, precision and accuracy (e.g. mean error, variance, standard deviation, mean square error, root mean square error, mean absolute error, and all their scaled counterparts) which may be used to evaluate estimator performance. We also provide mathematical formulas and a worked example for most performance measures. Since every measure of estimator performance should be viewed as suggestive, not prescriptive, we also mention several other performance measures that have been used by biostatisticians or ecologists. We then outline several guidelines of how to test the performance of species richness estimators: the detailed description of data simulation models and resampling schemes, the use of real and simulated data sets on as many different estimators as possible, mathematical expressions for all estimators and performance measures, and the presentation of results for each scaled performance measure in numerical tables with increasing levels of sampling effort. We finish with a literature review of promising new research related to species richness estimation, and summarize the results of 14 studies that compared estimator performance, which confirm that with most data sets, non-parametric estimators (mostly the Chao and jackknife estimators) perform better than other estimators, e.g. curve models or fitting species-abundance distributions.
Skin homeostasis is maintained by stem cells, which must communicate to balance their regenerative behaviors. Yet, how adult stem cells signal across regenerative tissue remains unknown due to ...challenges in studying signaling dynamics in live mice. We combined live imaging in the mouse basal stem cell layer with machine learning tools to analyze patterns of Ca2+ signaling. We show that basal cells display dynamic intercellular Ca2+ signaling among local neighborhoods. We find that these Ca2+ signals are coordinated across thousands of cells and that this coordination is an emergent property of the stem cell layer. We demonstrate that G2 cells are required to initiate normal levels of Ca2+ signaling, while connexin43 connects basal cells to orchestrate tissue-wide coordination of Ca2+ signaling. Lastly, we find that Ca2+ signaling drives cell cycle progression, revealing a communication feedback loop. This work provides resolution into how stem cells at different cell cycle stages coordinate tissue-wide signaling during epidermal regeneration.
Objective
Ultrasound is widely regarded as an important adjunct to antenatal care (ANC) to guide practice and reduce perinatal mortality. We assessed the impact of ANC ultrasound use at health ...centres in resource‐limited countries.
Design
Cluster randomised trial.
Setting
Clusters within five countries (Democratic Republic of Congo, Guatemala, Kenya, Pakistan, and Zambia)
Methods
Clusters were randomised to standard ANC or standard care plus two ultrasounds and referral for complications. The study trained providers in intervention clusters to perform basic obstetric ultrasounds.
Main outcome measures
The primary outcome was a composite of maternal mortality, maternal near‐miss mortality, stillbirth, and neonatal mortality.
Results
During the 24‐month trial, 28 intervention and 28 control clusters had 24 263 and 23 160 births, respectively; 78% in the intervention clusters received at least one study ultrasound; 60% received two. The prevalence of conditions noted including twins, placenta previa, and abnormal lie was within expected ranges. 9% were referred for an ultrasound‐diagnosed condition, and 71% attended the referral. The ANC (RR 1.0 95% CI 1.00, 1.01) and hospital delivery rates for complicated pregnancies (RR 1.03 95% CI 0.89, 1.20) did not differ between intervention and control clusters nor did the composite outcome (RR 1.09 95% CI 0.97, 1.23) or its individual components.
Conclusions
Despite availability of ultrasound at ANC in the intervention clusters, neither ANC nor hospital delivery for complicated pregnancies increased. The composite outcome and the individual components were not reduced.
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Antenatal care ultrasound did not improve a composite outcome that included maternal, fetal, and neonatal mortality.
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Antenatal care ultrasound did not improve a composite outcome that included maternal, fetal, and neonatal mortality.
There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is ...lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma.
Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index.
In total, 17,930 LNs from 763 patients were examined. LN response classified as
(LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%),
(LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%),
(LNRS 4-5; n = 303, 39.7%), or
(no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio HR, 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%).
Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.
