A Method for Squareness Error Verification on a Coordinate
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bonferroni correction method -回复什么是Bonferroni校正方法?Bonferroni校正方法是一种经典的多重检验修正方法,旨在控制实验中的类型I错误率。
它是由意大利统计学家Carlo Emilio Bonferroni在20世纪30年代提出的,并被广泛应用于各种科学研究领域。
多重检验问题是指在进行多个假设检验时,由于多次进行统计检验可能导致错误的显著性结论。
例如,在一项研究中,研究人员可能同时测试数十个变量与一个金标准之间的关系。
如果在未经校正的前提下,每个变量的显著性水平设定为α=0.05,那么很容易造成错误的结果。
Bonferroni校正方法的基本原理是将整体错误率α平均分配到所有的假设检验中,以确保实验整体上的类型I错误率控制在理论设定的水平内。
具体而言,对于需要进行校正的假设检验个数m,我们将显著性水平α除以m,得到每个单独假设检验的新显著性水平α'。
在进行假设检验时,只有当单个检验的p值低于α'时,才会产生显著性结论。
Bonferroni校正方法的计算简单直观,并且通常能够有效控制整体错误率。
然而,它也具有一些局限性。
首先,Bonferroni校正方法假设所有的假设检验是相互独立的,而在实际科研中,这种假设可能并不成立。
此外,Bonferroni校正方法也可能导致过于保守的结果,即错误地否定了一些真实的关系或效应。
为了克服Bonferroni校正方法的局限性,还有一些其他的多重检验方法被提出。
其中一种常见的方法是BH校正方法(Benjamini-Hochberg procedure),它在控制实验整体错误率的同时,还考虑了假设检验结果的相关性。
Bonferroni校正方法的应用范围十分广泛。
在医学研究中,它被用于分析临床试验和流行病学调查数据。
在基因组学领域,它被用于处理高通量基因表达数据中的差异分析。
此外,在社会科学研究和市场研究中,Bonferroni校正方法也常常用于控制多个统计检验的错误率。
一种实验验证方法英文IntroductionExperimental verification is a crucial process in scientific research, as it provides empirical evidence to support or refute hypotheses. It allows researchers to test their ideas and theories in a controlled environment, providing insights into the underlying mechanisms of natural phenomena. This article presents a method for conducting experimental verification, outlining the necessary steps and considerations for ensuring reliable and valid results.MethodologyStep 1: Formulate a HypothesisThe first step in experimental verification is to formulate a hypothesis. This involves proposing an explanation or a prediction about the relationship between variables. The hypothesis should be specific, testable, and should aim to answer a research question.Step 2: Design the ExperimentDesigning a well-structured experiment is vital to obtaining accurate and meaningful results. The experiment should be carefully planned, ensuring that all relevant variables are identified and controlled. Considerations such as sample size, experimental conditions, and data collection methods should be taken into account during this step.Step 3: Identify VariablesIdentifying and controlling variables is crucial to minimize confounding factors and ensure that the observed effects are due to the manipulated variables. Variables can be classified as independent, dependent, or controlled. Independent variables are manipulated by the researcher, dependent variables are the outcomes or the observed effects, and controlled variables are kept constant to prevent their influence on the results.Step 4: Conduct the ExperimentOnce the experiment has been designed and variables have been identified, it is time to conduct the experiment. Follow the established protocol, collecting relevant data and observations. Take into consideration the ethical guidelines and safety precautions to ensure the integrity of the experiment and the well-being of participants.Step 5: Analyze and Interpret the ResultsAfter data collection, it is important to analyze and interpret the obtained results. Statistical analysis methods can be employed to determine the significance of the observed effects. Consider factors such as margin of error, confidence intervals, and p-values to draw meaningful conclusions.Step 6: Draw ConclusionsBased on the results obtained, draw conclusions regarding the hypothesis. If the data supports the hypothesis, it provides evidence tovalidate the proposed explanation. However, if the data contradicts the hypothesis, it suggests a revision of the initial hypothesis or the formulation of a new one. Ensure that the conclusions are based on sound scientific reasoning and are supported by the empirical evidence obtained from the experiment.Considerations and Potential Challenges- Sample size: Ensure that the sample size is sufficient to achieve statistical power and accurately capture the effects of variables.- Control group: Create a control group to serve as a basis of comparison, allowing the evaluation of the impact of the independent variable.- Replicability: Conduct the experiment multiple times to ensure the reliability of the results. Replicability adds strength to the validity of the findings.- Ethical considerations: Adhere to ethical guidelines and obtain necessary consent from participants to maintain the ethical integrity of the experiment.- External validity: Consider the generalizability of the results to the broader population or other settings. It is important to acknowledge any limitations or potential biases that might affect the external validity. ConclusionExperimental verification is a foundational aspect of scientific research. By following the outlined methodology and taking into account theconsiderations and potential challenges, researchers can conduct experiments that generate reliable and valid results. Through rigorous experimentation, scientists are able to advance knowledge, inspire further research, and make important contributions to their respective fields.。
Analytical Procedures and Methods Validation for Drugsand BiologicsDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to . Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Registe r.For questions regarding this draft document contact (CDER) Lucinda Buhse 314-539-2134, or (CBER) Office of Communication, Outreach and Development at 800-835-4709 or 301-827-1800.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)February 2014CMCAnalytical Procedures and Methods Validation for Drugsand BiologicsAdditional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 2201Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach andDevelopment, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448ocod@/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm(Tel) 800-835-4709 or 301-827-1800U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Febr uary 2014CMCTABLE OF CONTENTSI.INTRODUCTION (1)II.BACKGROUND (2)III.ANALYTICAL METHODS DEVELOPMENT (3)IV.CONTENT OF ANALYTICAL PROCEDURES (3)A.Principle/Scope (4)B.Apparatus/Equipment (4)C.Operating Parameters (4)D.Reagents/Standards (4)E.Sample Preparation (4)F.Standards Control Solution Preparation (5)G.Procedure (5)H.System Suitability (5)I.Calculations (5)J.Data Reporting (5)V.REFERENCE STANDARDS AND MATERIALS (6)VI.ANALYTICAL METHOD VALIDATION FOR NDA, ANDAs, BLAs, AND DMFs (6)A.Noncompendial Analytical Procedures (6)B.Validation Characteristics (7)pendial Analytical Procedures (8)VII.STATISTICAL ANALYSIS AND MODELS (8)A.Statistics (8)B.Models (8)VIII.LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES (9)A.Revalidation (9)B.Analytical Method Comparability Studies (10)1.Alternative Analytical Procedures (10)2.Analytical Methods Transfer Studies (11)C.Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA (11)IX.FDA METHODS VERIFICATION (12)X.REFERENCES (12)Guidance for Industry11Analytical Procedures and Methods Validation for Drugs and2Biologics345This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 6thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 7bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 8the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA9staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 10the appropriate number listed on the title page of this guidance.11121314I. INTRODUCTION1516This revised draft guidance supersedes the 2000 draft guidance for industry on Analytical17Procedures and Methods Validation2,3 and, when finalized, will also replace the 1987 FDA18guidance for industry on Submitting Samples and Analytical Data for Methods Validation. It19provides recommendations on how you, the applicant, can submit analytical procedures4 and20methods validation data to support the documentation of the identity, strength, quality, purity,21and potency of drug substances and drug products.5It will help you assemble information and 22present data to support your analytical methodologies. The recommendations apply to drug23substances and drug products covered in new drug applications (NDAs), abbreviated new drug 24applications (ANDAs), biologics license applications (BLAs), and supplements to these25applications. The principles in this revised draft guidance also apply to drug substances and drug 26products covered in Type II drug master files (DMFs).2728This revised draft guidance complements the International Conference on Harmonisation (ICH) 29guidance Q2(R1)Validation of Analytical Procedures: Text and Methodology(Q2(R1)) for30developing and validating analytical methods.3132This revised draft guidance does not address investigational new drug application (IND) methods 33validation, but sponsors preparing INDs should consider the recommendations in this guidance.34For INDs, sufficient information is required at each phase of an investigation to ensure proper35identity, quality, purity, strength, and/or potency. The amount of information on analytical36procedures and methods validation will vary with the phase of the investigation.6 For general371 This guidance has been prepared by the Office of Pharmaceutical Science, in the Center for Drug Evaluation andResearch (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and DrugAdministration.2 Sample submission is described in section IX, FDA Methods Verification.3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDADrugs guidance Web page at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.4Analytical procedure is interchangeable with a method or test procedure.5The terms drug substance and drug product, as used in this guidance, refer to human drugs and biologics.6 See 21 CFR 312.23(a)(7).guidance on analytical procedures and methods validation information to be submitted for phase 38one studies, sponsors should refer to the FDA guidance for industry on Content and Format of39Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including40Well-Characterized, Therapeutic, Biotechnology-Derived Products. General considerations for 41analytical procedures and method validation (e.g., bioassay) before conduct of phase three42studies are discussed in the FDA guidance for industry on IND Meetings for Human Drugs and 43Biologics, Chemistry, Manufacturing, and Controls Information.4445This revised draft guidance does not address specific method validation recommendations for46biological and immunochemical assays for characterization and quality control of many drug47substances and drug products. For example, some bioassays are based on animal challenge48models, and immunogenicity assessments or other immunoassays have unique features that49should be considered during development and validation.5051In addition, the need for revalidation of existing analytical methods may need to be considered 52when the manufacturing process changes during the product’s life cycle. For questions