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["HESI Genetic Toxicology Technical Committee (GTTC) \nHistorical Control Distribution (HCD) Working Group Survey"]
["     The GTTC HCD Working Group is querying laboratories about their experiences with compiling, maintaining and using historical control data and distributions for genetic toxicology assay acceptance and evaluation. The compiled data will be used to determine where consensus approaches exist and, where possible, make recommendations on compiling, maintaining and monitoring historical control data and distributions.\n     Whilst we would like your experience for all genetic toxicology assays, if this is not possible in the timeframe given, we ask that you provide information for the most commonly used assays as noted in the Excel-based survey. Although we would be interested to know if different approaches are used for the most commonly used/routine assays versus those that are not performed routinely in your laboratory, if the same approach for compiling, maintaining and monitoring historical control data and distributions (i.e., the same answers apply) for multiple assays / endpoints, please indicate which assays are applicable in the survey. \n     Please use this document as a reference as you fill-out this Excel-based survey. Ensure that the macros are enabled (otherwise you may not be able to select multiple respones for some questions.) Completed surveys should be sent to Connie Chen (cchen@hesiglobal.org) by April 1, 2022. \n     If you have any questions regarding the survey, please reach out to the project co-leads Robert Smith (robert.p.smith@labcorp.com) and Robert Heflich (robert.heflich@fda.hhs.gov). "]
[]
["Question","Drop-down menu options (if applicable)","Response"]
["Contact Details",null,"Note: Your contact information and lab will be kept anonymous to the HCD WG."]
["Name"]
["Organization/Company/Laboratory"]
["Email"]
["Can we contact you with additional/clarifying questions?","• Yes\n• No"]
["Do you consider use of Historical control data and distributions as critical for assay evaluation of genetic toxicology study data independent of test guideline requirement?","• Yes\n• No"]
["Comments"]
["What do you consider the usefulness of historical control distributions to be? (Several answers can be chosen.)","•\tA reference interval / range to flag outliers during study data evaluation \n•\tA measure of the biological noise for the assay \n•\tA measure of the normal background variability for the assay \n•\tUsed for comparison to study controls to assess study reliability \n•\tUsed for comparison to study controls to identify drift in data / species / strain \n•\tA replacement for concurrent control data \n• Used alongside statistical analysis of study results (such as pairwise comparison or trend tests) for overall evaluation of study data \n• Used for assessment of the biological relevance of statistically significant increases in study data \n• An indication of how well the laboratory is performing the assay\n• Never consider HCDs\n• Other purpose than listed, please specify in ‘Comments’"]
["Comments"]
["Do you compare your laboratory HCDs against other laboratory’s HCDs or published vehicle control data, for example?","• Yes\n• No"]
["Comments"]
["If no, would you see benefit from a ‘global’ HCD for the assay / endpoint, similar to the use of a predefined induced mutant frequency (known as the Global Evaluation Factor (GEF)) to define positive and negative responses for the Mouse Lymphoma Assay (MLA)?","• Yes\n• No"]
["Comments"]
["In your opinion, what can limit the use of historical control data when available? (Several answers can be chosen)","• Insufficient information on the criteria for selecting historical control data (e.g. number of studies, number of replicates, study conditions, etc.) \n• Insufficient level of details in reporting historical control data \n• Insufficient number of studies to source historical control data \n• Insufficient number of replicate values included in the historical control data set \n• Lack of consistent terminology \n• Lack of consistent format \n• Lack of guidance on how to use, report and interpret historical control data \n• Lack of information related to the methods and settings used to collect the data \n• Lack of information on how HCDs are generated \n• Nothing \n• Other, please specify in ‘Comments’ below. "]
["Comments"]
["What best describes the way your laboratory handles statistical analyses, including HCD?","• Study directors are responsible for statistical analyses, and their resources are primarily SOPs and scientific literature\n• We outsource for statistical guidance and specific analyses as necessary\n• In-house statistician(s) provide guidance and oversee analyses related to genotoxicity studies"]
["Comments"]
["What type of data do you use to derive your HCD?","• GLP\n• Non-GLP\n• Both"]
["Comments"]
["Do you think non-GLP data can be included in establishing historical control distribution?","• Yes\n• No"]
["Comments"]
["If the GTTC HCD WG were to perform a collection of historical control data, would you be willing to share historical control data?","• Yes\n• No"]

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["We've provided the most commonly used assays, but if there are additional assays performed please replace the \"Other (please specify) header with your assay. You can delete the assays for which you don't plan on providing answers.  Please use the drop-down menus and comment boxes provided. "]
[null,null,"In Vivo Assays",null,null,null,null,null,"In Vitro Assays"]
["Questions","Drop-Down Menu Options (if appliable)","Bone Marrow Micronucleus","Peripheral Blood Micronucleus","Comet Assay","Pig-a Assay","Transgenic Rodent Gene Mutation Assay","Other (please specify)","Ames","In Vitro Micronucleus","tk Gene Mutation Assay","HPRT Gene Mutation Assay","In Vitro Chromosome Aberration","Other (please specify)"]
