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Classification of Companion Diagnostics: A New Framework for Biomarker-Driven Patient Selection
Cynthia Huber ORCID: orcid.org/0000-0003-2035-36821,
Tim Friede1,
Julia Stingl2 &
Norbert Benda3,1
Therapeutic Innovation & Regulatory Science volume 56, pages 244–254 (2022)Cite this article
Modern personalized medicine strategies builds on therapy companion diagnostics to stratify patients into subgroups with differential benefit/risk. In general, stratification for drug response implies a treatment-by-subgroup interaction. This interaction is usually suggested by the drug's mechanism of action and investigated in pharmacological research or in clinical studies. In these candidate genes or pathway approaches, either biological reasons for a differential benefit/risk or statistical interaction regarding a pharmacological or clinical endpoint or both may be given. For successful drug approval, demonstration of a positive benefit/risk balance in the intended patient population is required. This also applies to situations with biomarker-selected populations. However, further regulatory considerations relate to the usefulness and plausibility of the selected patients and benefit/risk extrapolations or alternative therapy options in biomarker-negative populations.
To facilitate the specification of regulatory requirements and support the design of clinical development programmes, a systematic classification of biomarker-drug pairs is needed, in particular with regard to the expected underlying molecular mechanism and the clinical evidence.
A classification of five biomarker-drug categories is proposed related to increasing evidence on the biomarker's predictive value in relation to a specific drug. We classified biomarkers into five ascending categories with increasing evidence on the predictive nature of the biomarker in relation to a specific drug according to the comparative pharmacological and clinical evidence.
The proposed classification will facilitate regulatory decision-making and support drug development with respect to biomarker-related subgrouping, both, during clinical programme and at the time of marketing authorization application, since the grade of evidence on the differential power of the biomarker can be considered as an indicator for the usefulness of a biomarker-related subgrouping.
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Precision medicine offers a promising vision on the development of new targeted drugs, in particular in areas with a high medical need. Assuming that some drugs may act differently in different patients, precision medicine is searching for a relevant interaction between patient and treatment resulting in an improved efficacy or tolerability in a given subgroup of patients. Whereas the expectations regarding tailor made medicines are high in many therapeutic areas, essentially only cancer drugs have been successfully approved yet in biomarker-defined subgroups [1, 2]. Advances in genomic sequencing increasingly lead to the investigation of genetic profiles used for stratifying patients to treatment response. In contrast to the high expectations in precision medicine, the usefulness of the biomarker-based selection of patients with respect to clinical outcomes is often not substantiated by clinical data and expectations may be too optimistic.
The investigation of a predictive biomarker profile assumes a positive treatment-by-subgroup interaction, i.e. a differential treatment effect in subgroups allowing for discriminating patient groups with different expected treatment effects. Predictive biomarkers should be capable to discriminate subgroups with different expected treatment effects related either to an efficacy or to a safety outcome, whereas prognostic biomarkers should indicate a favourable or unfavourable natural course of the disease [3,4,5]. In the context of personalized therapy, the focus is on predictive biomarkers whereas purely prognostic biomarkers are not of primary interest.
The treatment-by-subgroup interaction is usually driven by pharmacological drug action and investigated in pre-clinical research or in surrogate endpoints in clinical studies suggesting that biological reasons for differential benefit/risk and statistical interactions are interrelated. Demonstration of a true (and relevant) interaction with respect to a clinically relevant endpoint as part of a confirmatory analysis can be either done by a prespecified subgroup analyses or by a statistical model including treatment-by-subgroup interactions [6]. This, however, often remains a difficult task as the required sample sizes are often too large. Furthermore, an interaction on a specific statistical scale does not necessarily imply that there is a biological interaction but may just be induced by the choice of the scale.
Successful drug approval usually needs demonstration of the effectiveness and tolerability in the biomarker-defined subgroup but does not necessarily need a proof of the usefulness of the restriction to a limited population. However, in drugs that have been approved in a biomarker-restricted population, extrapolation of benefit risk to the biomarker-negative population may apply later on, and enlarge the indicated patient population for which a drug is authorized. In this case, heterogeneity analyses of the overall population need to be done, and data in biomarker-negative persons are required. In case a drug has been approved in a biomarker-restricted population only, and the mode of action of a drug-biomarker combination makes it unlikely that biomarker-negative persons will have a positive benefit/risk, it is unnecessary, and may be even unethical to demand data from treatment in biomarker-negative subjects. Thus, evidence of a truly predictive biomarker that is capable to discriminate patients that will benefit from treatment from those who do not is important. However, such evidence is often scarce, because clinical trials are usually not powered to detect a statistically significant treatment-by-subpopulation interaction, which is further complicated by additional sources of variability, see, e.g. [7, 8].
Extrapolation of the benefit-risk balance to the biomarker-negative population largely depends on the level of biological plausibility of the biomarker with respect to its predictivity regarding a given medicine. Biological plausibility together with the empirical evidence generated by clinical or non-clinical studies, both, define the usefulness of the biomarker with respect to stratified medicine. Since specific regulatory considerations relate to this selection of patient subgroups, the usefulness and discriminative value of a supposedly predictive biomarker is of regulatory interest as well. To facilitate the specification of regulatory requirements and to support the design of clinical development programmes, a classification of biomarkers is needed, that is capable to properly separate between empirical evidence versus biological plausibility, and allow a decision towards extrapolation of the benefit-risk balance to the biomarker-negative population. Available biomarker classifications just distinguish between prognostic (forecasting the course of the disease), predictive (predicting a differential treatment effect) and surrogate endpoints (intended to replace a clinical endpoint) [9,10,11]. The categories proposed by the FDA [12] additionally differ between diagnostic, monitoring, safety, susceptibility and pharmacodynamic biomarkers. Classifications of biomarker-drug pairs proposed by PharmGKB [13] and Vivot et al. [14] refer to the guidance for genetic testing based on the drug label and do not take the type of presented evidence supporting the type of biomarker (predictive/prognostic) into account.
Tsourounis et al. [1] discuss new options to develop diagnostic tools and new treatments for cancer, genetic disorders, and infectious diseases that may be particularly effective in biomarker-defined subpopulations, and discuss the key developmental and regulatory challenges and the importance of related regulatory and policy considerations. Ansari [15] presents an overview of the changing regulatory landscape for companion diagnostics through predictive biomarkers along with the challenges associated with developing a successful global regulatory strategy for a companion diagnostic. Enzmann et al. [16] describe the EMA's principles for the assessment of the impact of companion diagnostics on the benefit–risk balance of medicines.
Patient subgroups are often defined based on biomarkers; the subgroup serves various purposes including improved definition of the disease or prognosis, exclusion of patients at increased risk of harm, prediction of beneficial drug response [17]. However, the evidence justifying the selection of patients based on specific biomarkers is highly heterogeneous. Within the scientific advice procedures at EMA, specific procedures are dedicated to support the qualification of innovative development methods including qualification of new biomarkers, see, e.g. [18] for novel biomarkers in Alzheimer disease. This procedure as well as FDA's biomarker qualification programme offer the possibility to drug developers to discuss new biomarkers with respect to different context of use. For qualified biomarkers "specific interpretation and application in drug development and regulatory decision-making" can be relied upon within the stated context of use during drug development [19]. Although a specific interest lies in the capability of the biomarker to define a relevant patient population to be treated, the main focus of biomarker qualification is often on the prognostic value of a biomarker. In contrast, evidence for the predictive value of a biomarker, although more relevant to the indication of the related drug, is often sparse or unclear. Sources of this evidence are diverse, its relevance may be vague and a clear classification of the degree of evidence is missing.
Therefore, a framework is needed that allows for a reasonable classification of the underlying evidence resulting in regulatory and scientific recommendations for biomarker-based selection.
In this paper we propose a framework that allows for a classification according to the available evidence with respect to the biomarker's capability to select subpopulations in which the benefit (or benefit-risk) of a given treatment is expected to be considerably superior to that in the complementary group. To illustrate the proposed classification and the available evidence in successful past approvals, we give examples for each category of biomarker-related drug approvals. The different classification groups should support regulatory decisions on clinical study/evidence of treatment data in biomarker-negative patients. The consequence of a biomarker test could then be used (1) to exclude biomarker-negative patients from treatment, (2) to stratify treatment to different dosing/ combination treatments/alternatives, (3) to be aware of an altered safety/efficacy risk in the biomarker-negative populations (as an example, resulting in a warning information in the Summary of Product Characteristics (SmPC)). It is further suggested that the use of promising biomarkers in precision medicine is not self-evident and that methodological effort is needed to substantiate the usefulness of a biomarker in the presence of limited clinical databases.
The development of the classification scheme involves the following aspects: the evidence for predictive and/or prognostic biomarkers, the data type and the need for dichotomization, the scale of the effect size and the type of outcome related to the differential treatment effect.