on53appropriate validation approaches for analytical procedures or submission of information not54addressed in this guidance, you should consult with the appropriate FDA product quality review 55staff.5657If you choose a different approach than those recommended in this revised draft guidance, we58encourage you to discuss the matter with the appropriate FDA product quality review staff before 59you submit your application.6061FDA’s guidance documents, including this guidance, do not establish legally enforceable62responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 63be viewed only as recommendations, unless specific regulatory or statutory requirements are64cited. The use of the word should in Agency guidances means that something is suggested or65recommended, but not required.666768II.BACKGROUND6970Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, 71strength, quality, purity, and potency of the drug substance and drug product.7 Each BLA must 72include a full description of the manufacturing methods, including analytical procedures that73demonstrate the manufactured product meets prescribed standards of identity, quality, safety,74purity, and potency.8 Data must be available to establish that the analytical procedures used in 75testing meet proper standards of accuracy and reliability and are suitable for their intended76purpose.9 For BLAs and their supplements, the analytical procedures and their validation are77submitted as part of license applications or supplements and are evaluated by FDA quality78review groups.79807 See 21 CFR 314.50(d)(1) and 314.94(a)(9)(i).8 See 21 CFR 601.2(a) and 601.2(c).9 See 21 CFR 211.165(e) and 211.194(a)(2).Analytical procedures and validation data should be submitted in the corresponding sections of 81the application in the ICH M2 eCTD: Electronic Common Technical Document Specification.108283When an analytical procedure is approved/licensed as part of the NDA, ANDA, or BLA, it84becomes the FDA approved analytical procedure for the approved product. This analytical85procedure may originate from FDA recognized sources (e.g., a compendial procedure from the 86United States Pharmacopeia/National Formulary (USP/NF)) or a validated procedure you87submitted that was determined to be acceptable by FDA. To apply an analytical method to a88different product, appropriate validation studies with the matrix of the new product should be89considered.909192III.ANALYTICAL METHODS DEVELOPMENT9394An analytical procedure is developed to test a defined characteristic of the drug substance or95drug product against established acceptance criteria for that characteristic. Early in the96development of a new analytical procedure, the choice of analytical instrumentation and97methodology should be selected based on the intended purpose and scope of the analytical98method. Parameters that may be evaluated during method development are specificity, linearity, 99limits of detection (LOD) and quantitation limits (LOQ), range, accuracy, and precision.100101During early stages of method development, the robustness of methods should be evaluated102because this characteristic can help you decide which method you will submit for approval.103Analytical procedures in the early stages of development are initially developed based on a104combination of mechanistic understanding of the basic methodology and prior experience.105Experimental data from early procedures can be used to guide further development. You should 106submit development data within the method validation section if they support the validation of 107the method.108109To fully understand the effect of changes in method parameters on an analytical procedure, you 110should adopt a systematic approach for method robustness study (e.g., a design of experiments 111with method parameters). You should begin with an initial risk assessment and follow with112multivariate experiments. Such approaches allow you to understand factorial parameter effects 113on method performance. Evaluation of a method’s performance may include analyses of114samples obtained from in-process manufacturing stages to the finished product. Knowledge115gained during these studies on the sources of method variation can help you assess the method 116performance.117118119IV.CONTENT OF ANALYTICAL PROCEDURES120121You should describe analytical procedures in sufficient detail to allow a competent analyst to 122reproduce the necessary conditions and obtain results within the proposed acceptance criteria. 123You should also describe aspects of the analytical procedures that require special attention. An 124analytical procedure may be referenced from FDA recognized sources (e.g., USP/NF,12510 See sections 3.2.S.4 Control of Drug Substance, 3.2.P.4 Control of Excipients, and 3.2.P.5 Control of DrugProduct.Association of Analytical Communities (AOAC) International)11 if the referenced analytical126procedure is not modified beyond what is allowed in the published method. You should provide 127in detail the procedures from other published sources. The following is a list of essential128information you should include for an analytical procedure:129130A.Principle/Scope131132A description of the basic principles of the analytical test/technology (separation, detection, etc.); 133target analyte(s) and sample(s) type (e.g., drug substance, drug product, impurities or compounds 134in biological fluids, etc.).135136B.Apparatus/Equipment137138All required qualified equipment and components (e.g., instrument type, detector, column type, 139dimensions, and alternative column, filter type, etc.).140141C.Operating Parameters142143Qualified optimal settings and ranges (allowed adjustments) critical to the analysis (e.g., flow144rate, components temperatures, run time, detector settings, gradient, head space sampler). A145drawing with experimental configuration and integration parameters may be used, as applicable. 146147D.Reagents/Standards148149The following should be listed:150151•Grade of chemical (e.g., USP/NF, American Chemical Society, High152Performance or Pressure Liquid Chromatography, or Gas153Chromatography and preservative free).154•Source (e.g., USP reference standard or qualified in-house reference material). 155•State (e.g., dried, undried, etc.) and concentration.156•Standard potencies (purity correction factors).157•Storage controls.158•Directions for safe use (as per current Safety Data Sheet).159•Validated or useable shelf life.160161New batches of biological reagents, such as monoclonal antibodies, polyclonal antisera, or cells, 162may need extensive qualification procedures included as part of the analytical procedure.163164E.Sample Preparation165166Procedures (e.g., extraction method, dilution or concentration, desalting procedures and mixing 167by sonication, shaking or sonication time, etc.) for the preparations for individual sample tests. 168A single preparation for qualitative and replicate preparations for quantitative tests with16911 See 21 CFR 211.194(a)(2).appropriate units of concentrations for working solutions (e.g., µg/ml or mg/ml) and information 170on stability of solutions and storage conditions.171172F.Standards Control Solution Preparation173174Procedures for the preparation and use of all standard and control solutions with appropriate175units of concentration and information on stability of standards and storage conditions,176including calibration standards, internal standards, system suitability standards, etc.177178G.Procedure179180A step-by-step description of the method (e.g., equilibration times, and scan/injection sequence 181with blanks, placeboes, samples, controls, sensitivity solution (for impurity method) and182standards to maintain validity of the system suitability during the span of analysis) and allowable 183operating ranges and adjustments if applicable.184185H.System Suitability186187Confirmatory test(s) procedures and parameters to ensure that the system (equipment,188electronics, and analytical operations and controls to be analyzed) will function correctly as an 189integrated system at the time of use. The system suitability acceptance criteria applied to190standards and controls, such as peak tailing, precision and resolution acceptance criteria, may be 191required as applicable. For system suitability of chromatographic systems, refer to CDER192reviewer guidance on Validation of Chromatographic Methods and USP General Chapter <621> 193Chromatography.194195I.Calculations196197The integration method and representative calculation formulas for data analysis (standards,198controls, samples) for tests based on label claim and specification (e.g., assay, specified and199unspecified impurities and relative response factors). This includes a description of any200mathematical transformations or formulas used in data analysis, along with a scientific201justification for any correction factors used.202203J.Data Reporting204205A presentation of numeric data that is consistent with instrumental capabilities and acceptance 206criteria. The method should indicate what format to use to report results (e.g., percentage label 207claim, weight/weight, and weight/volume etc.) with the specific number of significant figures 208needed. The American Society for Testing and Materials (ASTM) E29 describes a standard209practice for using significant digits in test data to determine conformance with specifications. For 210chromatographic methods, you should include retention times (RTs) for identification with211reference standard comparison basis, relative retention times (RRTs) (known and unknown212impurities) acceptable ranges and sample results reporting criteria.213214215V.REFERENCE STANDARDS AND MATERIALS216217Primary and secondary reference standards and materials are defined and discussed in the218following ICH guidances: Q6A Specifications: Test Procedures and Acceptance Criteria for 219New Drug Substances and New Drug Products: Chemical Substances (ICH Q6A), Q6B220Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological221Products, and Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical222Ingredients. For all standards, you should ensure the suitability for use. Reference standards for 223drug substances are particularly critical in validating specificity for an identity test. You should 224strictly follow storage, usage conditions, and handling instructions for reference standards to225avoid added impurities and inaccurate analysis. For biological products, you should include226information supporting any reference standards and materials that you intend to use in the BLA 227and in subsequent annual reports for subsequent reference standard qualifications. Information 228supporting reference standards and materials include qualification test protocols, reports, and 