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PubMed2026

A doubly robust framework for addressing outcome-dependent selection bias in multi-cohort EHR studies.

Selection bias can hinder accurate estimation of association parameters in binary disease risk models using non-probability samples like electronic health records (EHRs). The issue is compounded when participants are recruited from multiple clinics/centers with varying selection mechanisms that may depend on the disease/outcome of interest. Traditional inverse-probability-weighted (IPW) methods, based on constructed parametric selection models, often struggle with misspecifications when selection mechanisms vary across cohorts. This paper introduces a new Joint Augmented Inverse Probability Weighted (JAIPW) method, which integrates individual-level data from multiple cohorts collected under potentially outcome-dependent selection mechanisms, with data from an external probability sample. JAIPW offers double robustness by incorporating a flexible auxiliary score model to address potential misspecifications in the selection models. We outline the asymptotic properties of the JAIPW estimator, and our simulations reveal that JAIPW achieves up to 6 times lower relative bias and 5 times lower root mean square error (RMSE) compared to the best performing joint IPW methods under scenarios with misspecified selection models. Applying JAIPW to the Michigan Genomics Initiative (MGI), a multi-clinic EHR-linked biobank, combined with external national probability samples, resulted in cancer-sex association estimates closely aligned with national benchmark estimates. We also analyzed the association between cancer and polygenic risk scores (PRS) in MGI to illustrate a situation where the exposure variable is not measured in the external probability sample.

Selection Bias↗

PubMed2026

The antimicrobial gut resistome of the Wayampi reveals a shared background of antibiotic and metal resistance genes with industrialized populations, underscoring the "robust-yet-fragile" architecture of human gut microbiomes.

BACKGROUND: Metagenomics enables detailed profiling of genes encoding antimicrobial resistance. However, most studies focus exclusively on antibiotic resistance genes (ARGs), excluding those associated with non-antibiotic antimicrobials (metals, biocides), and often rely on methods with low-sensitivity and low-specificity. Furthermore, they rarely examine populations exposed to minimal anthropogenic pollution. We analyzed fecal resistomes of 95 Wayampi individuals, an Indigenous community in remote French Guiana, using a targeted metagenomic capture platform covering 8667 genes, including ARGs, metal resistance genes (MRGs) and biocide resistance genes (BRGs) (PMID: 29335005). Resistome profiles were compared with those of Europeans to assess population-level differences. RESULTS: ARG richness was similar between groups (259 in Wayampi vs. 264 in Europeans, 159 shared), but MRGs + BRGs gene richness was significantly higher in Wayampi (11,930 vs. 7419). Most genes appeared in a minority of individuals (mean 5% for ARGs, 2% for MRGs + BRGs), but several ARGs for tetracyclines [tet(32), tet(40), tet(O), tet(Q), tet(W), tet(X), tetAB(P)], aminoglycosides (ant6'-I, aph3-III), macrolides (ermB, ermF, mefA), and sulfonamides (sul2) were present in all individuals. Tetracycline resistance genes predominated overall, while beta-lactam resistance genes were more common in Wayampi, and genes conferring resistance to aminoglycosides, amphenicols, and folate inhibitors were more frequent in Europeans. Among MRGs, copper and arsenic resistance genes prevailed in both groups, followed by those for zinc, iron, cobalt, and nickel. Up to 76% of Wayampiis carried acquired MRGs for copper (pcoABCDRS and tcrB), silver (silACFPRS), arsenic (ars), and mercury (mer) detoxification. Shannon diversity indices were similar for ARGs, MRGs, and BRGs, but composition and evenness differed significantly. UMAP and ADONIS analyses distinguished cohorts based on ARG profiles (p < 0.001), but not on MRGs or BRGs. Correlation analysis revealed conserved gene-sharing networks and introgression of acquired ARGs and MRGs within both gut microbiomes. CONCLUSIONS: The diverse and balanced Wayampi resistome reflects a less perturbed microbiome compared to industrialized populations, and reveals a background of "core" and "shell" acquired ARGs and MRGs, consistent with the "robust-yet-fragile" architecture of scale-free networks. The patchy yet resilient gene distribution suggests varying levels of conserved gene sharing highways among populations, likely shaped by long-term microbial-human evolution, and supports a broader view on acquired antimicrobial resistance. Video Abstract.

Humans↗

PubMed1996

Robust Bayesian approaches for clinical trial monitoring.