Essential Aspects for Biomarker Classification
Data Type and Dichotomization
A prognostic or predictive biomarker may be a binary, categorical or continuous variable. Often an originally continuous outcome is dichotomized to split the overall patient population. Dichotomization and specification of the cut-off value used are relevant for the size of the differential treatment in the resulting biomarker-defined subpopulations.
Predictive and/or Prognostic Biomarker
A predictive biomarker predicts the response or lack of response to a particular treatment relative to another available treatment: Patients with specific values of the biomarker are expected to profit from the treatment more than others, i.e. the expected effect difference to a control in these patients is larger or smaller than in the others. A predictive biomarker is measured to determine the best treatment prior to the start of treatment. In statistical terms, a predictive biomarker implies a non-negative interaction between biomarker and drug. In contrast, a prognostic biomarker forecasts the course of the disease. Figure 1 shows how prognostic and predictive biomarker differ regarding the outcome in biomarker-positive patients (BM+) and its complementary group (BM−).
Schematic description of prognostic and predictive biomarkers related to differential treatment outcome. BM+ denotes biomarker-positive patients and BM− refers to biomarker-negative patients
Example for evidence on a predictive role of a biomarker: Gefitinib (IRESSA) was approved in the EU in 2009. In the initial application, the applicant had submitted a marketing authorisation application (MAA) for the following indication: IRESSA (gefitinib) for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) eligible for further chemotherapy after receiving prior platinum based chemotherapy [19].
Corresponding to the proposed indication, progression free survival was significantly improved in the overall population (HR = 0.74, 95% CI (0.65, 0.85), p < 0.0001) [20].
However, following the assessment and objections raised by the CHMP, a new indication was proposed: IRESSA is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK [21]
In a clinical study (IPASS), treatment effect sizes with respect to objective response rate as well as progression free survival were clearly different in EGFR mutated patients as compared to EGFR non-mutated patients. Whereas a positive effect compared to Paclitaxel was shown for EGFR mutations, a negative effect was seen in non-mutated patients. Although this result was obtained in post hoc analysis where the majority of the patients could not be classified with respect to EGFR mutation, the result suggested a clear interaction between treatment and biomarker, though much less important in overall survival, see Table 1.
Table 1 Example: Results of the IPASS Study comparing Gifitinib (Iressa) vs carboplatin–paclitaxel in selected NSCLC patients [10]
Hence, EGFR mutation can be regarded as a predictive biomarker with respect to Gifitinib and the endpoints ORR and PFS with highly significant results on the corresponding interaction. Accordingly, the indication of IRESSA was restricted to adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR tyrosine kinase.
Treatment Effect Scale
The scale on which the effects are evaluated matters and may lead to different conclusions: e.g., an effect may be given either as a difference in response probability (risk difference) or as the corresponding odds ratio. A prognostic biomarker would lead to an increased response probability in both study arms (verum or placebo) in the biomarker-selected subpopulation (BM+). Whether the effect difference of the active drug compared to control is larger in BM+ depends, however, on the scale used, as illustrated in the hypothetical example in Table 2, where no interaction is given for the risk difference, but a positive for the odds ratio [21]. More generally, if a positive treatment effect is given, the absence of interaction on one scale usually implies a non-zero interaction on the other.
Table 2 Hypothetical example: Scale dependency of predictive biomarker selection given a prognostic biomarker. Biomarker is predictive w.r.t. the odds ratio but not w.r.t. the risk difference
It is therefore important to base the assessment of the biomarker-drug pair on a specific scale that is considered most relevant.
Type of Outcome Related to the Biomarker's Predictivity: Efficacy/Safety/Exposure
In this category it is assumed that the biomarker is linked to specific efficacy measures but not to the tolerability of the drug. I.e. an interaction between drug and (dichotomized) biomarker is given for a relevant efficacy parameter.
In this category the biomarker is linked to specific safety measures but not to the efficacy of the drug. I.e. an interaction between drug and (dichotomized) biomarker is given for tolerability/safety (involving a different risk ratio in both subgroups).
Metabolism, Efficacy and Safety
In this category the biomarker is linked to both efficacy and tolerability of the drug, especially in those settings where the biomarker measures the metabolic activity, and biomarker-positive patients are expected to undergo a higher drug exposition than others potentially leading to a higher efficacy but also to a lower tolerability. In these cases, dose may be adjusted according to the categorization by the biomarker. Full dichotomization may not necessarily be useful in these cases.
Evidence Based Biomarker-Drug Classification
In general, there is a need to differentiate biomarkers that are purely prognostic from those that are predictive since a prognostic marker would not necessarily justify that a part of the patients are not treated with the new treatment. Also given the difficulties to fully investigate the interaction between biomarker and treatment with respect to the relevant clinical outcome at least in a medium-sized clinical trial as described in "Introduction" section, it appears paramount to classify a biomarker-drug pair with respect to the biomarker's capability to properly identify the drug target preferably prior to large clinical investigations, see, e.g. [5]. A clinical trial that is powered to detect an interaction in a clinical endpoint indicating a predictive biomarker would usually be rather large unless the interaction is extremely large.
The usefulness of a biomarker for a given drug has to be assessed with respect to the biological plausibility relating to the pathogenic process and the drug's mechanism of action and the empirical evidence determining the capability to predict a certain drug effect. Hence, two dimensions should be considered in a classification of biomarker-drug pairs. The first dimension concerns the mechanism of the biomarker measuring the drug's action, i.e. the biological plausibility of a biomarker acting directly in the drug target. The second aspect concerns the precision of the biomarker in predicting the clinical outcome in drug efficacy or safety, regardless of the pharmacological mechanism behind.
Therefore, we propose to classify biomarker-drug pairs according to the pharmacological mechanisms and biological plausibility on one hand and the evidence with respect to clinical data on the other. In both cases the evidence is called comparative, if conclusions can be made whether the treatment benefit is differential with respect to the biomarker-related selection, which is related to the predictive value of the biomarker. Evidence may be derived, e.g., from a comparative animal or clinical study where a specific drug is compared to a control or relate to the specific drug action or target. If, e.g., a biomarker characterizes the drug target, it may be assumed that biomarker-positive patients benefit more than biomarker-negative patients. If the mechanism of action indicates that biomarker-negative patients may be harmed by the drug, ethical considerations might prevent the inclusion of biomarker-negative patients into clinical studies. If comparative evidence is given, the biomarker is specific to a given drug. Clinical evidence is considered to be comparative if clinical data are given that allow for evaluating the interaction between drug and biomarker.
In that sense, we propose the following higher-level classification:
A: biomarkers with non-comparative pharmacological evidence only
These are biomarkers where pharmacological mechanisms indicate a prognostic value, but that is unrelated to the drug target. Clinical investigations on any predictive value are not available. Nevertheless, indication of a prognostic value may qualify these biomarkers as candidates for predictive biomarkers requiring further investigations regarding the pharmacological effect in BM negative and BM positive patients.
This category includes phenotypes of drug action mechanism that may not be causally linked to the pathogenetic process, usually because of incomplete knowledge about the molecular mechanisms that link the biological effect of the drug with response. It applies to biomarkers that measure the effect of the drug on their biological substrate, where the causal relationship between this substrate and response is unknown or uncertain. A weak causal link between molecular drug action and response may be suggested. It includes phenotypes whose association with response may exclusively be of statistical nature. These biomarkers may still be predictive, but the mechanism at the basis of this prediction is essentially unknown.
B: biomarkers with comparative clinical data only
In this category comparative clinical data are available but with respect to the knowledge about the molecular mechanisms its characterization is similar to those in group A. With other words, unless a well conducted large trial stratified in BM positive and negative patients has demonstrated a significant interaction, a chance finding regarding the biomarker's predictivity cannot be excluded. It appears highly unrealistic that a biomarker without sufficient information on its causal link to molecular drug action is investigated in a large clinical trial and shown to be predictive.
C: biomarkers with comparative pharmacological evidence
These biomarkers are to be characterized based on the phenotype's capability to identify the causal mechanism that is responsible for therapy. Within this group, biomarker phenotypes may be classified into several groups, characterized by decreasing degrees of identification of a causal link between the phenotype and response.
This group consists of phenotypes that measure a pathogenetic process, such as a molecular mechanism of pathology, on which the drug directly acts. This phenotype is causally most specific, since it detects changes in the mechanism that is itself contributing to the disease pathology.
This group provides reasonable candidates for further investigation in subsequent clinical trials or for further analysis using data from existing trials. However, in cases where pharmacologic evidence suggests negative effects on patients, clinical evidence (as requested in the following levels) of a differential treatment effect in subgroups becomes unnecessary or impossible because of ethical concerns.
D: biomarkers with comparative pharmacological and clinical evidence
These biomarkers are to be characterized by the evidence described for group C and for which clinical data have been generated that allow for evaluating a differential effect in BM+ and BM− patients.