229certificates of analysis (including stability protocols and relevant known impurity profile230information, as applicable).231232Reference standards can often be obtained from USP and may also be available through the233European Pharmacopoeia, Japanese Pharmacopoeia, World Health Organization, or National 234Institute of Standards and Technology. Reference standards for a number of biological products 235are also available from CBER. For certain biological products marketed in the U.S., reference 236standards authorized by CBER must be used before the product can be released to the market.12 237Reference materials from other sources should be characterized by procedures including routine 238and beyond routine release testing as described in ICH Q6A. You should consider orthogonal 239methods. Additional testing could include attributes to determine the suitability of the reference 240material not necessarily captured by the drug substance or product release tests (e.g., more241extensive structural identity and orthogonal techniques for purity and impurities, biological242activity).243244For biological reference standards and materials, we recommend that you follow a two-tiered 245approach when qualifying new reference standards to help prevent drift in the quality attributes 246and provide a long-term link to clinical trial material. A two-tiered approach involves a247comparison of each new working reference standard with a primary reference standard so that it 248is linked to clinical trial material and the current manufacturing process.249250251VI.ANALYTICAL METHOD VALIDATION FOR NDA, ANDAs, BLAs, AND 252DMFs253254A.Noncompendial Analytical Procedures255256Analytical method validation is the process of demonstrating that an analytical procedure is257suitable for its intended purpose. The methodology and objective of the analytical procedures 258should be clearly defined and understood before initiating validation studies. This understanding 25912 See 21 CFR 610.20.is obtained from scientifically-based method development and optimization studies. Validation 260data must be generated under an protocol approved by the sponsor following current good261manufacturing practices with the description of methodology of each characteristic test and262predetermined and justified acceptance criteria, using qualified instrumentation operated under 263current good manufacturing practices conditions.13 Protocols for both drug substance and264product analytes or mixture of analytes in respective matrices should be developed and executed. 265266ICH Q2(R1) is considered the primary reference for recommendations and definitions on267validation characteristics for analytical procedures. The FDA Reviewer Guidance: Validation of 268Chromatographic Methods is available as well.269270B.Validation Characteristics271272Although not all of the validation characteristics are applicable for all types of tests, typical273validation characteristics are:274275•Specificity276•Linearity277•Accuracy278•Precision (repeatability, intermediate precision, and reproducibility)279•Range280•Quantitation limit281•Detection limit282283If a procedure is a validated quantitative analytical procedure that can detect changes in a quality 284attribute(s) of the drug substance and drug product during storage, it is considered a stability285indicating assay. To demonstrate specificity of a stability-indicating assay, a combination of286challenges should be performed. Some challenges include the use of samples spiked with target 287analytes and all known interferences; samples that have undergone various laboratory stress288conditions; and actual product samples (produced by the final manufacturing process) that are289either aged or have been stored under accelerated temperature and humidity conditions.290291As the holder of the NDA, ANDA, or BLA, you must:14 (1) submit the data used to establish292that the analytical procedures used in testing meet proper standards of accuracy and reliability, 293and (2) notify the FDA about each change in each condition established in an approved294application beyond the variations already provided for in the application, including changes to 295analytical procedures and other established controls.296297The submitted data should include the results from the robustness evaluation of the method,298which is typically conducted during method development or as part of a planned validation299study.1530013 See 21 CFR 211.165(e); 21 CFR 314.50 (d), and for biologics see 21 CFR 601.2(a), 601.2(c), and 601.12(a).14 For drugs see 21 CFR 314.50 (d), 314.70(d), and for biologics see 21 CFR 601.2(a), 601.2(c), and 601.12(a). For aBLA, as discussed below, you must obtain prior approval from FDA before implementing a change in analyticalmethods if those methods are specified in FDA regulations15 See section III and ICH Q2(R1).pendial Analytical Procedures302303The suitability of an analytical procedure (e.g., USP/NF, the AOAC International Book of304Methods, or other recognized standard references) should be verified under actual conditions of 305use.16 Compendial general chapters, which are complex and mention multiple steps and/or306address multiple techniques, should be rationalized for the intended use and verified. Information 307to demonstrate that USP/NF analytical procedures are suitable for the drug product or drug308substance should be included in the submission and generated under a verification protocol.309310The verification protocol should include, but is not limited to: (1) compendial methodology to 311be verified with predetermined acceptance criteria, and (2) details of the methodology (e.g.,312suitability of reagent(s), equipment, component(s), chromatographic conditions, column, detector 313type(s), sensitivity of detector signal response, system suitability, sample preparation and314stability). The procedure and extent of verification should dictate which validation characteristic 315tests should be included in the protocol (e.g., specificity, LOD, LOQ, precision, accuracy, etc.). 316Considerations that may influence what characteristic tests should be in the protocol may depend 317on situations such as whether specification limits are set tighter than compendial acceptance318criteria, or RT or RRT profiles are changing in chromatographic methods because of the319synthetic route of drug substance or differences in manufacturing process or matrix of drug320product. Robustness studies of compendial assays do not need to be included, if methods are 321followed without deviations.322323324VII.STATISTICAL ANALYSIS AND MODELS325326A.Statistics327328Statistical analysis of validation data can be used to evaluate validation characteristics against 329predetermined acceptance criteria. All statistical procedures and parameters used in the analysis 330of the data should be based on sound principles and appropriate for the intended evaluation.331Reportable statistics of linear regression analysis R (correlation coefficient), R square332(coefficient of determination), slope, least square, analysis of variance (ANOVA), confidence 333intervals, etc., should be provided with justification.For information on statistical techniques 334used in making comparisons, as well as other general information on the interpretation and335treatment of analytical data, appropriate literature or texts should be consulted.17336337B.Models338339Some analytical methods might use chemometric and/or multivariate models. When developing 340these models, you should include a statistically adequate number and range of samples for model 341development and comparable samples for model validation. Suitable software should be used for 342data analysis. Model parameters should be deliberately varied to test model robustness.34334416 See 21 CFR 211.194(a)(2) and USP General Chapter <1226> Verification of Compendial Procedures.17 See References section for examples including USP <1010> Analytical Data – Interpretation and Treatment.。
_diffrn_measured_fraction_theta_full Low ....... 0.93 采集数据的完成度偏低,通常要在0.97 以上。
最好是重新收集数据。
解决方法:omit0 50问题:No su's on H-atoms, but refinement reported as . mixed报告中显示对H 原子的修正方法是混合模式但没有列出H 原子相关的偏差。
解决方法:把.CIF 中的"mixed" 改成"constr" 就可以了。
问题:CIF Contains no X-H Bonds ...................... ?CIF Contains no X-Y-H or H-Y-H Angles .......... ?解决方法:在ins 文件中将Bond 改为Bond $h 命令,再在XL 中精修一下就可以了问题:PLAT080_ALERT_2_A Maximum Shift/Error ............................ 0.37 修正轮数不够多Maximum Shift/Error 值应该接近于0,至少要在0.02 以下。
解决方法:增加修正轮数(L.S. 后的数值改大)问题:PLAT220_ALERT_2_A Large Non-Solvent O Ueq(max)/Ueq(min) ... 7.95 Ratio PLAT222_ALERT_3_A Large Non-Solvent H Ueq(max)/Ueq(min) ... 7.78 Ratio 这二条是指原子有较大的非正定,说明没有修正好。
解决方法:可以考虑将这个有较大无序的O 进行分比(如占位率0.5:0.5)再修。
如果是衍射数据质量不够好而无法得到好的修正结果,那只有重新采集数据了。
问题:DENSX01_ALERT_1_A The ratio of the calculated to measured crystal density lies outside the range 0.80 <> 1.20Calculated density = 1.753Measured density = 0.000PLAT093_ALERT_1_A No su's on H-atoms, but refinement reported as . mixed解决方法:在cif 里将_exptl_crystal_density_meas 0 改为:_exptl_crystal_density_meas ?将_refine_ls_hydrogen_treatment mixed改为:_refine_ls_hydrogen_treatment constrPLAT211_ALERT_2_A ADP of Atom C3 is NPD ..................... ? 解决方法:原子非正定,无序或者空间群错误,或者数据不好。