The inappropriate activation of protein-tyrosine kinases (PTKs) has been associated with initiation and progression of several types of human cancers. We therefore postulated that immortalization by ...DNA tumor viruses results in the induction of PTKs fundamental to these processes. An RT-PCR-based screen was thus used to identify PTKs that were abundantly expressed in HPV-18-immortalized epithelial cells and HPV-containing carcinoma cell lines. One of the genes isolated in this screen was the focal adhesion kinase (FAK; pp125FAK), a cytoplasmic protein kinase that is activated in v-src transformed cells or by stimulation with mitogenic polypeptides. FAK also becomes catalytically active upon integrin engagement with extracellular matrix proteins, such as fibronectin. We found that FAK expression and activity were significantly elevated in HPV-18 E6/E7-immortalized human genital epithelial cells relative to their primary cell counterparts. Protein expression and tyrosine phosphorylation of the putative FAK substrate, paxillin, were also notably increased upon HPV-18 immortalization of genital epithelial cells and in HPV-containing cervical carcinoma cell lines. Most significantly, these cells expressed markedly higher levels of both intracellular and extracellular fibronectin, thus providing a mechanism for activation of FAK and increased tyrosine phosphorylation of paxillin. These findings suggest a role for the integrin/FAK-mediated signaling pathway in cervical carcinogenesis and represent one of the first demonstrations of a tyrosine kinase whose activity is elevated following viral immortalization.
Objectives
2-deoxy-2
18
FFluoro-
d
-glucose (FDG) PET-CT has an emerging role in assessing response to neoadjuvant therapy in oesophageal cancer. This study evaluated FDG PET-CT in predicting ...pathological tumour response (pTR), pathological nodal response (pNR) and survival.
Methods
Cohort study of 75 patients with oesophageal or oesophago-gastric junction (GOJ) adenocarcinoma treated with neoadjuvant chemotherapy then surgery at Guy’s and St Thomas’ NHS Foundation Trust, London (2017–2020). Standardised uptake value (SUV) metrics on pre- and post-treatment FDG PET-CT in the primary tumour (mTR) and loco-regional lymph nodes (mNR) were derived. Optimum SUV
max
thresholds for predicting pathological response were identified using receiver operating characteristic analysis. Predictive accuracy was compared to PERCIST (30% SUV
max
reduction) and MUNICON (35%) criteria. Survival was assessed using Cox regression.
Results
Optimum tumour SUV
max
decrease for predicting pTR was 51.2%. A 50% cut-off predicted pTR with 73.5% sensitivity, 69.2% specificity and greater accuracy than PERCIST or MUNICON (area under the curve AUC 0.714, PERCIST 0.631, MUNICON 0.659). Using a 30% SUV
max
threshold, mNR predicted pNR with high sensitivity but low specificity (AUC 0.749, sensitivity 92.6%, specificity 57.1%,
p
=
0.010
). pTR, mTR, pNR and mNR were independent predictive factors for survival (pTR hazard ratio HR 0.10 95% confidence interval CI 0.03–0.34; mTR HR 0.17 95% CI 0.06–0.48; pNR HR 0.17 95% CI 0.06–0.54; mNR HR 0.13 95% CI 0.02–0.66).
Conclusions
Metabolic tumour and nodal response predicted pTR and pNR, respectively, in patients with oesophageal or GOJ adenocarcinoma. However, currently utilised response criteria may not be optimal. pTR, mTR, pNR and mNR were independent predictors of survival.
Key Points
• FDG PET-CT has an emerging role in evaluating response to neoadjuvant therapy in patients with oesophageal cancer.
• Prospective cohort study demonstrated that metabolic response in the primary tumour and lymph nodes was predictive of pathological response in a cohort of patients with adenocarcinoma of the oesophagus or oesophago-gastric junction treated with neoadjuvant chemotherapy followed by surgical resection.
• Patients who demonstrated a response to neoadjuvant chemotherapy in the primary tumour or lymph nodes on FDG PET-CT demonstrated better survival and reduced rates of tumour recurrence.
Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of melanocytes. Here we show that zebrafish golden ...mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor. The human ortholog is highly similar in sequence and functional in zebrafish. The evolutionarily conserved ancestral allele of a human coding polymorphism predominates in African and East Asian populations. In contrast, the variant allele is nearly fixed in European populations, is associated with a substantial reduction in regional heterozygosity, and correlates with lighter skin pigmentation in admixed populations, suggesting a key role for the SLC24A5 gene in human pigmentation.
Peri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus ...capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates.
Cohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas’ Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells.
Patients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50–0.94) and disease-free survival (HR = 0.75, 95% CI 0.58–0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups.