This is related to the predictive value of the biomarker. Evidence may be given, e.g., from a comparative animal or clinical study where a specific drug is compared to a control or relate to the specific drug action or target. If, e.g., a biomarker characterizes the drug target, it may be assumed that biomarker-positive patients benefit more than biomarker-negative patients. If comparative evidence is given, the biomarker is specific to a given drug.
E: biomarkers demonstrated to be predictive in confirmatory clinical studies
This group relates to the biomarker-drug pairs from group D for which a confirmatory clinical trial stratified in BM positive and negative patients has demonstrated a significant and relevant interaction between biomarker selection and treatment. For this group highest evidence for the usefulness of the biomarker would be given. It would require a pre-planned confirmatory analysis strategy. However, due to the fact, that sample sizes that exceed usual clinical trials are required to detect at least moderate interaction sizes, biomarker-drug pairs falling into this category are expected to remain scarce.
Types of Biomarker Predictivity
For biomarker-drug pairs from category C, D and E several aspects like the pathogenetic mechanism, biomarker-efficacy and biomarker-safety relationship should be considered. Here we can distinguish three cases. For each case, we present examples of biomarker-drug pairs with comparative evidence in Table 3.
The first example refers to a molecular change that is indicative for pathology and is also the direct drug target (e.g. BCR-Abl). The drug can act only in cells in which the molecular change assessed by the biomarker is present. Therefore, the efficacy is zero in biomarker-negative patients.
The second example refers to a biomarker measures a specific pathway activation (e.g. driver mutation in tumour) but the efficacy finally depends on other surrounding factors like tumour heterogeneity or context of driver mutation (additional mutations downstream). In this case, drug response may depend not only on biomarker detection, and the biomarker may not be valid in all contexts (reduced biomarker specificity): as an example, K-ras is valid as biomarker in colon cancer but not in lung cancer for the detection of an inactive EGFR pathway in treatment with EGFR inhibitors.
In the last example, potential drug targets (gene expression/genetics of EGFR, Her2) are estimated quantitatively. The drug effect on quantitative estimation is potentially contaminated by noise, what raises the issue of precision of estimate. Moreover, the efficacy depends on the overall quantitative amount of the target molecule and diagnostics relies on biopsy locus, time and tissue contribution.
Table 3 Examples of biomarker-drug pairs with comparative evidence
Some biomarker-drug pairs cannot be classified into categories D or E as its pharmacological comparative evidence (level C) suggests that the risk benefit becomes negative in BM- patients. Therefore, the generation of data in BM- patients needed for levels D and C may be unethical.
Examples of Biomarker-Defined Drugs Approved by EMA
In the following, we present examples of 10 biomarker-drug pairs of 9 drugs for the proposed categories approved by the European Medicine Agency (EMA).
Identification of biomarker-defined drugs which are authorized in the EU is based on the PharmGKB Database [9]. Evidence for biomarker-defined subgroups are taken from documents published on http://www.ema.europa.eu like European Assessment Reports (EPAR) or SmPC [22,23,24,25,26,27,28,29,30].
Table 4 gives an overview of these biomarker-drug pairs classified in the proposed categories. The drugs' indication is extracted from the drug labels published on the EMA homepage. Moreover, this table includes the biomarker's data type, the type of outcome related to the biomarker-drug pair and the PGx label of PharmGKB referring to the genetic testing proposed in the drug labels of the EMA and US Food and Drug Administration (FDA).
Table 4 Examples of biomarker-drug pairs classified according to their evidence
Table 4 gives examples of biomarker-drug pairs where comparative evidence either on a non-clinical level or both on clinical and non-clinical level is given (categories C and D). No biomarker-drugs pair could be identified yet, where sufficient confirmatory evidence (category E) is given to fully demonstrate biomarker-drug interaction on clinical endpoints. It is important to note that our proposal classifies the given evidence for biomarker-drug pairs. The available evidence on a biomarker-drug pair can change when further studies on biomarkers or biomarker-drug pairs are conducted. Therefore, the category a biomarker-drug pair is assigned to can change over time and has to be updated regularly.
For instance, osimertinib is classified into category C which means that only comparative pharmacological evidence is presented for the biomarker EGFR T790. Osimertinib is authorized for the treatment of advanced non-small cell lung cancer as first-line treatment for patients with activating epidermal growth factor receptor (EGFR) mutations or for patients with EGFR T790M mutations. Based on the EPAR [26] the inhibitory activity against EGFR was demonstrated in vitro. Tumour shrinkage in EGFRm and T790M NSCLC mouse lung tumour models was showed in vivo. However, the clinical studies for osimertinib did not include any patients without EGFR mutations. Therefore, osimertinib is classified into category C as EGFR is considered to be predictive for osimertinib based on pharmacological evidence, but it is not supported by clinical data.
An example for category D is vandetanib authorized for the treatment of medullary thyroid cancer [27]. For patients without Rearranged during transfection (RET) mutation the EMA drug label states a potential lower benefit of vandetanib compared to patients with RET mutation. Based on study 058 the hazard ratio (HR) of progression free survival (PFS) in the subgroups of RET mutation positive patients (n = 187) was 0.45 (95% CI 0.26–0.78), whereas in 79 patients proven without M918T mutation and with no other RET mutation the HR of PFS was 0.57 (95% CI 0.29–1.13), For vandetanib clinical data support the evidence of a differential treatment effect in patients with and without RET mutation and is therefore classified into category D.
Biomarkers used to define specific subpopulations of patients constitute the basis for a stratified or personalized medicine. In this context they are intended to predict either an improved treatment effect or a better safety profile in those patients who are defined by this biomarker. In contrast to prognostic biomarkers that indicate a favourable or unfavourable course of the disease, predictive biomarkers are capable to discriminate patient groups with different treatment effects.
Due to the potentially limited evidence on predictive biomarkers, difficulties in differentiating prognostic and predictive biomarkers and the possibility of chance findings in searches for biomarker-by-drug interactions in the presence of multiple options, it appears paramount to use a scheme that indicates increasing evidence for the usefulness of the biomarker.
In this paper we proposed a classification of biomarkers that is related to the mechanism of action, the relation to the drug target, and to the clinical evidence. The classification helps to differentiate levels of evidence and to assess whether current evidence is acceptable for drug-specific definitions of patient subgroups. The proposed classification could be used to strengthen and focus the discussion of novel biomarkers in the FDA's and EMA's biomarker qualification procedures and improve the comparability between different biomarker-drug pairs using clearer criteria. In addition, emerging new evidence (e.g. new clinical data in biomarker-defined subgroups) may be integrated by updating the initially proposed classification. Classification is based on the currently available evidence (with unclear evidence resulting in a lower classification) and could be upgraded in case new evidence is available. The proposed classification could be implemented in regulatory scientific advice to inform either further clinical development or the indication and product characteristics.
We classified biomarkers into five ascending categories with increasing evidence on the predictive nature of the biomarker in relation to a specific drug. Three subtypes are proposed to further describe the relation of the drug target. This classification is expected to support regulatory decision-making with respect to biomarker-related subgrouping, both, during clinical programmes and at the time of marketing authorization application. Whether a biomarker-related subgrouping is useful or not depends on the level of evidence.
In order to demonstrate the applicability of the proposed classification, we identified drugs with labels containing pharmacogenetic information. The corresponding biomarker-drug pairs approved by the European Medicine Agency were classified based on the proposed scheme. Typically, drugs classified in category C (biomarkers with comparative pharmacological evidence) were authorized in a biomarker-defined subgroup, only. We would like to encourage the collection of data in biomarker-negative patients to estimate the treatment effect in these patients as well unless prevented by ethical considerations. Nevertheless, these analyses do not require statistical significance; rather they are intended to substantiate stratification, refine the drugs indication and potentially improve benefit-risk. They could suggest, underpin or demonstrate a differential treatment effect, and hence support regulatory decision-making with respect to the definition of the patient population.
In other categories, empirical evidence is required. Here, studies using an adaptive enrichment design that adaptively select the population of interest can be used for efficient clinical development programmes [31, 32].
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This work was co-funded by the BfArM and the University Medical Center Göttingen and is a result of the collaborative project Identifikation und Konfirmation von Biomarker-definierten Populationen in der personalisierten Pharmakotherapie ("Identification and confirmation of biomarker-defined populations in the personalized pharmacotherapy").
Department of Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, 37073, Göttingen, Germany
Cynthia Huber, Tim Friede & Norbert Benda
Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Julia Stingl
Research Department, Federal Institute for Drugs and Medical Devices, Bonn, Germany
Norbert Benda
Cynthia Huber
Tim Friede
Correspondence to Cynthia Huber.
The views expressed in this article are the authors personal views and do not necessarily represent those of the Federal Institute for Drugs and Medical Devices (BfArM).
Huber, C., Friede, T., Stingl, J. et al. Classification of Companion Diagnostics: A New Framework for Biomarker-Driven Patient Selection. Ther Innov Regul Sci 56, 244–254 (2022). https://doi.org/10.1007/s43441-021-00352-2
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Roberto Candido (born 13 March 1993) is an Italian football player.