Non-constant error varianceHere's an example of non-constant error variance.Here is a plot of the X versus the residuals. It is from a regression of life expectancy (e0_95) on logged income, and the Studentized residuals are plotted as a function of logged income.12p r e s i dl P c G D P 95 3.5835210.6553-3.772373.2514F r a c t i o npresid - 3.772373.2514.207865Here we see that there is a pattern to the residuals.Note that this occurs even though the distribution of residuals appears sort of normal:We don’t seem to improve the situation much by transforming life expectancy. Here’s the residual plot after regressing logged lifeexpectancy:3p r e s i d 3lPcGDP95 3.5835210.6553-3.850283.0907p r e s i d 4lPcGDP953.5835210.1496-2.93662.00008Sometimes nonconstant error variance is a sign that something important hasn ’t been controlled for.Here ’s what we get after controlling for female illiteracy:Female illiteracy seems to have a strong association with life expectancy, and it varies more with countries at low levels ofincome.4CollinearityOne problem that can wreak havoc with a regression is collinearity , or as it is sometimes called, multicollinearity .This occurs when an independent variable has a strong association with one or more of the other independent variables. Why is this? Recall the formula for the sample variance of the least-squares estimate of the coefficient in a multiple regression:Remember that the numerator on the right is the error variance, and S j 2 is the variance of variable X j .R j 2 is the coefficient of multiple correlation from the regression of X j on the other independent variables in the model.As R j 2 approaches 1, i.e. the association between X j and the other independent variables becomes stronger, 1 over 1-R j 2 begins to increase quite rapidly. When R j 2 reaches 1, this term explodes completely.The implication is that as R j 2 approaches 1, the sampling variance of the coefficient B j becomes very large. The standard error on the estimate grows accordingly.The estimate of B j, in other words, is likely to vary considerably from one sample to the next. In some cases this leads to bizarrely large coefficient estimates.There are a variety of purported remedies for the problem of collinearity, and according to Fox most of them are suspect.Before we discuss them, let's clarify when collinearity is likely to present a problem.5yx 0.1.2.3.4.5.6.7.8.9112345678910When is collinearity a problem?The extent to which collinearity is a problem in a model depends on the precise value of the 1/(1-R j 2), which the book refers to as the VIF, or variance inflation factor.In practice, values of R j 2 up to 0.6 or 0.7 are not necessarily too problematic. Once you get above those values, however, problems escalate rapidly.The following, which plots 1/(1-R j 2) as a function of R j 2, clarifies why this is the case:Out to r 2 = 0.7 or 0.8, the sampling variance of the coefficient is only being doubled or tripled. This is bad, but not disastrous,especially if the sample is large.Past this, however, the sampling variance of the coefficient begins to skyrocket.How can it be detected?Pairwise correlations generated by the correlate command may identify situations where pairs of independent variables are highly correlated.Another tip-off that there may be a problem is the presence of coefficients with bizarrely large magnitudes and often opposingsigns.Also, coefficients that change dramatically with the addition or deletion of small numbers of cases may suggest a problem.Another way to detect collinearity is if the standard errors of the coefficients change a lot when you add other variables to theequation.If you suspect something, you can regress the independent variables on each other to check.In practice when is it likely to occur?Collinearity can be a frequent problem in certain types of time series analysis.In sociology, one area where this tends to crop up is in studies that attempt to include effects of age, period, and cohort, all at the same time.Interaction terms are also collinear (since they are justcombinations of variables already in the equation). It is generallyuseful to take them out of the equation if they are not significant.6What can be done about it?Increasing the sample size may help to reduce the sampling variance of the coefficient estimate.Better measurement of the variables may reduce the error variance. If collinearity is an issue because more than one variable are in theory measuring the same underlying dimension, combining ordiscarding variables may help.If the variables do not in theory measure the same underlying dimension, or dimensions, then you have a serious problem. You may need to reconsider the substantive questions you areattempting to investigate with the model, or seek additional data to add to the model.There are some purported 'fixes' available but using these may have a penalty. Either implicitly or explicitly, you may be adding constraints to the model. You may also be introducing biases inthe coefficient estimates.But, in general not too much will work, actually.7。
heteroskedastic-robust standard errorsHeteroskedastic-robust standard errors are a type of standard error that accounts for the heteroskedasticity of the data, meaning that the variance of the errors is not constant across the range of the data. This is a problem in many statistical models, particularly in regression analysis, where the variance of the errors can be systematically related to the level of the predictor variables.In such cases, the heteroskedastic-robust standard errors provide a more accurate estimate of the true standard error of the regression coefficient estimates. These standard errors are usually larger than the regular standard errors, which is due to the fact that they take into account the heteroskedasticity of the data.There are several ways to estimate heteroskedastic-robust standard errors, including the White method, the Huber-White method, and the Jackknife method. These methods differ in their assumptions and the way they estimate the standard errors, but they all provide a way to account for heteroskedasticity in the data.Overall, heteroskedastic-robust standard errors are an important tool for accurately estimating the standard errors of regression coefficients in the presence of heteroskedasticity.。
以下是一段英文版本的“Unable to validate the factsage education package”的翻译,希望能够帮助到您:"Unable to validate the FactsAge education package" - this error message usually appears when there is a problem with the installation or validation of the FactsAge education package.Some possible reasons for this issue include:1.Missing or incorrect installation: This could be due to a failed installation, uninstall, or an incomplete installation.2.Invalid package: The package may be corrupted, incomplete or invalid.3.Hardware or system requirements: The system may not meet the minimum hardware or software requirements to install or run the package.4.File permissions: The installer may not have sufficient permissions to access or modify files during installation.5.Outdated or incompatible software: The FactsAge package may be incompatible with the existing software version or configuration on the system.To resolve this issue, you can try the following troubleshooting steps:1.Check if the installation file is corrupted or incomplete. If it is, download it again from a reliable source and try installing it again.2.Make sure your system meets the minimum hardware and software requirements for the FactsAge package. If not, upgrade your system accordingly.3.Check if your antivirus or firewall software is blocking the installation process. If it is, add an exception in the antivirus or firewall settings for the installation file.4.Verify if you have sufficient permissions to install the package. If not, try running the installer as an administrator.5.Check if there is any outdated or incompatible software on your system that may be causing conflicts with the FactsAge package. If found, uninstall or upgrade the conflicting software.6.Contact the FactsAge support team for further assistance if you still experience issues after trying these troubleshooting steps. They may be able to provide additional help and support for your specific issue.。
verification methodVerification MethodIntroductionVerification is the process of checking whether a product, system or service meets the specified requirements and standards. It is an essential part of the quality assurance process, ensuring that products and services are reliable, safe and effective. There are various verification methods used in different industries to ensure that products and services meet the required standards.Types of Verification Methods1. InspectionInspection involves reviewing a product or service to ensure that it meets the specified requirements and standards. This method can be done visually or through the use of tools such as gauges or measuring devices.2. TestingTesting involves subjecting a product or service to various conditions to determine its performance and functionality. This method can be done through physical testing, simulation testing or computer-based testing.3. AnalysisAnalysis involves using mathematical models or simulations to determine whether a product or service meets the required standards. This method is commonly used in engineering, science and technology industries.4. CertificationCertification involves obtaining independent verification from a third-party organization that a product or service meets the required standards. This method is commonly used in industries such as food safety, environmental management and information security.5. SamplingSampling involves selecting a representative sample of a product or service for verification purposes. This method is commonly used in industries such as manufacturing, where itmay not be feasible to test every single item produced.6. ReviewReview involves examining documentation such as design specifications, test plans and user manuals to ensure that they meet the required standards. This method is commonly used in software development and other documentation-intensive industries.Verification Process1. PlanningThe first step in the verification process is planning. This involves determining what needs to be verified, how it will be verified, who will perform the verification and when it will take place.2. ExecutionThe second step in the verification process is execution. This involves carrying out the planned verification activities such as inspection, testing, analysis or review.3. EvaluationThe third step in the verification process is evaluation. This involves reviewing the results of the verification activities to determine whether the product or service meets the required standards.4. ReportingThe final step in the verification process is reporting. This involves documenting the results of the verification activities and communicating them to relevant stakeholders such as customers, regulators or management.Benefits of Verification1. Improved qualityVerification helps to ensure that products and services meet the required standards, resulting in improved quality and reliability.2. Reduced riskVerification helps to identify potential issues or defects before they become major problems, reducing the risk of product failures or safety incidents.3. Increased customer satisfactionVerification helps to ensure that products and services meet customer expectations, resulting in increased customer satisfaction and loyalty.4. Compliance with regulationsVerification helps to ensure that products and services comply with relevant regulations and standards, reducing the risk of legal or regulatory penalties.ConclusionVerification is an essential part of ensuring that products and services are reliable, safe and effective. There are various verification methods used in different industries to ensure that products and services meet the required standards. The verification process involves planning, execution, evaluation and reporting. The benefits of verification include improved quality, reduced risk, increased customer satisfaction and compliance with regulations.。
方法验证指南The process of method validation is an essential part of ensuring the accuracy and reliability of analytical results in various fields such as pharmaceuticals, clinical testing, and environmental monitoring. 方法验证的过程是确保在制药、临床测试和环境监测等各个领域的分析结果准确性和可靠性的重要环节。