The interim monitoring and final analysis of data arising from a clinical trial require an inferential method capable of convincing a broad group of potential consumers: doctors; patients; politicians; members of the media, and so on. While Bayesian methods offer a powerful and flexible analytic framework in this setting, this need to convince a diverse community necessitates a practical approach for studying and communicating the robustness of conclusions to the prior specification. In this paper we attempt to characterize the class of priors leading to a given decision (such as stopping the trial and rejecting the null hypothesis) conditional on the observed data. We evaluate the practicality and effectiveness of this procedure over a range of smoothness conditions on the prior class. First, we consider a non-parametric class of priors restricted only in that its elements must have certain prespecified quantiles. We then obtain more precise results by further restricting the prior class, first to a non-parametric class whose members are quasi-unimodal, then to a semi-parametric normal mixture class, and finally to the fully parametric normal family. We illustrate all of our comparisons with a dataset from an AIDS clinical trial that compared the effectiveness of the drug pyrimethamine and a placebo in preventing toxoplasmic encephalitis.

AIDS-Related Opportunistic Infections↗

PubMed1997

Limitations to the robustness of binormal ROC curves: effects of model misspecification and location of decision thresholds on bias, precision, size and power.

This paper concerns robustness of the binormal assumption for inferences that pertain to the area under an ROC curve. I applied the binormal model to rating method data sets sampled from bilogistic curves and observed small biases in area estimates. Bias increased as the range of decision thresholds decreased. The variance of area estimates also increased as the range of decision thresholds decreased. Together, minor bias and inflated variance substantially altered the size and power of statistical tests that compared areas under bilogistic ROC curves. I repeated the simulations by applying the binormal assumption to data sampled from binormal curves. Biases in area estimates were minimal for the binormal data, but the variance of area estimates was again higher when the range of decision thresholds was narrow. The size of tests that compared areas did not vary from the chosen significance level. Power fell, however, when the variance of area estimates was inflated. I conclude that inferences derived from the binormal assumption are sensitive to model misspecification and to the location of decision thresholds. A narrow span of decision thresholds increases the variability of area estimates and reduces the power of area comparisons. Model misspecification produces bias that alters test size and can exaggerate the loss of power that accompanies increased variability.

Bias↗

PubMed1998

On the calculation of a robust S-estimator of a covariance matrix.

An S-estimator of multivariate location and scale minimizes the determinant of the covariance matrix, subject to a constraint on the magnitudes of the corresponding Mahalanobis distances. The relationship between S-estimators and w-estimators of multivariate location and scale can be used to calculate robust estimates of covariance matrices. Elemental subsets of observations are generated to derive initial estimates of means and covariances, and the w-estimator equations are then iterated until convergence to obtain the S-estimates. An example shows that converging to a (local) minimum from the initial estimates from the elemental subsets is an effective way of determining the overall minimum. None of the estimates gained from the elemental samples is close to the final solution.

Biometry↗

PubMed1999

The minimum sum of absolute errors regression: a robust alternative to the least squares regression.

This paper concerns the minimum sum of absolute errors regression. It is a more robust alternative to the popular least squares regression whenever there are outliers in the values of the response variable, or the errors follow a long tailed distribution, or the loss function is proportional to the absolute errors rather than their squared values. We use data from a study of interstitial lung disease to illustrate the method, interpret the findings, and contrast with least squares regression. We point out some of the problems with the least squares analysis and show how to avoid these with the minimum sum of absolute errors analysis.

Algorithms↗

PubMed1999

Unobserved covariates in the two-sample comparison of survival times: a maximum efficiency robust test.

In analysing a clinical trial with the logrank test, the hazards between the two groups are usually assumed to be proportional. Nevertheless, this hypothesis is no longer valid with unobserved covariates. As a consequence, there is a loss of power of the logrank test for testing the null hypothesis H(0) of no treatment effect. We propose a test suited for taking into account unobserved covariates. The proposed approach is based on a proportional hazard frailty model whereby the omitted covariates are considered as an unobserved frailty variable. The procedure is as follows. In a first step, the weighted logrank test optimal for testing H(0) against a general proportional hazard frailty model is obtained and its specialization for a gamma frailty variable is derived. In a second step, the proposed test is obtained by combining the maximin efficiency robustness principle and the gamma frailty distribution properties. Simulation studies investigate the power properties of the test for different frailty distributions. A breast cancer clinical trial is analysed as an example. The proposed test might be recommended rather than the logrank for practical situations in which one expects heterogeneity related to omitted covariates.

Breast Neoplasms↗

PubMed1999

High-throughput single-strand conformation polymorphism analysis by automated capillary electrophoresis: robust multiplex analysis and pattern-based identification of allelic variants.