Club career
He made his Serie B debut for Sassuolo on 27 March 2011 in a game against Siena.

On 9 July 2015 Bassano announced to have signed him on a free transfer.

References

External links

1993 births
Sportspeople from Monza
Living people
Italian footballers
Association football midfielders
U.S. Sassuolo Calcio players
F.C. Südtirol players
A.C. Monza players
Aurora Pro Patria 1919 players
Bassano Virtus 55 S.T. players
Calcio Padova players
Rimini F.C. 1912 players
Serie B players
Serie C players
Footballers from Lombardy

redpajama_set_name: RedPajamaWikipedia


Bishutin S.G., Tulpinova N.V., Mitin A.S. Estimation of stability of abrasive disk on criterion of maintenance of complex parameter of quality of processed surface. The results of research on estimation of changes of single and complex parameters of quality of processed surface during exploitation of abrasive disk are presented.
Key words: grinding; quality of a surface; stability(resistance) of the tool; super firm steel.
Serenkov P.S., Solomakho V.L., Gorlenko O. A. Methodology of quality management systems creation using approaches of compound systems organizational design. The application possibility of approaches of compound systems organizational design was well-founded for quality management systems (QMS) engineering component creation. The QMS complex modeling algorithm was developed, including development and analysis of the three interrelated models (functional, data collection and analysis system, decision making model).
Key word: quality management systems; engineering component; models; organizational design; compound systems; analysis.
Korsakova I.M., Korsakov A.V. Improvement ergonomicheskih features of the equipment for provision of safety to vital activity of the enterprise. The Problem of the work – consider the questions an human factors to modernizations of the technological equipment, show their urgency for comfort and safe condition creation of the personnel and decisions of the row ecological and economic problems industrial enterprise. In work are brought some examples the human factors to modernizations of the technological equipping the machine-building enterprise.
Key words: human factors, modernizations of the technological equipment; comfort and safe condition creation of the personnel; modern requirements to ecological safety; ecological standardization; installing the reliable protectors; need for modernizations.
Kazakov V.S., Klimenko T.V. Modern methods of research the indices of reliability and environmental safety by operation of power and technological equipment. The results of review, systematization and analysis of normative documents, recommendations of designing organizations and industrial enterprises, research materials from special literature about the diagnostic methods of indices of reliability and environmental safety of power and technological equipment.
Key word: power plant; operation; reliability diagnostics; environmental safety.
Malinkovich M.D. Research of straight line gears mesh. The process of straight line gears mesh as process of self-excited oscillation what is the result of the action quasi-elastic dynamic forces are considered. Vacillating blanket of gears represents like shock-absorber. Some recommendations to softening actions of forces are gives.
Key word: gear mesh; vacillating blanket; dynamic forces; gearing.
Titenok I.A. Conception of increase the evolvent toothing efficiency. The process of development of cylindrical powertrains of machine tools driving gears is investigated by the method of historical and technical analysis. The system of views on the development of the forms of teeth profiles is formulated. The practical recommendations on improving the quality of contact interaction of teeth surfaces are posed. They are represented as inventions.
Key words: gearing; toothing; contact; deterioration; lubrication; microspheres.
Gorlenko A.O., Matlakhov V.P., Shetz S.P. Tribotechnical tests of bearings automobile electr îstarters. The technique of bench tests of bearings of automobile electrostarters and technological methods of reception on their surfaces of antifrictional wearproof coatings by spraying the nitride of the titan (TiN) with the subsequent electromechanical processing are submitted. By results of bench tests conclusions about influence of strengthening technologies on wear resistance of bearings are made.
Key words: bench tests; tribology; modeling; maintenance and increase of wear resistance; a nitride - titanic coatings; electromechanical processing.
Tarasik V.P., Mrochek T.V. Methods and stand for testing of steering boosters. On the basis of the methods of the stand test of hydraulic steering boosters, prescribed by the standard of the Council for Mutual Economic Aid 1629-79, is designed methods of the test of hydraulic steering boosters, including both test, provided by standard, and complex of the test, offered by authors. The requirements to construction of the stand, realizing improved methods of the testing of hydraulic steering boosters, are stated.
Key word: hydraulic steering boosters; methods of the stand test.
Gogolev I.G., Drokonov A.M., Nikolaev A.D. Automatic monitoring system of turbo machine rotor axial load. The paper considers power and design characteristics of electromagnetic control piston devices. The article offers automatic control system of the level of axial force effecting turbo machine thrust bearing.
Key words: axlied effort; thrust bearing; electric magnet; turbine rotor; control system.
Gornostayev N.S. The model of the reliability of system of electrical apparatuses with the discrete change of conditions in the course of time. The article considers the application of the statistical tests method for the reliability evaluation of the reserved electrical apparatus.
Key word: Reliability; modeling; system; condition; refusal; relay; reserving.
Lagerev A.V., Lagereva E.A. Mathematic simulation of liquid film kinematics and separation in steam turbine elements. Mathematic models of liquid film kinematics and separation in characteristically steam turbine elements are considered in this article.
Poroshin V.V., Bogomolov D.Y., Radygin V.Y. The fem based program module for calculating of leakages in the ring seals. This paper presents the mathematical model of the flow of a liquid in the axisymmetric ring sealsThe program module for calculating of leakages is presented. It was based on the finite-elements method. This program module was tested on the modeling experiments.
Key words: leakages; tightness; fem; Reynolds approach; axisymmetric ring seals; program module.
Nifaeva O. V. Consideration of Regulations Requirements in an Audit of the Enterprise Financial Statements. The audit regulating models are covered, the necessity of legislation requirements consideration in an audit of the enterprise financial statements is substantiated. The auditor's activities when revealing the facts of regulations infringement by an enterprise considering the audit practice in Russia and valid legislation are analyzed.
Key words: audit; financial statements; audit regulating; auditing standards; regulations infringement.
Konovalova G.E. The experience of working out of the outlay management system at the big industrial enterprise. The problems of outlay's management and its influence on the enterprise activity are considered. The ways of problems decision with use of detailed methodology of production's and outlays planning and calculation in one model are offered.
Key words: system; model; planning; methodology; calculation.
Erohin D.V., Strizhakova E.N., Strizhakov D.V. Risk estimation methods, used at introduction risk-management in the industrial enterprise. Working of enterprises in the conditions of changing external environment implies the presence of mechanism for the effective protecting from its negative influence. Present contradictions and threats into an enterprise also compel to search the ways for the possible harm reduction. In the article the analysis of existent methods of risk estimation is given and there are recommendations how to use them in the conditions of the industrial enterprise.
Key words: Risk-management; estimation and management of risk; methods and technology of an estimation of risk; introduction of elements of risk-management at the industrial enterprise.
Evenko V.V., Soldatenkov V.Y. Public-private partnership: the alliance of scepter and capital. There are considered the main characteristics and features of public-private partnership. There is given the analysis of the necessity of public-private partnership development in Russia. A brief analysis of the problems of public-private partnership development in Russia, in particular concession development, has been done. There are shown the basic measures for the development of public-private partnership.
Key word: public-private partnership; concession; state; business; public ownership.
E.A.Dergacheva, N.N.Chernetsova. Increasing competitiveness and quality of educational services in the university. Universities must increase quality and competitiveness of educational services in accordance with the European Association for Quality Assurance in Higher Education (ENQA).
Key words: competitiveness; quality; european association for quality assurance in higher education.
Reveko L.S. Social cultural aspects of foreign communication professional-oriented training. There are considered the purposes of inter language communication student training. There are given the methods of using authentic materials and video-audio means in the lecture-room.
Key words: social cultural skills; an authentic text; linguistic country-studying; foreign communication; a translator.
Vorontsova U.A. Taking international exams on English. There are considered the conditions and possibilities for taking international exams on revealing the level of knowing English. There are analyzed the levels of knowing English, considered by the Russian, European, British standards and there are stated the exams which correspond to each level.
Key words: international examinations; to issue a license; to reveal the English skill levels; to get the international certificate; lexical-grammatical means; to determine the examination format.
Trubnikov S.V. The new approach to the numerical solution of linear boundary problems for ordinary second-order differential equations. The new approach to the building of new numerical methods of solution of linear boundary problems for ordinary second-order differential equations is proposed. The new effective numerical method of solution of linear boundary problems for ordinary second-order differential equations is considered.


text:
Criminal Minds mistakes
West Side Story ending
The Amazing Spider-Man 2 mistakes
Dark Shadows questions
The Dark Knight Rises trivia
Hunt for the Wilderpeople quotes
Boy Meets World mistake picture
The Nightmare Before Christmas plot
Question: When Aragon and the others were a day's journey behind the Uruk-hai in the canyon, and one of the Uruk-hai was able to smell "man-flesh", so how is it that the Riders of Rohan were able to sneak up on the Uruk-hai while they are camped by the forest and the Uruk-hai not smell them?