As a crucial step in the development and implementation of a new analytical method, validation helps to demonstrate that the method is suitable for its intended use and produces consistent and reproducible results. 作为一种新分析方法开发和实施过程中的关键步骤,验证有助于证明该方法适合其预期用途,并能产生一致和可重复的结果。
It involves a series of experiments and evaluations that assess the performance characteristics of the method, including accuracy, precision, specificity, detection limits, quantitation limits, linearity, range, and robustness. 它涉及一系列实验和评估,评估方法的性能特征,包括准确性、精密度、特异性、检测限、定量限、线性、范围和稳健性。
Verification of Equivalent-Results MethodsK.Rustan M.Leino and Peter M¨u llerMicrosoft Research,Redmond,WA,USA{leino,mueller}@Abstract.Methods that query the state of a data structure often return identicalor equivalent values as long as the data structure does not change.Program ver-ification depends on this fact,but it has been difficult to specify and verify suchequivalent-results methods and their callers.This paper presents an encoding from which one can determine equivalent-resultsmethods to be deterministic modulo a user-defined equivalence relation.It alsopresents a technique for checking that a query method returns equivalent resultsand enforcing that the result depends only on a user-defined influence set.The technique is general,for example it supports user-defined equivalence rela-tions based on Equals methods and it supports query methods that return newlyallocated objects.The paper also discusses the implementation of the techniquein the context of the Spec#static program verifier.0IntroductionComputer programs contain many methods that query the state of a data structure and return a value based on that state.As long as the data structure remains unchanged,one expects different invocations of the query method to produce equivalent return values. For methods returning scalar values,the return values are expected to be the same.For methods returning object references,the most interesting equivalences are reference equality and equivalence based on the Equals method.A simple and common example of a query method is the Count method of a col-lection class,like List in Fig.0,where for a given collection the method returns the number of elements stored in the collection.Obviously,one expects Count to return identical values when called twice on the same collection.Another example is shown in the Calendar class in Fig.2,where invocations of the GetEarliestAppointment will yield equivalent results as long as the state of the calendar does not change.However, since GetEarliestAppointment returns a newly allocated object,the results will not be identical.Due to object-allocation,query methods cannot be expected to be deter-ministic.Nevertheless,their results are expected to be equivalent.Therefore,we shall refer to such query methods as equivalent-results methods.Query methods(also called pure methods)are particularly important in assertion languages such as JML[15]or Spec#[1]because they allow assertions to be expressed in an abstract,implementation-independent way.For instance,Count is used in the precondition of GetItem(Fig.0)to refer to the number of elements in the list without revealing any implementation details.However,reasoning about assertions that contain query methods is difficult.The client program in Fig.1illustrates the problem.It uses aclass List T {int Count()ensures0 result;{...}T GetItem(int n)requires0 n<Count();{...}...}Fig.0.A List class whose Count method returns the number of elements in a given list and whose GetItem method returns a requested element of the list.The postcondition of Count promises the return value to be non-negative,and the precondition of GetItem requires param-eter n to be less than the value returned by Count.List T list;...if(n<list.Count()){S//some statement that changes the state,but not the listt=list.GetItem(n);}Fig.1.A code fragment that uses the List class from Fig.0.The if statement guards the invoca-tion of GetItem to ensure that GetItem’s precondition is met.To verify the correctness of this code,one needs to be able to determine that the two invocations of Count return the same value.conditional statement to establish the precondition of GetItem.We assume that state-ment S does not change the list structure.Therefore,we expect that the condition still holds when GetItem is called,that is,that the two calls to Count yield the same result. There are essentially three approaches for a program verifier to conclude this fact.Thefirst approach is to require that the postcondition of the query method is strong enough for a caller to determine exactly what value is returned.Typically,this can be achieved by having a postcondition of the form result=E.In our example,this post-condition would allow the verifier to compare the state affected by S to the state read by E to determine whether the two calls to Count return the same result.However, requiring such strong postconditions may entail a dramatic increase in the complexity of the specification.For Count,one would have to axiomatize mathematical lists and use that mathematical abstraction in the specification of the List class.We consider this burden too high,in particular for the verification of rather simple properties.The second approach is to define the return value of the method to be a function of the program state.If the program state has not changed by the time the method is invoked again,this approach allows one to conclude the return value is the same as before.But this approach is too brittle,for two reasons.First,it treats state changes too coarsely.For example,statement S in Fig.1may change the program state,but as long as it does not change the state of the list,we want to be able to conclude that the resultof Count is unchanged.Second,this approach is too precise about the return value. For example,the object references returned by two calls to GetEarliestAppointment in Fig.2are not identical,yet the data they reference are equivalent.Queries that return newly allocated objects are very common,especially in JML’s model classes[16].The third approach is to require that all query methods used in specifications are equivalent-results methods whose results depend only on certain heap locations.We call this set of locations the influence set of a query method.With this approach,the code in Fig.1can be verified by showing that the locations modified by S are not in the influence set of Count.From the equivalent-results property and the fact that Count returns an integer,we can conclude that the two calls to Count yield the same results.Existing program verifiers such as the Spec#static program verifier Boogie[0]and ESC/Java2[14]apply the third approach.However,these systems do not enforce that query methods actually are equivalent-results methods and that their result actually de-pends only on the declared influence set.Blindly assuming these two properties is un-sound.Checking the properties is not trivial,even for methods that return scalar values. For instance,GetHashCode is an equivalent-results method and should be permitted in assertions,but returning the hash code of a newly allocated object leads to non-determinism and must be prevented.In this paper,we present a simple technique to check that a query method is an equivalent-results method and that its result depends only on its parameters and the de-clared influence set.This technique supports user-defined equivalence relations based on,for instance,Equals methods.We use self-composition[2,20]to simulate two ex-ecutions of the method body from start states that coincide in the influence set and to prove that the respective results are indeed equivalent.We also present axioms that en-able reasoning about equivalent-results methods and argue why they are sound.Our technique is very general:it supports user-defined equivalence relations,it does not re-quire a particular way of specifying influence sets,and it uses a relaxed notion of purity. In particular,implementations of query methods may use non-deterministic language features and algorithms,and may return newly allocated objects.We plan to implement our technique for pure methods in Boogie,but our results do not rely on the specifics of Spec#.Therefore,they can be adopted by other program verifiers.Outline.Section1provides the background on program verification that is needed in the rest of this paper.Section2presents an encoding of equivalent-results methods that enables the kind of reasoning discussed above.Section3explains our technique for checking the equivalence of results.Section4discusses the application of our technique to Spec#.The remaining sections summarize related work and offer conclusions.1Background on Program VerificationIn this section,we review details of program verification relevant to our paper.For a more comprehensive and tutorial account of this material,we refer to some recent Marktoberdorf lecture notes[19].class Appointment{int time;//...morefields herepure override bool Equals(object o)ensures GetType()=typeof(Appointment)⇒(result⇐⇒o=null∧GetType()=o.GetType()∧time=((Appointment)o).time∧...more comparisons here);{...}}class Calendar{pure Appointment GetEarliestAppointment(int day){Appointment a;//find earliest appointment on day day...return a.Clone();}void ScheduleMorningMeeting(int day,List Person invitees)requires10 GetEarliestAppointment(day).time;{...