Patients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.
•Better survival in patients treated with fluorouracil plus leucovorin, oxaliplatin and docetaxel.•Better pathological and radiological response to chemotherapy with FLOT.•Higher rates of complete pathological response in patients treated with FLOT.•Patients treated with FLOT were less likely to have a positive resection margin.•Comparable rates of surgical complications, adverse events and chemo completion.
Objective
Limited data are available from low‐ and middle‐income countries (LMICs) on the relationship of haemoglobin levels to adverse outcomes at different times during pregnancy. We evaluated the ...association of haemoglobin levels in nulliparous women at two times in pregnancy with pregnancy outcomes.
Design
ASPIRIN Trial data were used to study the association between haemoglobin levels measured at 6+0–13+6 weeks and 26+0–30+0 weeks of gestation with fetal and neonatal outcomes.
Setting
Obstetric care facilities in Pakistan, India, Kenya, Zambia, The Democratic Republic of the Congo and Guatemala.
Population
A total of 11 976 pregnant women.
Methods
Generalised linear models were used to obtain adjusted relative risks and 95% CI for adverse outcomes.
Main outcome measures
Preterm birth, stillbirth, neonatal death, small for gestational age (SGA) and birthweight <2500 g.
Results
The mean haemoglobin levels at 6+0–13+6 weeks and at 26–30 weeks of gestation were 116 g/l (SD 17) and 107 g/l (SD 15), respectively. In general, pregnancy outcomes were better with increasing haemoglobin. At 6+0–13+6 weeks of gestation, stillbirth, SGA and birthweight <2500 g, were significantly associated with haemoglobin of 70–89 g/l compared with haemoglobin of 110–129 g/l The relationships of adverse pregnancy outcomes with various haemoglobin levels were more marked at 26–30 weeks of gestation.
Conclusions
Both lower and some higher haemoglobin concentrations are associated with adverse fetal and neonatal outcomes at 6+0–13+6 weeks and at 26–30 weeks of gestation, although the relationship with low haemoglobin levels appears more consistent and generally stronger.
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Both lower and some higher haemoglobin concentrations were associated with adverse fetal and neonatal outcomes at 6–13 weeks and 26–30 weeks of gestation.
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Both lower and some higher haemoglobin concentrations were associated with adverse fetal and neonatal outcomes at 6–13 weeks and 26–30 weeks of gestation.
Objective
We sought to classify causes of stillbirth for six low‐middle‐income countries using a prospectively defined algorithm.
Design
Prospective, observational study.
Setting
Communities in ...India, Pakistan, Guatemala, Democratic Republic of Congo, Zambia and Kenya.
Population
Pregnant women residing in defined study regions.
Methods
Basic data regarding conditions present during pregnancy and delivery were collected. Using these data, a computer‐based hierarchal algorithm assigned cause of stillbirth. Causes included birth trauma, congenital anomaly, infection, asphyxia, and preterm birth, based on existing cause of death classifications and included contributing maternal conditions.
Main outcome measures
Primary cause of stillbirth.
Results
Of 109 911 women who were enrolled and delivered (99% of those screened in pregnancy), 2847 had a stillbirth (a rate of 27.2 per 1000 births). Asphyxia was the cause of 46.6% of the stillbirths, followed by infection (20.8%), congenital anomalies (8.4%) and prematurity (6.6%). Among those caused by asphyxia, 38% had prolonged or obstructed labour, 19% antepartum haemorrhage and 18% pre‐eclampsia/eclampsia. About two‐thirds (67.4%) of the stillbirths did not have signs of maceration.
Conclusions
Our algorithm determined cause of stillbirth from basic data obtained from lay‐health providers. The major cause of stillbirth was fetal asphyxia associated with prolonged or obstructed labour, pre‐eclampsia and antepartum haemorrhage. In the African sites, infection also was an important contributor to stillbirth. Using this algorithm, we documented cause of stillbirth and its trends to inform public health programs, using consistency, transparency, and comparability across time or regions with minimal burden on the healthcare system.
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Major causes of stillbirth are asphyxia, pre‐eclampsia and haemorrhage. Infections are important in Africa.
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Major causes of stillbirth are asphyxia, pre‐eclampsia and haemorrhage. Infections are important in Africa.
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