Answer: We don't know that they didn't smell them. We just know that the riders found the camp and that there was a fight. If you read the books, it says that they knew the riders were coming, but there was no way they could outrun them on the plain; they headed for Fangorn Forest, hoping they wouldn't follow, but the riders caught up with them just outside of it. Obviously, some things are skipped in the movie, so it's a little less fluid. Check out The Two Towers, ch. The Uruk-Hai, about 1/2 way into the chapter.
The Matrix Revolutions (2003)
Question: When Neo and Trinity are flying towards the machine city, a sentinel hovers in front of the hovercraft and flies directly into the windshield. In later scenes the glass is not broken so it couldn't have gone through the ship (no physical damage either) but it flies through Neo in the "Matrix vision" and it obviously affects him. I don't understand what happens here.
Answer: He felt its 'consciousness', or rather its life force. When the Sentinel was destroyed, its machine essence remained suspended, and Neo felt it.
furious1116
Fight Club (1999)
Question: Near the beginning of the film when Edward Norton and Meatloaf are hugging Edward's character says something along the lines of "things like this make me grow a big rubbery one". What does he mean by this, exactly?
Answer: Sharing of feelings and hugs and crying are the antithesis of arousal. While something erotic or bad-ass might cause him to have an erection, this scene causes the opposite: a rubbery one would be a flaccid, unexcited penis, flopping around like rubber (not stiff). A mood killer.
The Lord of the Rings: The Fellowship of the Ring (2001)
Question: In an interview in the Extended DVD Peter Jackson says at one time that they had cast the character of Aragorn "a little too young" and changed their decision to Viggo Mortensen on pretty short notice. Just wondering, does anyone know who they had originally cast as Aragorn?
Answer: Stuart Townsend was originally cast as Aragorn but after filming a few scenes it was deemed he was a little too young and Viggo Mortenson was cast as Aragorn.
Question: How are Indy and Marion able to avert the Angel of Death by merely closing their eyes?
Answer: The Angel of Death can only kill those who look directly at her/it, therefore closing their eyes killed only the Nazis and Belloq.
Question: Why is the Black Pearl able to sail so fast (let alone faster than the Interceptor) with tattered sails? If the ship is cursed like the crew, then you'd think they'd only look tattered in moonlight. And even still, it's hard to settle why a cursed ship would be faster than normal. The curse means the crew can't be killed, not that they're superhuman. So how does the "supership" come into it? It might have been the crew using the oars, but the Pearl sails just fine even without the oars. With those sails, it shouldn't be moving hardly at all.
Answer: First of all, the tattered sails are only to make it look more the part of a ship or a cursed crew. While still technically a mistake, it is intentional. Secondly, the curse has nothing to do with the speed of the Pearl. It is the fastest, as it is the best built ship of the time.
X-Men 2 (2003)
Question: What happened to Jason? I know Stryker said he died but it sure didn't seem like that.
Answer: Of course he died! He was left in the collapsing/flooding cerebro, which Professor X was only barely rescued from safely.
Question: I don't know if this can be answered, but does Rose die at the end? And why does she throw the necklace into the ocean at the end of the movie? I have a feeling it was left unclear so everyone has different interpretations of the movie, but I was hoping someone may have information to give a definite answer to these 2 questions.
Answer: Rose does die at the end. She dies above the wreck of the Titanic and returns to the ship (metaphorically) with all those who perished on. I think she throws the necklace into the ocean because people should be interested in what happened and feel sorry for those who died rather than to look for treasures (my interpretation).
My interpretation is that she threw the diamond into the ocean giving her heart and the heart of the ocean back to Jack or the Titanic.
Answer: The ending is left ambiguous. After lying down in the bed she either, a) has one more dream of Jack or b) has died in her sleep and is now reunited with Jack.
Answer: According to director James Cameron, what happened to Old Rose is ambiguous so that people watching the movie can decide for themselves if she is still alive and having one more dream about Jack or if she had finally died and is now reunited with Jack. According to the actual screenplay, "We PAN OFF the last picture to Rose herself, warm in her bunk. A profile shot. She is very still. She could be sleeping, or maybe something else."
Answer: My interpretation is that Rose dies. Prior to Jack's passing, he makes her promise that she will never let go of the will to live. He tells her how she will go on to have a few babies, live a life full of adventure, and die in a warm bed at a very old age. He makes her promise that she will never let go of the will to live no matter how hopeless a situation may seem. After telling her story of Jack, we see her in a warm bed surrounded by photos of her life. The photos are of her family, a glamour shot from her time as an actress, a photo of her by an airplane, and lastly, one of her on a horse, at the beach, by the Santa Monica Pier. As she has fulfilled her promise to Jack, while also returning the diamond [as Mr. Lovett now sees the real value is that of life and no longer has any interest in it], she passes away in her sleep. The final scene shows her back on Titanic, which may also represent her afterlife, marrying Jack as only the people who perished in the sinking are featured.
Invader_Gir
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Question: What is the name of the style of the Merovingian's tie knot? How is it done? He also has a different mystery style in the dinner and fight scenes in Reloaded.
Answer: In Reloaded the knot always looked to me as if it's a regular necktie, tied in a windsor knot, only backwards. At a lot of angles it's tricky to see, but the narrow end of the blade is at the front, and the wide end is at the back. Tie a windsor and turn it around, you'll see. One method to duplicate the Merovingian's knot from Revolutions is to first tie a normal Windsor knot. Then with the small blade of the tie from behind, wrap it loosely around the base of the knot twice, tucking it through the loop you've just made down the back again.
Question: This is for all 3 of the movies. I know that they are filmed in New Zealand but are they filmed on the North Island, the South Island, or both?
Answer: Both. See, for example, http://www.tourmasters.co.nz/tm/content.cfm/ID/25
Question: Often when Gollum is in the middle of a sentence, he will cough the words "Gollum, Gollum". Why is that? It does that in the book too but I don't understand it.
Answer: It is not known exactly why he makes this noise only that it started after he recieved the ring. Since any people that knew him are now dead or have forgotten his name, the sound he makes (gollum,gollum) is what people now call him.
bessytheevilcow
The Ring (2002)
Question: Why was the videotape made? I don't think it was ever explained.
Answer: The tape was never made as such, Samara projected the images onto the tape when the college kids tried to record the football match. In the original novel she is trying to spread her curse across the country - each person will see it and pass it on to another person, or two other people to be safe and so on until everyone is infected. There is no reason given - she is just angry with the world after her mother's death.
28 Days Later (2002)
Question: The box for the Region 1 DVD of this movie says that there are 3 alternate endings on the DVD, but I've only seen two listed (one showing Jim dying in the hospital, the other being an almost identical version of the original ending, but with Jim cut out). Does anyone know where the last alt. ending is located on the disc?
Answer: Special Features -> Alternate Endings then at the bottom of the page is a arrow pointing right. Select this and you get the option "Radical Alternative Ending". It is worth seeing since it is much more than an ending. It is a completely new film starting at the point they reach the roadblock in Manchester. It is presented in storyboard format.
Question: Trolls usually turn to stone if they are exposed to daylight (like in the Hobbit). How is it then that the trolls that were opening and closing the Black Gate (when Sam and Frodo wanted to try to sneak in after the foreign army) weren't turned to stone and it was the middle of the day?
Answer: It was so cloudy that not enough sun came through. Or it could be that the Trolls were of Sauron's new Troll-breed, Olog-Hai, who could withstand direct sunlight
Empire Records (1995)
Question: When Mark is watching a video in which he views himself being swallowed by a random monstrosity, he says, "I love you Eddie." Now, I took it as a reference to the "Eddie" that was part of a famous Iron Maiden stage show back in the eighties. A friend of mine took it as him (Mark) being thankful for his friend, Eddie, giving him the drug inbibed brownies that he was eating. Which was it?
Answer: I'm pretty sure it was the Eddie that gave him the brownies, because the band we see that is onstage at the time is Gwar, if I am not mistaken. They were famous for having a monster onstage that would 'eat' fans.
Yeah, cause Eddie gave him the pot brownies that made him hallucinate being in a Gwar show, so he's thanking him.
Question: When they are having thanksgiving at Harry's and Peter's apartment, why does Norman get up and leave so quickly?What has come to his attention?
Answer: Seeing the cut on Peter's arm makes him realise that Peter is Spider-Man, as Spider-Man was injured in the same area earlier. He leaves either to stop himself losing control and/or to plan his next moves.
Question: I've just rented the Director's Cut and I'm wondering what differs from the original. I've seen the original so many times I almost know it by heart and I couldn't find anything different in the DC.
Answer: According to the IMDB, "This was supposed to be the director's cut with additional 20 seconds of footage. But due to company policy (which does not allow to release unrated DVDs), the same cut as on the 1997 DVD was put onto this DVD. The director's cut was available on laserdisc."