}}class Person{void Invite(Calendar c,...){if(10 c.GetEarliestAppointment(5).time){//compute inviteesList Person invitees=new List Person ();while(...){...invitees.Add(p);}//schedule those inviteesc.ScheduleMorningMeeting(5,invitees);}}}Fig.2.A Calendar program whose GetEarliestAppointment method returns an equivalent value as long as the calendar does not change.The correctness of the code fragment at the bot-tom of thefigure depends on that the call to GetEarliestAppointment in the precondition of ScheduleMorningMeeting returns a value that is equivalent to the one returned by the call to GetEarliestAppointment in the guard of the if statement.Architecture of Program Verifiers.To verify a program,the program’s proof obliga-tions(e.g.,that preconditions are met)are encoded as logical formulas called verifica-tion conditions.The verification conditions are valid formulas if and only if the program is correct with respect to the properties being verified.Each verification condition is fed to a theorem prover,such as an SMT solver or an interactive proof assistant,which at-tempts to ascertain the validity of the formula or construct counterexample contexts that may reveal errors in the source program.As has been noted by several state-of-the-art verifiers,it is convenient to generate verification conditions in two steps:first encode the source program in an intermediate verification language,and then generate input for the theorem prover from the intermediate language[0,11,4].Since the second step con-cerns issues that are orthogonal to our focus in this paper,we look only at thefirst step. The notation we will use for the intermediate verification language is BoogiePL[0,10].A BoogiePL program consists of afirst-order logic theory,which in particular specifies the heap model of the source language,and an encoding of the source program.We explain these two parts in the following subsections.Heap Model.We model the heap as a two-dimensional array that maps object iden-tities andfield names to values[23],so afield selection expression o.f is modeled as $Heap[o,f].By making the heap explicit,we correctly handle object aliases,as is well known[3,23].In the encoding,we use a booleanfield$alloc in each object to model whether or not the object has been allocated.The subtype relation is denoted by<:.For any set S of locations(that is,of object-field pairs),we define a relation≡S that relates two heaps if they have the same values for all locations in S.More precisely: (∀H,K,S•(H≡S K⇐⇒(∀o,f•(o,f)∈S⇒H[o,f]=K[o,f])))Note that≡S is an equivalence relation:it is reflexive,symmetric,and transitive.If H≡S K,we say that H and K are equivalent modulo S.We assume that pure methods do not modify the state of any object that is allocated in the pre-state of the method execution.This definition allows a pure method to allocate and modify new objects such as iterators[24].More precisely,if H0and H1denote the heaps immediately before and after the call to a pure method,and S is a set of locations of objects that are allocated in H0,the following property holds: H0≡S H1(0)Encoding of Source Programs.Each source-language method is encoded as a proce-dure in the intermediate verification language.To understand the basic encoding,con-sider a method M in a class C with afield y,shown in Fig.3.The specification of M has a precondition that obligates the callers of M to pass a non-negative argument value.In turn,the precondition lets the implementation of M assume x to be non-negative on entry.The specification also has a modifies clause and a postcondition that obligate the implementation to make sure that its return value, parameter x,and the yfield of the method’s receiver object are related as specified, and to modify only this.y.A caller can assume these properties upon return of a call.class C{int y;int M(int x)requires0 x;modifies this.y;ensures result+x this.y;{...}Fig.3.An example class in the source language,showing an instancefield y and a method M with a method specification.procedure C.M(this,x)returns(result);requires this=null;free requires$Heap[this,$alloc]∧$typeof(this)<:C;ensures result+x $Heap[this,C.y];ensures(∀o,f•o=this∧old($Heap)[o,$alloc]⇒$Heap[o,f]=old($Heap)[o,f]∨(o=this∧f=y));free ensures(∀o•old($Heap)[o,$alloc]⇒$Heap[o,$alloc]);Fig.4.A BoogiePL procedure declaration that encodes the signature and specification of the example method C.M.A representative encoding of M as a BoogiePL procedure is shown in Fig.4. The procedure declaration makes the implicit receiver parameter this explicit,and the anonymous return value is encoded as a named out-parameter.The types in BoogiePL are more coarse-grained than those in the source language,and for the purposes of this paper,they are only a distraction,so we omit them altogether.Three things are worth noting about the procedure specification.First,method M’s pre-and postconditions have direct analogs in the BoogiePL procedure,where the implicit dereferencing of the heap in afield selection expression is made explicit in the BoogiePL encoding.Second,the method’s modifies clause is encoded as a BoogiePL postcondition that dictates which locations in the heap are allowed to change.The latter says that for any non-null object o allocated on entry to the method and for anyfield f,the heap at location o.f is unchanged except possibly at location this.y.Third,to verify a program,one often needs to know some properties that are guar-anteed by the source language.For example,the static type of the receiver parameter of method M is C and the source-language type checker thus guarantees that the allo-cated type of the receiver is some subtype of C.The source language also guarantees that all object references in use by a program are allocated and(thanks to thefiction created by the garbage collector)remain allocated forever.To incorporate these guar-anteed conditions in the encoding,BoogiePL conveniently offers free pre-and post-conditions as part of a procedure declaration.Free preconditions are assumed on entry to a procedure implementation,but not checked at call sites,and analogously for free postconditions.Proof Obligations and Soundness.Proving the correctness of a BoogiePL program amounts to statically verifying that the program does not abort due to a violated as-sertion(such as a precondition or postcondition).To do that,each assertion is turned into a proof obligation.One can then use an appropriate program logic to show that the assertions hold.For the proof,one may assume the conditions expressed as free precon-ditions,free postconditions,and explicit assume statements.The verification is sound if all of these assumptions actually hold.2Encoding of Equivalent-Results MethodsOur idea is to define an equivalence class of return values for each equivalent-results method.We define the equivalence class via a programmer-defined similarity rela-tion.Typical choices for the similarity relation are reference equality and the Equals method.Rather than letting the similarity relation be the equivalence relation,we define the equivalence class to be those values that are related by the similarity relation to a particular element,called the anchor element.This has the advantage that the similarity relation need not be symmetric and transitive,which in practice the Equals method often is not[25].Another advantage is that using an anchor element allows us to state axioms that are handled more efficiently by the theorem prover.In this section,we explain similarity relations,anchor elements,and the influence sets that define the dependencies of method results.Similarity Relations.For a method M,we let R M(H,r,H′,r′)denote M’s sim-ilarity relation,relating r whose state is evaluated in heap H and r′whose state is evaluated in heap H′.For example,if R M denotes equality of scalar values or refer-ence equality for object values,we have:R M(H,r,H′,r′)⇐⇒r=r′(1) and if R M uses the Equals method,we have:R M(H,r,H′,r′)⇐⇒@Equals(H,r,H′,r′)(2) where@Equals is a function automatically generated from the specification of Equals. Value r is always a return value of the method;r′is either a return value,in which case H=H′or the anchor element,in which case H′is a special heap AnchorHeap M(p) where we evaluate anchor elements.The similarity relation defines an equivalence class of values that are related to the anchor element.For the Appointment.Equals method in Fig.2,the following axiom is automati-cally generated for function@Equals:(∀H,this,K,o•this=null∧$typeof(this)<:Appointment∧$typeof(o)<:Object⇒(@Equals(H,this,K,o)⇐⇒(3)o=null∧$typeof(this)=$typeof(o)∧H[this,time]=K[o,time]∧...more comparisons here))where,here and throughout,quantifications over H and K range over well-formed heaps.It is not the subject of our paper to describe how axioms for pure methods are described,but see our previous work with´Ad´a m Darvas[9,8];the difference is that here we use one heap argument for each of the two parameters to Equals.Influence Sets.The influence set is a set of locations in the heap.Let F M(H,p)de-note the influence set of M as computed for parameters p in a heap H.Note that the computation of the influence set may depend on the heap.For example,consider a class Schedule with an Appointmentfield a.Suppose the influence set for some method applied to a schedule s is given by the set of path expressions{s.a,s.a.time}. Viewed in the intermediate-language notation,these path expressions denote the follow-ing object-field pairs:(s,a),($Heap[s,a],time).We require every influence set to be self-protecting[13],which means that any two heaps equivalent modulo the influence set compute the influence set the same way:K⇒F M(H,p)=F M(K,p))(4) (∀H,K,p•H≡FM(H,p)Self-protection can be enforced by requiring the set of path expressions that specify the influence set to be prefix closed:if it contains a path expression E.x.y,then it must also contain the path expression E.x.Therefore,the expression E.x.y denotes the same location in heaps H and K.The influence set specifies which parts of the program state are allowed to influence the return value.To afirst order of approximation,the influence set is the read set or read effect of the method[5],but,technically,we actually allow methods to read any part of the state,as long as the values of things outside the influence set have no bearing on the return value.Anchor Elements.The encoding of equivalent-results methods has to allow us to prove that two calls to an equivalent-results method M return equivalent results if the two heaps before the calls are equivalent modulo the influence set of M.We reach this conclusion in two steps.First,we encode by an axiom that the anchor element remains the same as long as the program state indicated by the influence set does not change. Second,we encode by a free postcondition that the actual return value of M is related to the anchor element by the similarity relation.Hence,the results of the two calls to M are in the same equivalence class.Step A:In our intermediate-language encoding,we introduce a function Anchor M that yields an anchor element for the equivalence class of the return values of M.We axiomatize Anchor M as follows:K⇒Anchor M(H,p)=Anchor M(K,p))(5) (∀p,H,K•H≡FM(H,p)The axiom says that we pick the same anchor element whenever M is invoked with the same arguments p in two heaps H and K that are equivalent modulo F M(H,p).In other words,the anchor element is a function of the program state projected onto the influence set.H0:=$Heap;call r:=GetEarliestAppointment(c,5);H1:=$Heap;if(10 $Heap[r,time]){//code to compute invitees...K0:=$Heap;call r′:=GetEarliestAppointment(c,5);K1:=$Heap;assert10 $Heap[r′,time];...