Genetic diagnosis of an inherited disease or cancer often involves analysis for unknown point mutations in several genes; therefore, rapid and automated techniques that can process a large number of samples are needed. We describe a method for high-throughput single-strand conformation polymorphism (SSCP) analysis using automated capillary electrophoresis. The operating temperature of a commercially available capillary electrophoresis instrument (ABI PRISM 310) was expanded by installation of a cheap in-house designed cooling system, thereby allowing us to perform automated SSCP analysis at 14-45 degrees C. We have used the method for detection of point mutations associated with the inherited cardiac disorders long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM). The sensitivity of the method was 100% when 34 different point mutations were analyzed, including two previously unpublished LQTS-associated mutations (F157C in KVLQT1 and G572R in HERG), as well as eight novel normal variants in HERG and MYH7. The analyzed polymerase chain reaction (PCR) fragments ranged in size from 166 to 1,223 bp. Seventeen different sequence contexts were analyzed. Three different electrophoresis temperatures were used to obtain 100% sensitivity. Two mutants could not be detected at temperatures greater than 20 degrees C. The method has a high resolution and good reproducibility and is very robust, making multiplex SSCP analysis and pattern-based identification of known allelic variants as single nucleotide polymorphisms (SNPs) possible. These possibilities, combined with automation and short analysis time, make the method suitable for high-throughput tasks, such as genetic screening.

Alleles↗

PubMed2000

Robust multiresolution alignment of MRI brain volumes.

An algorithm for the automatic alignment of MRI volumes of the human brain was developed, based on techniques adopted from the computer vision literature for image motion estimation. Most image registration techniques rely on the assumption that corresponding voxels in the two volumes have equal intensity, which is not true for MRI volumes acquired with different coils and/or pulse sequences. Intensity normalization and contrast equalization were used to minimize the differences between the intensities of the two volumes. However, these preprocessing steps do not correct perfectly for the image differences when using different coils and/or pulse sequences. Hence, the alignment algorithm relies on robust estimation, which automatically ignores voxels where the intensities are sufficiently different in the two volumes. A multiresolution pyramid implementation enables the algorithm to estimate large displacements. The resulting algorithm is used routinely to align MRI volumes acquired using different protocols (3D SPGR and 2D fast spin echo) and different coils (surface and head) to subvoxel accuracy (better than 1 mm).

Algorithms↗

PubMed1999

Cleavage of double-stranded copy RNA by RNase 1 and RNase T1 provides a robust means to detect p53 gene mutations in clinical specimens.

Detecting somatic mutations in patient specimens is challenging because of the wide variation in quality and quantity of genomic DNA in clinically derived material. In cancer specimens, the challenge of detecting mutations is usually compounded by the presence of large numbers of nonmutated normal cells that dampen the relative signal that can be obtained from employing any mutation detection strategy. In the case of somatic mutations in the gene encoding the tumor suppressor, p53, a clinically useful mutation detection assay must be able to detect a wide variety of types of mutations scattered over five coding exons and their flanking intron sequences. This study examined the ability of a mutation detection strategy, termed NIRCA, to identify single-base mutations in the clinically relevant domain of the p53 gene. This strategy relies on RNase digestion-mediated cleavage of double-stranded copy RNA transcribed in vitro from polymerase chain reaction (PCR)-amplified genomic templates to detect mismatched base pairs resulting from hybridization of complimenting mutant and wild-type copy RNA strands. This assay system was found to robustly detect all twelve possible mismatches and the plus one and minus one frame shifts. Furthermore, the assay could detect mutations in clinical specimens when the mutant alleles composed as few as 4% of the total population of alleles isolated in bulk specimen genomic DNA. This mutation detection strategy worked efficiently in bladder, breast, colon and lung tumors as well as sediments from bladder cytology specimens.

Humans↗

PubMed2001

Interpretability and robustness of sieve analysis models for assessing HIV strain variations in vaccine efficacy.