Mulholland Drive (2001)
Question: Can somebody please explain to me everything that happened in Mulholland Drive? What is up with the bum behind the diner, the little people chasing Naomi Watts at the end, who is who, what is the key for? Ideally give a website reference which has a full answer, as a full answer will dominate this page.
Answer: There is no one right answer. See http://film.guardian.co.uk/features/featurepages/0,4120,634856,00.html for some theories from movie critics.
Answer: Naomi Watts killed her lover, Laura Harring, rather than lose her to someone else. She felt such guilt, she created an alternate reality using everything and everyone she knew, to create a happy and peaceful world. But the real world was sneaking in and the key was to unlock her blocked memories.
Question: What did Samara's dad mean when he said, "my wife wasn't meant to have a child"?
Answer: She's infertile. She wasn't ever supposed to have children. It's hinted that she made a deal with evil forces to have Samara.
Friends (1994)
The One With The Girl From Poughkeepsie - S4-E10
Question: What does Chandler mean when he says "they're signing over their 401k's to me" and also when he asks Rachel "you graduated (something), right?"
Answer: A 401K is a pension plan. Graduating 'magna cum laude' means you were at the top of your class.
Mistake & trivia booksMost popular pagesBest movie mistakesBest mistake picturesBest comedy movie quotesMovies with the most mistakesNew this monthCriminal Minds mistakesWest Side Story endingThe Amazing Spider-Man 2 mistakesDark Shadows questionsBiggest Bond movie mistakesTimothy Olyphant movies & TV showsThe Dark Knight Rises triviaHunt for the Wilderpeople quotesBoy Meets World mistake pictureThe Nightmare Before Christmas plot

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ANGELA SAWYER "The Last January"
Playing with toys, machines and voice, Angela Sawyer is a seasoned sound craftsperson. There is a first person diary-like account inside the cover, which may or may not explain these two sides of sound to tape. Maybe witnessing an Angela Sawyer performance would reveal any questions as to what and how, regarding the instruments and sounds. Something cathartic is happening, this is the document, and it might heal the player and listener alike. It's real stuff happening here, with its own plan and structure, by a solitary human. It's minimal but vast. It's good for what ails you.


Make learning a delight with a healthy mix of optimum resources.
Provide an environment to all students to bring out the best in them.
Build a place for the parents and professionals of the highest excellence to come together to develop the citizens of tomorrow.
Strike the optimal balance between resources and economics to make the most affordable experience for all.
Gain more practical education and basic values in life.
Build a stronger bond with family and society.
Be ready to understand and face the real world.
Be compassionate and respectable global citizen.
We greatly acknowledge the contribution of different persons and organisations to August Foundation and its founding family that allowed us to be able to take the first big steps in setting up this foundation. August Foundation consists of eminent personalities from different walks of life who wish to participate In the strong development of society and its young and bubbling citizens tomorrow.


text:
Category Archives: wisdom
Stafne Challenges whether DelBene is a good Congressional Representative
May 22, 2016 Bankers, Banksters, DelBene, Democratic Party, democrats, economic disparity, homelessness, Main stream media evil, main stream media fluff, News Articles, Republican Party, Stafne, super delegate, two party political system, Washington State, wisdom
Stafne challenges whether DelBene is a good representative when she won't support Bernie The democratic party has put its Congressional representatives in an untenable, but familiar position by anointing them "super-delegates" but then requiring them to support Hillary regardless of the fact that Bernie is clearly the better candidate. Obviously, the democratic party has long since forgotten that under the United States Comstitution the role of a "representative" is to represent the people, not the democratic party. The dictionary defines "representative" to mean: " having people who are chosen in elections to act or speak for or in support of the people who voted for them." My opponent for Congress in District 1, incumbent Suzane DelBene said on her 2014 campaign web page that she wants to lead people. Specifically she writes: We need a leader who understands the power of innovation and who has the experience and determination to get things done in Washington, D.C. We need a leader who values creative and lasting solutions over empty partisanship. We need someone committed to the Democratic principles of honesty, integrity, equality of opportunity, and fair play. We need someone who will never lose sight of our shared commitment to the common good, but who also knows how to reach out across political divides to bring together diverse and competing interests to create progress. Given her steadfast refusal to support Bernie notwithstanding that he is the presidential candidate her constituents prefer one must wonder if she is content with the job … Continue Reading
Media Coverage of May Day Protests illustrates Bias
May 2, 2016 Democratic Party, democrats, economic disparity, evil, Faith, Federal Constitution, Judicial Watch, Justice, Main stream media evil, main stream media fluff, Republican Party, spiritual, spiritual movement, two party political system, wisdom
Media Coverage of May Day Protests illustrates Bias I don't watch much television. But last night while attempting to watch the news I got stuck watching Channel 7's coverage of Seattle's May Day protests. It was obvious that their comments were scripted by those who support the empire as it is. They kept calling the protesters "anarchists". That's just flat out misleading. An "anarchist" is a noun defined as: 1. a person who advocates or believes in anarchy or anarchism. 2. a person who seeks to overturn by violence all constituted forms and institutions of society and government, with no purpose of establishing any other system of order in the place of that destroyed. 3. a person who promotes disorder or excites revolt against any established rule, law, or custom. To protest a corrupt government that evicts millions of vulnerable people to die in the streets, incarcerates innocent people who have not committed a crime solely for purposes of keeping private prisons full pursuant to the terms of government contracts, and perpetuation of a pharmaceutical system developed to keep people sick does not mean you are an anarchist. It more likely means these people want a better government; not that they are against all government. Most of us so-called "anarchists" want governments that are more local in nature and provide a meaningful link between those who are elected to represent us. We do not want the Republican and Democratic parties filtering our access to our elected representatives. Ironically, the media has become an … Continue Reading
Reaching Planetary Consensus.
March 27, 2016 Bankers, Banksters, church, courts, Democratic Party, democrats, devout, economic disparity, evil, Faith, Government, hedge fund, homelessness, judicial department, Judicial Watch, Justice, Memorial Day, Republican Party, spiritual, spiritual movement, two party political system, Washington State, wisdom
Reaching Planetary Consensus. A facebook friend, who appears to share many of the views I do, posted the following quote and picture: "Religion is regarded by the common people as true,by the wise as false,and by the rulers as useful"~Seneca There are many "religions." Many sects of religions. I do not believe wisdom teaches us that they are false. They are one, of many modalities, by which communities (local, national, and planetary) reach consensus. In this regard, religions are not much different than nations, political parties, clubs, generations, and other peer groups. It is true that rulers find promoting differences between us as being in their own best interests because this keeps us, the people, divided… It stops us from focusing on them and their obscene greed as being the root cause of society's problems. I am not a religious scholar. But I do know that religions are not the problem… They did not bring on the bankcrime or leaderscum which has left so many of us hopeless and without resources. We need to unite those local gardens of creative and spiritual consensus, which already exist, so that their members can do the the work in their community necessary to remove those who always put their own good ahead of what is most beneficial for the whole. If you doubt the moral similarities among religions (and there is no reason why you should not) then read a little about them. There is not one that exalts the money lenders our governments prostitute us … Continue Reading
Why I became a Libertarian in 2016.
March 13, 2016 Bankers, Banksters, Bettendorf, church, courts, Democratic Party, democrats, economic disparity, evil, Faith, Federal Constitution, Government, homelessness, Iowa, judicial department, Judicial Watch, Justice, Opinions, Republican Party, spiritual, spiritual movement, two party political system, Washington State, wisdom
Why I became a Libertarian in 2016. I believe: "[a]ll political power is inherent in the people, and governments derive their just powers from the consent of the governed, and are established to protect and maintain individual rights." Individual rights are those which are bestowed on each of us by our creator, not privileges the government can franchise to corporations to sell to us for their own benefit. We, as people, have traveled the path of civilization to a point where freedom and economic wealth have become an intersection where most us must stop because we do not have the economic resources to exercise our most basic liberties. As a Libertarian I object to the government becoming an ally of the rich in enslaving people to debt which makes it impossible to exercise their freedoms. When our country was founded capitalism provided an adequate mechanism for most people to accumulate sufficient economic resources to enable them to exercise their personal liberties. Today, the crony capitalism promoted by the republican and democratic parties has created such disparity of wealth that only a few have access to those fundamental freedoms our forefathers took for granted. I cannot continue to support the two party tyranny which has created the greatest system of injustice the world has ever seen. No longer do we engage in debate over entitlement programs; we simply evict our vulnerable and let them die unknown on our streets. Of course, there are several third parties out there I could have … Continue Reading
LOVE is the universal force
February 27, 2016 Bettendorf, church, Decoration Day, Democratic Party, democrats, devout, economic disparity, evil, Faith, Federal Constitution, Government, hedge fund, homelessness, Iowa, Opinions, Republican Party, spiritual, spiritual movement, wisdom
LOVE is the universal force. I like social media because it helps me learn. That does not mean I accept everything I read there as being true. For example, I frequently see quotes attributed to people whom I presume never spoke or wrote them. This does not detract from my appreciation of the quote itself. This is the situation with the following letter purportedly written by Albert Einstein to a daughter. While it would be nice to believe that Einstein wrote this (given that his theories are being proved correct all the time) ot os not necessary for him to be the author in order for the message to be worth reflecting upon. So according to a Facebook post this is a letter, recently made public, that Albert Einstein wrote to his daughter, Lieseral: According to the post: In the late 1980s, Lieserl, the daughter of the famous genius, donated 1,400 letters, written by Einstein, to the Hebrew University, with orders not to publish their contents until two decades after his death. This is one of them, for Lieserl Einstein. [The letter reads:] "When I proposed the theory of relativity, very few understood me, and what I will reveal now to transmit to mankind will also collide with the misunderstanding and prejudice in the world. I ask you to guard the letters as long as necessary, years, decades, until society is advanced enough to accept what I will explain below. There is an extremely powerful force that, so far, science … Continue Reading
We should initiate this empire's collapse politically now in 2016.