}Fig.5.A sketch of the code fragment from the bottom of Fig.2,giving the names H0,H1, K0,and K1to the intermediate values of the heap,and giving the names r and r′to the return values of the two calls to GetEarliestAppointment.The assert statement at the end shows the condition that we want to prove.Step B:We add to our encoding the following free postcondition:free ensures R M($Heap,result,AnchorHeap M(p),Anchor M($Heap,p));(6) To make sure the anchor object always denotes the same equivalence class,we evaluate its state in a special,constant heap AnchorHeap M.We postpone until Section3how to justify this free postcondition.Example.To prove the correctness of method Invite in Fig.2,it suffices to show that the two invocations of GetEarliestAppointment return equivalent values.Re-call,the second invocation takes place during the evaluation of the precondition of ScheduleMorningMeeting.Fig.5shows a BoogiePL encoding of that fragment.As illustrated by the assert statement in Fig.5,we wish to prove that H1[r,time]equals K1[r′,time].The influence set of GetEarliestAppointment contains thefields that make up the representation of the Calendar object.Let H0and H1denote the heaps immediately before and after thefirst call to GetEarliestAppointment,and let K0and K1denote the heaps immediately before and after the second call.Since GetEarliestAppointment is pure,it does not change the values of any pre-viously allocated locations(see condition(0)),so H0and H1are equivalent modulo F(H0,c,5),and K0and K1are equivalent modulo F(K0,c,5)(we drop the sub-script GetEarliestAppointment in this example).Assuming that the code that com-putes invitees has no effect on the values of the locations in the influence set,we also have that H1and K0are equivalent modulo F(H1,c,5).By self-protection(4),we know that the three influence sets are equal.Thus,we can conclude by transitivity: H1≡F(H1,c,5)K1(7) By axiom(5)and equation(7),we conclude that the anchor elements for the two calls are the same:Anchor(H1,c,5)=Anchor(K1,c,5)(8)procedure M(p)returns(result)requires P($Heap,p);free requires Q($Heap,p);ensures S(old($Heap),$Heap,p,result);free ensures T(old($Heap),$Heap,p,result);free ensures R M($Heap,result,AnchorHeap M(p),Anchor M($Heap,p));{var locals;Body}Fig.6.A procedure in the intermediate verification language,illustrating the general form of the procedure into which the method translates.Now let r and r′denote(as indicated in Fig.5)the values returned by the two calls to GetEarliestAppointment.The similarity relation is given by the Equals method. Thus,we conclude from postcondition(6):@Equals(H1,r,AnchorHeap(c,5),Anchor(H1,c,5))and@Equals(K1,r′,AnchorHeap(c,5),Anchor(K1,c,5))By axiom(3)and property(8),we haveH1[r,time]=AnchorHeap(c,5)[Anchor(H1,c,5),time]∧K1[r′,time]=AnchorHeap(c,5)[Anchor(H1,c,5),time]from which we conclude H1[r,time]=K1[r′,time],as required to establish the precondition of the call to ScheduleMorningMeeting.3Verifying Equivalence of ResultsAs we mentioned in Section1,soundness of a verification system comes down to jus-tifying every assumption that the proof system allows a proof to make use of.In the previous section,we introduced three conditions that we used as assumptions in the proof.Thefirst assumption is the axiom of self-protection(4).It can be justified by a syntactic check on the path expressions used to define the influence set.The second assumption is the axiom about Anchor M(5).It is justified on the basis that there ex-ists a function Anchor M that satisfies the axiom,for example any constant function. The third assumption is the free postcondition(6).In this section,we present a proof technique based on self-composition that justifies this assumption.Ordinarily,a method M gives rise to a verification condition prescribed by a Boo-giePL procedure implementation like procedure M in Fig.6,where p denotes the in-parameters,P and S denote some checked pre-and postconditions,Q and T de-note some free pre-and postconditions(cf.Fig.4),locals are local variables,and Body is the BoogiePL encoding of the implementation of method M.For every equivalent-results method M,we will now prescribe a second BoogiePL procedure,whose validity will justify the free postcondition(6).The key idea is toprocedure M′(p)returns(result){var locals;var$oldHeap:=$Heap;assume P($Heap,p)∧Q($Heap,p);Body′assume S($oldHeap,$Heap,p,result)∧T($oldHeap,$Heap,p,result);assume Anchor M($Heap,p)=result∧AnchorHeap M(p)=$Heap;//L0havoc$Heap,locals,result;$oldHeap;assume$Heap≡FM($oldHeap,p)$oldHeap:=$Heap;assume P($Heap,p)∧Q($Heap,p);Body′assume S($oldHeap,$Heap,p,result)∧T($oldHeap,$Heap,p,result);assert R M($Heap,result,AnchorHeap M(p),Anchor M($Heap,p));//L1}Fig.7.A procedure that checks by assertion(L1)that M satisfies its free postcondition(6).execute the method body twice starting in states that agree on the values of the in-parameters and all objects in the influence set.We then prove that the two executions yield equivalent results.This second procedure has the form shown by M′in Fig.7and is described as follows:–The body of M′starts off with$Heap,locals,and result set to arbitrary values, saves the value of$Heap in$oldHeap,and assumes the preconditions P and Q.–It then performs Body′,which is Body with occurrences of old($Heap)replaced by$oldHeap and occurrences of assert statements(i.e.,checked conditions)re-placed by assume statements.These assume statements are justified by the fact that procedure M already prescribes checks for them,so if the conditions do not hold, the program verifier will generate appropriate errors when attempting to verify M.–Upon termination of Body′,the postconditions S and T are assumed.Again,S can be assumed here because it is checked by M.–We explain the assume statement(L0)below.–Next,the code prepares for another execution of Body′.The second execution of Body′is to start in a state where all locations of the influence set have the same values as in thefirst execution.Thus,$Heap,locals,and result are set to arbitrary values(using a havoc statement)and the value of$Heap is constrained(using an assume statement)to be equivalent to$oldHeap modulo the influence set.–The preconditions are assumed,Body′is executed a second time,and the postcon-ditions are assumed.–We explain the assert statement(L1)below.Thefirst half of M′culminates in assume statement(L0),which has the effect of defining Anchor M($Heap,p)and AnchorHeap M(p)to be the result value and resultheap of an arbitrary execution of the method(namely,thefirst execution of Body′).In fact,by axiom(5),(L0)defines Anchor M($Heap,p)for all heaps that are equivalent to$Heap modulo the influence set.The second half of M′checks that(6)is indeed a postcondition of the method for all those equivalent heaps.With that,we have justified all the assumptions that our technique introduces,and thus we have established that our technique is sound.4Application to Spec#In verifying Spec#programs,we have run across scores of examples like the one in Fig.0,where in Spec#the Count method tends to be a property getter,which is a form of parameter-less method.By default,property getters are treated as pure methods that read only the ownership cone of the receiver object.The ownership cone of an object is the set of locations that make up the object’s representation[6].Previously,our best solution for dealing with this situation in the Spec#program verifier was to introduce an axiom that says the return value of the method is a function of the ownership cone.But such an axiom is not sound if a pure method returns newly allocated object or values that are derived from such objects.Our technique in this paper gives a sound solution to the problem,and we intend to implement it.In this section,we describe some issues that pertain to the practical implementation of equivalent-results methods in Spec#.We intend to restrict the choices for R M in Spec#to support only the two choices (1)and(2).This will simplify the implementation while supporting the most common similarity relations.(The only other useful similarity we found puts all non-null refer-ences in one equivalence class.)To select between the two choices,we will introduce a default choice and a method annotation(a custom attribute)that can override the default.For the influence set,we will only support the union of the ownership cones for some subset of the parameters.Ownership provides a form of abstraction,allowing one to specify influence sets without being specific about implementation details.There is already a notion of confined in Spec#that says that a pure method reads the ownership cone of a parameter.Moreover,the Spec#program verifier already has an encoding that lets one deduce,for valid objects,whether or not the ownership cone of the object has changed.The encoding is simply to inspect the object’s ghostfield snapshot[8].An object is valid when its object invariant holds[18].Since this is the precondition of almost all methods,we will not attempt to prove ownership cones to be the same other than via the snapshotfield.Because of the snapshot encoding,we can write axiom(5) as:(∀p,H,K•H[p,valid]∧K[p,valid]∧H[p,snapshot]=K[p,snapshot]⇒Anchor M(H,p)=Anchor M(K,p))(We have abused notation slightly:by H[p,valid]and H[p,snapshot],we really mean to refer to the valid and snapshotfields of all the parameters in p that contribute to the influence set,and likewise for K.)In fact,there is an alternative way to encode this property that is significantly more efficient for the SMT solver because it avoids quan-tification over pairs of heaps.The alternative encoding[8]introduces an uninterpreted。
邓龙,周思,黄佳佳,等. 固相支撑液液萃取结合LC-MS/MS 快速测定生乳中32种农药残留[J]. 食品工业科技,2023,44(17):360−366. doi: 10.13386/j.issn1002-0306.2022120075DENG Long, ZHOU Si, HUANG Jiajia, et al. Determination of 32 Kinds of Pesticide Residues in Raw Milk by Supported Liquid Extraction with LC-MS/MS[J]. Science and Technology of Food Industry, 2023, 44(17): 360−366. (in Chinese with English abstract).doi: 10.13386/j.issn1002-0306.2022120075· 分析检测 ·固相支撑液液萃取结合LC-MS/MS 快速测定生乳中32种农药残留邓 龙1,周 思2, *,黄佳佳1,曾上敏1,张静文1(1.广东食品药品职业学院,广东广州 510520;2.广州市疾病预防控制中心,广东广州 510440)摘 要:将固相支撑液液萃取与超高效液相色谱串联质谱法结合,建立生乳中32种农药残留的快速检测方法,为保障生乳食品安全提供技术支持。
样品加入乙腈沉淀蛋白,高速离心分离,上清液用固相支撑液液萃取小柱净化,C 18色谱柱梯度洗脱分离后,经串联质谱电喷雾模式扫描,多反应监测模式检测,以基质匹配校准曲线外标法定量。
结果表明,32种目标物在一定范围内线性关系良好,相关系数大于0.9962,检出限为0.1~2.5 μg/kg ,定量限为0.3~7.5 μg/kg ,平均回收率为69.4%~113.8%,相对标准偏差(n=6)小于8.2%。
该方法简单、快速、可靠,适用于生乳中32种农药残留的测定。