From data on HIV-1 characteristics measured on viruses isolated from vaccinated and unvaccinated persons infected while enrolled in preventive HIV-1 vaccine trials, interpretable inferences into strain variations of vaccine efficacy can be made with recently developed sieve analysis models. Four assumptions are needed for the parameters in these models to have meaningful interpretations in terms of vaccine-induced reductions in strain-specific per-contact transmission probabilities: (A1) vaccination impacts each strain-specific transmission probability homogeneously in vaccinated persons (leaky vaccine effect); (A2) for each strain biological susceptibility to infection given exposure is homogeneous among vaccinated trial participants and among unvaccinated trial participants; (A3) the distribution of exposure is equal in vaccinated and unvaccinated trial participants; (A4) the relative prevalence of circulating HIV-1 strains during the trial follow-up period is constant. Through theoretical considerations and simulations of an ongoing phase III HIV-1 vaccine efficacy trial in Bangkok, we evaluate the importance and necessity of these assumptions. We show that the models still provide estimates of biologically interpretable parameters when A1 is violated, but with bias the extent to which vaccine protection is heterogeneous. We also show that the models are highly robust to departures from A4, with implication that the time-independent models are adequate for applications. In addition, we suggest extensions of the sieve analysis models which incorporate random effects that account for unmeasured heterogeneity in infection risk. With these mixed models, usefully interpretable strain-specific vaccine efficacy parameters can be estimated without requiring A2. The conclusion is that A3, which is justified by randomization and blinding, is the essential assumption for the sieve models to provide reliable interpretable inferences into strain variations in vaccine efficacy.

AIDS Vaccines↗

PubMed2000

The cyclic contryphan motif CPxXPXC, a robust scaffold potentially useful as an omega-conotoxin mimic.

Contryphan-R, from venom of the cone-shell Conus radiatus, represents a novel cyclic peptide scaffold onto which residues may be grafted to mimic unrelated protein surfaces. Three substitutions were made at the x and X positions of the disulfide-bridged motif CPxXPXC, where X and x represent any L- and D-handed residues, respectively, P represents proline or hydroxyproline, and C a half-cystine. These substitutions were designed to mimic part of the pharmacophore of the unrelated globular polypeptide omega-conotoxin GVIA, which blocks N-type calcium channels. The structure of this engineered contryphan, YNK-contryphan-R ([D-Tyr4, Asn5, Lys7]contryphan-R), is shown to be similar to that of native contryphan-R (Pallaghy et al., Biochemistry, 1999, Vol. 38, pp. 13553-13559), confirming that the scaffold is robust with respect to the multiple substitutions. In particular, the alpha-beta bond vectors characterising the orientation of the side chains relative to the backbone are similar in contryphan-R, YNK-contryphan-R, and omega-conotoxin GVIA, which is the required result for a scaffold-based approach to molecular design. The solution structure of YNK-contryphan-R has an N-terminal, nonhydrogen-bonded, chain reversal centered on Hyp3-D-Trp4, and a C-terminal type I beta-turn. A minor form due to cis-trans isomerism of the Hyp2-Cys3 peptide bond is present in YNK-contryphan-R in a larger proportion than in contryphan-R. It is evident, particularly from the (3)J(HalphaHN) coupling constants, that YNK-contryphan-R is more flexible than contryphan-R, probably due to the absence in YNK-contryphan-R of the Pro-Trp packing present in the native molecule. Nevertheless, the structure confirms that cyclic peptide molecular designs can achieve the intended conformations.

Amino Acid Motifs↗

PubMed2000

Robust LOD scores for variance component-based linkage analysis.

The variance component method is now widely used for linkage analysis of quantitative traits. Although this approach offers many advantages, the importance of the underlying assumption of multivariate normality of the trait distribution within pedigrees has not been studied extensively. Simulation studies have shown that traits with leptokurtic distributions yield linkage test statistics that exhibit excessive Type I error when analyzed naively. We derive analytical formulae relating the deviation from the expected asymptotic distribution of the lod score to the kurtosis and total heritability of the quantitative trait. A simple correction constant yields a robust lod score for any deviation from normality and for any pedigree structure, and effectively eliminates the problem of inflated Type I error due to misspecification of the underlying probability model in variance component-based linkage analysis.

Computer Simulation↗

PubMed2002

Anion exchange in the channels of a robust alkaline earth sulfonate coordination network.

The barium sulfonate network presented herein, [[Ba2(L)(H2O)5]Cl]infinity (1), represents the first metal sulfonate compound to possess a cationic framework. The network is layered with channels between pillaring ligands in which chloride ions reside. Compound 1 contracts slightly upon dehydration but retains its overall structural motif to 420 degrees C. Significantly, the chloride ions of the structure can be exchanged in 80% yield for fluoride ions in a facile manner. This exchange is quantified by elemental analyses, gravimetric determination, and 19F NMR spectroscopy. Confirmation of retention of structure is provided by standardized powder X-ray diffraction experiments. This last point is notable as the F-analogue of the structure is not attainable by a direct synthesis. These results illustrate one of the hallmark features of supramolecular chemistry, that a robust and functional framework can result through cooperative interactions between more weakly interacting units.