February 25, 2016 Bankers, Bettendorf, Democratic Party, democrats, economic disparity, Federal Constitution, Government, Iowa, judicial department, Justice, Republican Party, two party political system, Washington State, wisdom
We should initiate this empire's collapse politically now in 2016. I am on an Amtrak train riding back to Arlington, Washington from Portland, Oregon. I was in Portland from 9:00 am until 1:00 pm sharp deposing Chris Caldwell, a lawyer for 21st Mortgage servicing company. My client, Duncan Robertson, was with me. He's become well trained in the law while fighting corrupt banks and servicers aspiring to steal his real estate in Washington State. After the deposition recessed because of the deponent's schedule (I wanted to continue asking questions) Duncan dropped me off at Amtrak's Union Station where I met with Kay, a concerned citizen in Oregon. We met there to discuss strategies with regard to restoring our representative republic by increasing the number of legislators responsible to the people. Kay and I discussed how the value of our votes and the votes of all Americans had been systematically devalued by the 1929 Apportionment Act freezing the House of Representative at only 435 members, no matter how much the nation's population grew thereafter. Many, including myself, believe this decision by the republican and democratic parties destroyed the electoral accountability our founders intended members of the House would have to the constituents within their districts. By brazenly acting to facilitate their own best interests, the political powers have frustrated our founding fathers' intentions that Congress would initiate the passage of laws and have final oversight of all government officials in each of the three branches through its the exercise of its impeachment power. As Federalist Paper #49 observed the members … Continue Reading
Happy New Year! Will we make 2016 be a year of change?
January 1, 2016 Bankers, church, Democratic Party, democrats, devout, economic disparity, Faith, Government, homelessness, judicial department, Judicial Watch, Justice, spiritual, spiritual movement, Washington State, wisdom
Happy New Year… WOW!!! 2015 has been quite the year. Can't say I am sorry to see it end. My heart yearns for the hope that comes with a new beginning. January 1, 2016 is a beautiful day here in the foothills of the Cascade Mountains in Washington, State. It is chilly, but sunny. The sky is clear so I can see for miles. Of course, the beginning of a new year does not not erase history or the momentum of those events still in motion. But for as long as I can remember it has caused people to reflect about changes they want to make in their own lives. The lessons of the past are legion. But perhaps none is more significant than the impact of the power we have given a small number of people over the wellbeing of humanity. Doesn't it seem to you that far too many of us are imprisoned by the chains of debt that will never be cancelled? Does it make sense that we have allowed the pursuit of money to be the only purpose which will guarantee a person's survival? Plants grow toward the sun in heaven. Has money become humanity's sun? So what should be our collective New Year's resolutions for 2016? Should we resolve to move toward ending the empire's two party political system because it has failed to deliver that which it has promised us? Should we explore concepts of spirituality as a means of effecting political and economic … Continue Reading
The Eve of Spiritual Justice
December 24, 2015 church, courts, economic disparity, evil, Faith, homelessness, Justice, News Articles, Opinions, spiritual, spiritual movement, wisdom
The eve of spiritual justice is upon us. We, as a people, have reached a spiritual consensus that governments have failed to promote humanity's best interests . We intuit as a matter of our collective consciousness the governmental corruption that denigrates our value as people and seeks to enslave us to debt. We know instinctively that now is the time for a spiritual awakening to reassess our leaders' priorities; which appear to be only that greed which will sustain their power over the rest us. Everyone — from the rich to the poor; from the professional to the soldier — is aware of the evil which makes money, alone, a prerequisite to the exercise of our natural rights. There is a stench in the air, which we all smell and want to go away. It is worse than the smell of rotting flesh because it emanates from a rotting world that too few have controlled for too long. We are on the eve of change. Spiritual justice is now obtainable if we decide to create it.
Above all I am GRATEFUL
December 6, 2015 church, courts, Democratic Party, democrats, devout, economic disparity, Government, judicial department, spiritual, spiritual movement, Stafne, two party political system, Washington State, wisdom
I am grateful to be a part of a spiritual movement designed to take our country back from the stomach of the empire which has swallowed it. It is not always easy practicing law while fighting off the empire. You have to take your lumps. But difficulties are often the source of new beginnings. Certainly, this is not how I envisioned spending my sixties when I was in my twenties. The Vietnam War began in November, 1955 and ended twenty years later in 1975. It was the last real war in the sense that American youth were conscripted from the general population and made to fight in a war that many of us believed should not have been fought. (Now the empire employs mercenaries to fight its endless wars having figured out that the people would not tolerate their children coming home in coffins unless they were paid to put their young lives in danger.) I was 20 in 1970 studying in London when I wrote "The Nakedness of Love". I found the poem recently when I rummaged through boxes of my past. Although the poem is somewhat dated with regard to sexuality issues that are now being resolved, the third scene dealing with our government and politics still rings true. Scene 3: Act 1: Ashes are only ashes; Day is only day. Darkness always comes. It does no good to pray. The curtains will only open, they will never close. Man will become naked and refute all he knows. On … Continue Reading


Former President George H. W. Bush was a man who believed in duty to his country. He may have not always stood on the right side of history, but he always stood for on the right side of America.
Mr. Bush had his eyes on the Oval Office longer before he got there. When President Gerald R. Ford asked him to lead the CIA in 1975 Bush accepted the position out of a sense of duty. He went on to become known as the agency's best director and did much to raise morale at a time when it was sorely needed.
When he ran against Ronald Reagan for the Republican nomination for president and lost, he graciously accepted a post as vice president to help keep from dividing the party. Reagan and Bush went on to win the next two elections by a landslides, and finally it was his turn for a chance at the Oval Office.
In a letter to the NRA Bush wrote that LaPierre's comments were out of line.
The NRA declined to endorse Bush in his re-election campaign, but he knew that was coming and stood up to them anyway.
In a more recent visit to President Bush, President Clinton gets a laugh out of the socks Bush wore for the visit. The socks pictured Clinton on them.
President George H. W. Bush lived a long a full life. He made more friends than enemies. May he rest in peace.


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1Yale University
2Massachusetts Institute of Technology
4Princeton University
Students who want a place at one of the best research universities are in the right place with College Consensus. With the Top Consensus Ranked National Research Universities, College Consensus brings prospective college students all they need to know about the best research universities nationwide. For future professionals, researchers, scientists, and scholars, College Consensus gathers data from national and international ranking agencies and reliable student reviews for a complete view of their educational options.
How Did We Rank the Best National Research Universities?
College Consensus is an aggregated best schools ranking combining data from across the internet. For the Publisher Rating, we average every school's scores in rankings from U.S. News & World Report, The Wall Street Journal, and WalletHub. Then, we compute the Student Review Rating for each college from sites like Unigo, My Plan, and Students Review. Taken together, these rankings make up the College Consensus.
The top research universities include some of the most prestigious and world-renowned names in higher education. We define national research universities as institutions that draw a student body from across the US and world, rather than a primarily regional population. These are universities that are classified by the Carnegie Foundation as research universities: R1 (Highest Research Activity), R2 (Higher Research Activity), or R3 (Moderate Research Activity). These designations include well over 300 universities nationwide. National research universities are dedicated not only to teaching, but on creating new knowledge through scientific, social scientific, and humanities research.
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This ranking focuses on the best nationally-recognized, major research universities. For students who are interested in the more traditional atmosphere of a small college, College Consensus has also ranked the Best National Liberal Arts Colleges. For the full, comprehensive ranking of all American colleges and universities, regardless of size or class, see the Best Colleges and Universities.
The Top Consensus Ranked National Research Universities are listed in descending order by their Consensus score. In the event of ties, schools are ranked in alphabetical order with the same rank number.