反证法英文格式Proof by contradiction is a method of proof where you assume the opposite of what you're trying to prove and then demonstrate that this assumption leads to a contradiction.This proof method is also called the indirect proof, and it's particularly useful when you're trying to prove the negativeof a statement.The general outline of proof by contradiction is as follows:1. Assume that the statement you're trying to prove is false.2. Use logical reasoning and any available information to derive a contradiction.3. Conclude that the statement you assumed was false must, therefore, be true.Proof by contradiction has been used in mathematics and logic for centuries. It's a technique that's particularly useful in geometry, number theory, and analysis, and it's also used in many areas of science.One of the most famous examples of proof by contradiction is Euclid's proof of the infinitude of primes. Euclid's proof is based on the assumption that there are only a finite number of primes, and then he demonstrates that this assumption leads to a contradiction. If there were only a finite number of primes, then you could multiply them all together and add 1 to get a new number that's not divisible by any of them. However, this new number would also have to be prime, which contradicts the assumption that there are only a finite number of primes.Another example of proof by contradiction is the proof that the square root of 2 is an irrational number. Suppose the opposite of the statement is true, that the square rootof 2 is a rational number. Then, we can write the square root of 2 as a fraction, say a/b, where a and b are positive integers and have no common factors. This implies that a^2 = 2b^2, which means that a^2 is even, and therefore, a itself must be even. So we can write a as 2k. Substituting 2k for a in the equation a^2 = 2b^2 gives:(2k)^2 = 2b^24k^2 = 2b^22k^2 = b^2This means that b^2 is even, and therefore, b itself must be even. But if both a and b are even, then they have a common factor of 2, which contradicts the assumption that a and b have no common factors. Hence, the assumption that the square root of 2 is rational must be false.In conclusion, proof by contradiction is a powerful and widely used method of proof in mathematics and logic. It'sparticularly useful when you're trying to prove the negative of a statement or when you're faced with a problem that seems too difficult to solve directly. By assuming that the opposite of the statement you're trying to prove is true and then demonstrating that this assumption leads to a contradiction, you can often arrive at a readily understandable and conclusive proof.。
一、名词解释(5*3分=15分)(斜体表明仅供参考) 计量经济学:以经济理论和经济数据的事实为依据,运用数学和统计学的方法,通过建立数学模型来研究经济数量关系和规律的一门经济学科。
最小二乘法:指在满足古典假设的条件下,用使估计的剩余平方和最小的原则确定样本回归函数的方法,简称OLS 随机扰动项:总体回归函数中,各个Y值与条件期望的Y值的偏差,又称随机误差项。
是代表那些对Y有影响但又未纳入模型的诸多因素的影响。
总体回归函数:在给定解释变量X i条件下,总体被解释变量Y i的期望轨迹,函数式表示为E(Y i∣X i)=f(Xi)= β0+β1X i 样本回归函数:在总体中抽取若干个样本构成新的总体,然后在新的总体下,给定解释变量X i,被解释变量Y i的期望轨迹,函数式表示为E(Y i∣X i)=Y i^= β0^+β1^X i系数显着性检验:(t检验)对回归系数对应的解释变量是否对被解释变量有显着影响的统计学检验方法方程显着性检验:(F检验)对模型的被解释变量与所有解释变量之间的线性关系在整体上是否显着的统计学检验方法高斯-。
拟合优度多重共线性异方差(εi)=σi2σi2,根据最小自相关≠j)判断题(1234567891011 ( 乂 )12、变量不存在两两高度相关表示不存在高度多重共线性。
( 乂 )13、当异方差出现时,最小二乘估计是有偏的和不具有最小方差特性。
(乂)14、当异方差出现时,常用的t检验和F检验失效。
(√)15、在异方差情况下,通常OLS估计一定高估了估计量的标准差。
(乂)16、如果OLS回归的残差表现出系统性,则说明数据中有异方差性。
(√)17、如果回归模型遗漏一个重要的变量,则OLS残差必定表现出明显的趋势。
(√)18、在异方差情况下,通常预测失效。
(√)19、当模型存在高阶自相关时,可用D-W法进行自相关检验。
(乂)20、当模型的解释变量包括内生变量的滞后变量时,D-W检验就不适用了。
Egger's regression method is a statistical technique used to assess the presence of publication bias in meta-analyses. It 本人ms to examine whether there is a systematic bias in the results of studies included in a meta-analysis, particularly with respect to small study effects. In this article, we will explore the principles and application of Egger's regression method, as well as its limitations and alternatives.1. Principles of Egger's regression methodEgger's regression method is based on the concept of funnel plot asymmetry. A funnel plot is a graphical representation of the relationship between the effect size estimates from individual studies and their precision, typically represented by the standard error. In the absence of publication bias, the funnel plot should resemble a symmetrical inverted funnel, with smaller studies scattered widely at the bottom and larger studies clustering near the top. However, if there is publication bias, the funnel plot may show asymmetry, with smaller studies with more extreme effect sizes being missing from one side of the plot.Egger's regression method formalizes the assessment of funnelplot asymmetry by fitting a regression line to the funnel plot, with the effect size estimates as the independent variable and the standard error as the dependent variable. The intercept of this regression line provides an estimate of the extent of asymmetry, and its statistical significance can be tested to determine the presence of publication bias.2. Application of Egger's regression methodTo apply Egger's regression method, the first step is to construct a funnel plot based on the effect size estimates and their standard errors from individual studies included in the meta-analysis. The presence of asymmetry in the funnel plot can be visually examined, although formal testing using Egger's regression method is rmended for conclusive evidence.The regression analysis is performed by regressing the effect size estimates on their standard errors, and the coefficient of the intercept provides an estimate of the degree of asymmetry. If the intercept is significantly different from zero, it suggests the presence of publication bias. This finding should be interpreted cautiously, as the significance of the intercept may be influenced by the number of included studies and theprecision of their effect size estimates.3. Limitations of Egger's regression methodDespite its utility, Egger's regression method has several limitations that should be considered when interpreting its results. Firstly, the method relies on the assumption that publication bias is the only cause of funnel plot asymmetry, which may not always be the case. Other factors, such as study quality, heterogeneity, and selective oue reporting, can also contribute to funnel plot asymmetry and may confound the interpretation of the results.Additionally, Egger's regression method is sensitive to the number of included studies and their precision, as studies with larger sample sizes and more precise effect size estimates have more influence on the regression line. As a result, the significance of the intercept in Egger's regression analysis may be driven by a small number of influential studies, leading to potentially misleading conclusions about the presence of publication bias.4. Alternatives to Egger's regression methodIn light of the limitations of Egger's regression method, alternative approaches have been proposed to assess publication bias in meta-analyses. These include the use of other statistical tests, such as Begg's rank correlation test and the trim-and-fill method, as well as graphical methods, such as the "Galbr本人th plot" and the "L'Abbe plot".Begg's rank correlation test is based on the correlation between the effect size estimates and their ranks, and can be used to assess asymmetry in funnel plots. The trim-and-fill method addresses publication bias by imputing potentially missing studies to create a more symmetrical funnel plot. These methods offerplementary insights into the presence of publication bias and can be used in conjunction with Egger's regression method to strengthen the overall assessment.5. ConclusionEgger's regression method is a valuable tool for detecting publication bias in meta-analyses, but its interpretation should be cautious due to its limitations. By understanding the principles of Egger's regression method and consideringalternative approaches, researchers can make more informed judgments about the robustness of their meta-analytic findings and explore the potential impact of publication bias on the overall conclusions.。
the normalized mean squared error 代码-回复[The normalized mean squared error code]IntroductionThe normalized mean squared error (NMSE) is a popular metric used in the field of machine learning and statistical analysis to evaluate the performance of regression models. It measures the average squared difference between the predicted values and the true values, normalized by the variance of the true values. In this article, we will discuss the steps involved in calculating the NMSE code and its significance in evaluating regression models.Step 1: Importing the necessary librariesThe first step in calculating the NMSE code is to import the required libraries. In Python, we can use the following code to import the necessary libraries:import numpy as npfrom sklearn.metrics import mean_squared_errorHere, we import the NumPy library as np, which provides various mathematical functions and operations. We also importmean_squared_error from the scikit-learn library, which is a popular machine learning library in Python.Step 2: Generating the true and predicted valuesTo calculate the NMSE, we need two arrays of values - the true values and the predicted values. The true values represent the ground truth values or the actual values that we are trying to predict. The predicted values, on the other hand, are the values predicted by our regression model.Let's consider an example where we have the true values and predicted values stored in two arrays, true_values andpredicted_values. We can generate these arrays using any regression model or by loading data from a dataset.Step 3: Calculating the mean squared errorThe next step is to calculate the mean squared error (MSE) between the true values and the predicted values. The mean squared error measures the average of the squared differences between the predicted values and the true values.We can use the following code to calculate the mean squared error: mse = mean_squared_error(true_values, predicted_values)Here, we pass the true_values and predicted_values arrays to the mean_squared_error function, which calculates the mean squared error.Step 4: Calculating the variance of the true valuesAfter calculating the mean squared error, we need to calculate the variance of the true values. The variance measures the spread or dispersion of a set of values.We can use the following code to calculate the variance:variance = np.var(true_values)Here, we use the var function from the NumPy library to calculate the variance of the true_values array.Step 5: Calculating the normalized mean squared errorFinally, we can calculate the normalized mean squared error by dividing the mean squared error by the variance of the true values:nmse = mse / varianceThe normalized mean squared error provides a measure of how well the regression model is performing relative to the spread of the true values. A lower NMSE indicates a more accurate model, while a higher NMSE suggests greater errors in the predictions.ConclusionIn this article, we discussed the steps involved in calculating the normalized mean squared error code. The normalized mean squared error is an important metric for evaluating regression models and is widely used in various fields, including machine learning and statistical analysis. By understanding how to calculate the NMSE and its significance, we can effectively assess the performance of our regression models and make informed decisions based on the results.。