Journal Article↗

PubMed2001

Robust and cost-effective capillary electrophoresis-mass spectrometry interfaces suitable for combination with on-line analyte preconcentration.

This paper describes several successful cost-effective attempts to couple capillary electrophoresis (CE) and mass spectrometry (MS) without make-up flow or nebulizing gas. An in-depth analysis of several interfaces using conductive spray tips was performed as well as an easy-to-prepare T-junction with direct electrode contact, the latter being the most robust interface. No coating is necessary and the spray voltage is applied through a gold wire positioned at the gap between the separation and spray capillaries. The T-junction interface is made by puncturing a small piece of transparent rubber. The on-line preconcentration CE-MS system allows immunoassay sensitivity, as is demonstrated by a calibration plot in the picomolar range for angiotensin II and gonadorelin. It also shows good reproducibility and has the ability of excellent automation. The secure electrical contact gives a constant spray quality, even with 100% aqueous separation buffers. The described setup has a wide applicability as is demonstrated by the analysis of larger peptides, such as insulin and cytochrome c. Detailed information is given on critical factors in the preparation of the described interfaces.

Angiotensin II↗

PubMed2002

A robust approach for the analysis of peptides in the low femtomole range by capillary electrophoresis-tandem mass spectrometry.

A capillary electrophoresis-tandem mass spectrometry (CE-MS/MS) approach has been developed for routine application in proteomic studies. Robustness of the coupling is achieved by using a standard coaxial sheath-flow sprayer. Thereby, greater stability than nanoelectrospray ionization-mass spectrometry coupling of sheathless capillary electrophoresis or nanoliquid chromatography (nano-LC) is achieved, resulting in stable operation for several weeks and unattended overnight sequences. The applied sheath flow is reduced to 1-2 microL/min in order to increase sensitivity. Standard peptides and those of digests of standard proteins and gel-separated proteins can be detected in the low femtomole range (full scan and MS/MS). Detection limits are found to be as low as 500 amol. Low femtomole amounts are required for unequivocal identification by MS/MS experiments in the ion trap and subsequent database search. By applying a simple pH-mediated stacking the concentration sensitivity can be lowered to some tens of fmol/microL (nM), depending on capillary size. This sensitivity is close to published values for sheathless CE-MS and nano-LC-MS, respectively (a comparison to reference values is presented). Moreover, with capillaries of about 50 cm in length separations in less than 10 min are possible resulting in a throughput of up to four analyses per hour. This is a factor of 4-12 times faster than nano-LC separation, being the state-of-the-art techniques for proteomic studies.

Animals↗

PubMed2002

Application of robust pedigree analysis in studies of complex genotype-phenotype relationships in fragile X syndrome.

Relationships between the fragile X dynamic mutation and palmar and finger epidermal ridge measures were assessed using a robust modification of the maximum likelihood estimators for pedigree data. A total of 34 extended families affected with fragile X syndrome were used. Phenotypic traits included ridge count on the thumb and ridge breadth measured in the second palmar interdigital area bilaterally. Genotypic measures were represented by the number of CGG repeats in the FMR1 gene, the levels of specific FMR1 protein (FMRP), fragile X category defined by the size of the CCG repeat, and methylation status of the gene. The results demonstrated a significant fragile X effect (related to the number of CGG repeats) in the thumb ridge count in males. This effect was more evident in ridge breadth and was found in both sexes. However, the relationship between both phenotypic traits and the level of FMRP was nonsignificant. The study makes a useful contribution to the development of methodologies for the analysis of genotype-phenotype relationships in dynamic mutations, especially in overcoming extensive variability in both the genotype and phenotype, and in approaching the statistical problems related to intergenerational changes in repeat size. The findings support the hypothesis that the fragile X mutation affects limb development during an early fetal period.

Dermatoglyphics↗

PubMed1982

Robust and least-squares orthogonal mapping: methods for the study of cephalofacial form and growth.

A method is presented for the description and analysis of cephalofacial form and growth using two-dimensional coordinate data. The procedure permits the identification of shape differences at specific cephalofacial coordinate locations without reliance upon conventional cephalometric landmarks. The resulting size-standardized coordinates can be analyzed by statistical methods for further data exploration. Two methods of shape transformation--least-squares and robust fitting--are described and compared. An example of the utility of the technique for cephalofacial growth studies is provided.

Aging↗