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Why choose a research university? The best research universities offer opportunities for students to engage with faculty who are expanding their fields. Because professors are making new breakthroughs all the time, the learning environment is charged with excitement and students are able to learn about the latest studies before the results make it into their textbooks.
In addition, attending a research university often affords students opportunities they would not have at other schools. For example, they may have access to internships and have opportunities to do research with experts in their fields. They may even be invited to networking events with well-known professors, which could introduce them to valuable contacts and mentors.
What Makes a University a Research University?
So what is the difference between a research university vs. a teaching university? A focus on research is what makes a university a research university. The definition of a research university is a university that is committed to furthering our collective body of knowledge through research.
Unlike teaching universities, which put teaching above everything else, research universities place a higher importance on research. This does not mean that the teaching at a research university is sub-par, however. At the best research universities, professors who are excited about their research often carry their enthusiasm into the classroom. They ignite passion in their students by sharing the results of their research with their classes.
If you're looking for the best research universities, look through our research university rankings. We have carefully considered each school's strengths and weaknesses and compiled a list of the top research universities in the country. Our research university rankings will help you choose the right university for you.
What is the Relationship Between Government Funding and Research Universities?
Government funding to universities is currently around 60% of the total R&D budget. This is down from a high of 73% in the late 1960s. However, in inflation-adjusted dollars, the amount has actually increased from around $8 billion per year to over $30 billion in spite of the lower percentage. This indicates that, adjusted for inflation, R&D budgets at research universities have grown over the past few decades.
Still, federal research grants to universities account for over half of the R&D funding for these schools. However, since federal funding covers less of the costs than it has in the past, schools have had to cover a larger share of their R&D budgets themselves. The percentage paid by the schools was less than 10% in the late 60s, but has risen to more than 20% today.
Since government funding to universities now covers a smaller percentage of research costs, many universities have responded by charging higher tuition and fees to make up the difference. However, public outcry against the burgeoning student debt crisis is forcing research universities to come up with an alternative way to make up for the reduced federal research grants to universities.
Many research universities have come up with new ways to gain additional funding or reduce expenses. These include partnerships with corporations and cooperative agreements with other schools that allow for expanded research efforts at all of the partner schools. Some schools are also engaging in their own development projects in order to raise additional funding.
Top Research Universities by Funding
Looking at the top research universities by funding, Johns Hopkins University receives more than twice as much federal funding as the #2 school. Around $2 billion of Johns Hopkins's $2.3 billion R&D budget comes from the federal government. The school is followed by the University of Washington in 2nd place ($960.6 million), the University of Michigan in 3rd ($756.1 million), Stanford University in 4th ($679.6 million), and the University of California, San Diego in 5th ($643.0 million).
Are Research Universities Only for STEM Majors?
Although the best undergraduate research universities include the best science colleges in the world, research universities are not just for STEM majors. In fact, a recent study by Drexel University found that non-STEM students are just as likely to benefit from undergrad research experiences as STEM students.
The results were based on a survey of students who participated in the STAR (Students Tackling Advanced Research) program at Drexel University, one of the best science colleges in the world. Students indicated that they felt that the research benefited them in all areas of study, not just in STEM subject areas.
Some of the benefits students reported included improvements in their ability to work independently, feeling more comfortable discussing concepts or explaining projects to people outside of their fields, and gaining hands-on experience that they feel will help enhance their resumes.
At the best research universities, students have plenty of opportunities to participate in research. Regardless of major, being involved in a research project increases the chances that the student will remain in the program and eventually graduate. This effect is stronger when the research is conducted earlier in the program.
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Pipe penetrating radar (PPR), a new pipe inspection technology was used for condition assessment in a 27 inch interceptor in Denver, CO. Metro Wastewater Reclamation District (MWRD), the owner of the interceptor had limited information about the condition of the pipe, so they contacted SewerVUE in order to undertake a multisensory pipe condition assessment that included CCTV, PPR and laser profiling.
PPR results showed pipe wall thickness in the 2.5-3.3" range that matched the core sample obtained by MWRD. Locations where rebar cover was less than the minimum ASTM standard were identified, however, deficient rebar cover appeared to be due to the pipe manufacturing process and not to corrosion. No significant voids were detected along the inspected line. Laser profiling identified corrosion along the flow line.
The Harvard Gultch interceptor, originally constructed in the 1950's was replaced with reinforcement concrete pipe (RCP) in the late 1970's. In 1983 the ownership was transferred to MWRD and only limited information is available about the condition of the pipe.
Figure 1. Aerial photo showing the location of the Harvard Gultch Interceptor that was inspected.
Pipe penetrating radar (PPR) is the underground in-pipe application of ground penetrating radar (GPR). As the radar pulse travels through a pipe some of the energy will be reflected and refracted by any sharp change in material properties. These reflected waves are detected and recorded by a receiving antenna. The output is then processed and analyzed by a software that visualizes pipe wall thickness, rebar cover, voids outside the pipe as well as cracks or bedding symptoms.
Figure 2. The SewerVUE Surveyor, a fourth generation multi-sensor inspection robot equipped with pan, tilt, zoom CCTV, LIDAR, and PPR.
The SewerVUE Surveyor that was used in Denver is the first commercially available multi-sensor inspection (MSI) robot that uses visual and quantitative technologies (CCTV, LIDAR, and PPR) to inspect underground pipes. The robot can be adjusted between 21 and 36-inch diameter pipes, the PPR antennae can be rotated between the nine and three o'clock positions. The CCTV and LIDAR data are recorded continuously and simultaneously.
A 880ft long segment of the 27 inch RCP was inspected in two deployments while the pipe remained in service. The inspection data were processed using Pipe Penetrating Radar Data Interpretation Application (PP-RADIAN), SewerVUE's proprietary radar processing software. The interpreted PPR data showed the pipe wall thickness, rebar cover and grouted sections of the pipe. The pipe wall thickness from the PPR survey matched closely (98%) the core sample obtained earlier by MWRD personnel.
Figure 3. A typical PPR profile. The clock position and the frequency of the antenna are shown on the left side of the profile. The red color on the pipe condition marker indicates an area where immediate attention is recommended.
PPR data showed variations in pipe wall thickness, as well as location, depth and spacing of rebar. Pipe wall thickness appeared to be uniform with no significant pipe wall loss. The remaining pipe-wall thickness was between 2.5 - 3.3". The measured minimum pipe wall thickness was 2.5". Rebar cover, while showing variations along the surveyed clock positions appeared to be in the 0.25" and 3.2" range. Where rebar cover appeared to be less than 0.73" it was mostly due to the pipe manufacturing process and not the result of pipe wall loss. No significant voids were detected along the inspected line.
Figure 4. PPR results: the interpreted PPR profiles are correlated with the CCTV foldout view. Pipe condition is indicated by a three color marker below the PPR profies: green: acceptable, yellow: areas with potential problem, red: immediate attention is recommended.
PPR results are displayed with the interpretation superimposed on the actual depth profiles. The top two profiles typically show the individual PPR profiles with the corresponding clock position and antenna frequency denoted with an icon to the left of the corresponding profile. Horizontal scales are in feet, vertical scales are in inches.
The location of the scan lines are marked on the CCTV foldout view of the pipe at the bottom of each pipe segment with the corresponding clock positions on the vertical axis. Anomalies and other notable features are color coded. Pipe wall thickness is marked by a continuous black line, reinforcement is marked by red dots which are then connected by a red line. The CCTV data did not show significant pipe degradation.
Figure 5. PPR results: the interpreted PPR profiles are correlated with the CCTV foldout view. Pipe condition is indicated by a three color marker below the PPR profiles: green: acceptable, yellow: areas with potential problem, red: immediate attention is recommended.
The PPR results clearly showed areas where the rebar cover was less than 0.53", the recommended minimum by ASTM standards. The SewerVUE Surveyor's LIDAR data (Figure 6) is correlated with an onboard inertial navigation system (INS) to continuously calculate the position, orientation, and velocity (direction and speed of movement) of the robot without the need for external references. Both the foldout and the cross-sections show significant erosion at the current flow level at the 7:30 and 4:30 clock positions.
Figure 6. LIDAR results: Both the foldout and the cross-sections show significant erosion at the current flow level at the 7:30 and 4:30 clock positions.
PPR results showed pipe wall thickness in the 2.5-3.3" range that matched the core sample obtained by MWRD. Locations where rebar cover was less than the minimum ASTM standard were identified. No significant voids were detected along the inspected line.
PPR data show the presence of casing and grout between the casing and the sewer pipe. The grout is uniform with a 0.75 – 1" thickness. The integration of advanced pipe condition assessment technology into the MWRD pipeline condition assessment program will provide detailed supplemental inspection information in critical pipe segments where condition ratings are difficult to determine or where it is suspected that corrosion has significantly deteriorated the structural integrity, and consequently shortened the lifespan of these pipe segments.