["General Details (Use a separate column per endpoint, or include more than one endpoint here if the same criteria are used to establish HCDs for each endpoint stated)"]
["Scoring Method","Select all that apply\n• Manual scoring\n• Image analysis \n• Flow cytometry "]
["Comments"]
["Experience Performing Assay","• <1 year\n• 1 – 2 years \n•2 to 5 years \n• 5 to 10 years \n• >10 years  "]
["Approximate # of experiments per year","• <10 \n• 11 to 20 \n• 21 to 40 \n• >40 "]
["Historical Vehicle Control Database (A historical control database is compiled and used to determine the historical control distribution)"]
["Are group mean values or individual replicate values included in the historical control database to determine vehicle control HCDs? ","(Note: individual replicate refers to the experimental unit, which is usually the animal for in vivo assays, and the culture/plate for in vitro assays) \n• Individual replicate values (please state number of replicates included per experiment in ‘Comments’ below) \n• Mean values \n• Both (i.e. separate HCDs determined for both individual and group means) "]
["Comments"]
["Why are mean / individual values used in your laboratory to determine HCDs?","• Historically done this way \n• Acceptance / evaluation criteria\n• Benefits discussion of results"]
["Comments"]
["What is the basis for how many data points are included in the historical control? ","• Based on number of data points? E.g., 40, 100, 200, etc. \n• Based on time? E.g., previous year, 2 years, etc. "]
["Comments"]
["What criteria are used to exclude study vehicle control data from the historical control database? (Several answers can be selected – if criteria are not detailed in the below options, please state your criteria in ‘Comments’ below) ","•\tData does not fulfill the study acceptance criteria \n•\tData does not fall within the current laboratory observed historical control range (i.e. min/max values) \n•\tData does not fall within the current laboratory calculated laboratory historical control distribution \n•\tData falls outside ‘k’ standard deviations (SDs) of current laboratory HCD mean (state ‘k’ used in ‘Comments’ below and how SDs are generated, e.g. from Excel, control charts, etc.) \n•\tData is an unusual/extreme value (state criteria for unusual/extreme’ in ‘Comments’ below) \n•\tThere is a clear, valid and scientifically justified reason to do so (e.g. technical or obvious mistake. State criteria in ‘Comments’ below) \n•\tStatistical methods are used to exclude data from HCD (State methods used in ‘Comments’ below) \n•\tAll data is included \n•\tAll data included if no technical reason to exclude , • Data does not fulfill the study acceptance criteria \n• Data does not fall within the current laboratory observed historical control range (i.e. min/max values) \n• Data does not fall within the current laboratory calculated laboratory historical control distribution \n• Data falls outside ‘k’ standard deviations (SDs) of current laboratory HCD mean (state ‘k’ used in ‘Comments’ below and how SDs are generated, e.g. from Excel, control charts, etc.) \n• Data is an unusual/extreme value (state criteria for unusual/extreme’ in ‘Comments’ below) \n• There is a clear, valid and scientifically justified reason to do so (e.g. technical or obvious mistake. State criteria in ‘Comments’ below) \n• Statistical methods are used to exclude data from HCD (State methods used in ‘Comments’ below) \n• All data is included \n• All data included if no technical reason to exclude "]
["Comments"]
["If any vehicle control data is excluded from the historical control database (using any of the criteria stated above), do you monitor or investigate quality control?","• Yes (see question below) \n• No "]
["Comments"]
["How do you demonstrate that the assay is under control? Examples could include use of acceptance criteria for each experimental occasion, defined criteria (similar to these details above), run charts, control charts, statistical tools, etc. "]
["Historical Control Distributions (HCDs)"]
["What range do you use for the HCD? (Please state what method is used and rationale for why you use this method in the ‘Comments’ below)","• The observed range (i.e., the min/max) \n• A calculated distribution (e.g., standard deviation(s), point estimates such as parametric limits [confidence/tolerance/prediction interval, etc.], or non-parametric limits such as empirical percentiles)) (Note: please state what method is used and rationale for why you use this method in the ‘Comments’ below "]
["Comments"]
["Do you characterize whether the distribution of your historical vehicle control is normal?","• Yes  \n• No"]
["Comments"]
["Do you perform any statistical transformations on your vehicle control data prior to calculating HCDs?","• Yes  \n• No"]
["Comments"]
["To what extent are HCDs split for the assay / endpoint? (Select all that apply. Please add additional information in the ‘Comments’, for example if split per vehicle, is this organic v’s aqueous, or per vehicle)","In Vivo\n• Per species \n• Per strain \n• Per sex \n• Per tissue \n• Per vehicle \n• All data for the endpoint is included in one HCD \n• Comments: (Allow free text) \n\nIn Vitro\n• Cell type \n• Per strain (Ames) \n• Plate incorporation v’s pre-incubation (Ames) \n• Per treatment regimen \n• w/ and w/o S-9 \n• Source of S-9 (i.e. Aroclor v’s Phenobarbital/5,6-Benzoflavone induced, species, etc. Please state in Comments; below) \n• Per vehicle \n• All data for the endpoint is included in one HCD "]
["Comments"]
["What information is presented in HCD tables in a study report. (Select all that apply. Example table(s) can be provided)","• Number of experiments \n• Number of individual replicates \n• Mean \n• Median \n• 95% Confidence Interval\n• Standard Deviation (Please state in ‘Comments’ how SD is generated, e.g. excel, control chart, etc.) \n• Observed Range (min/max) \n• Calculated distribution (as stated above) \n• Date of HCD generation \n• Date range of study data included in the HCD \n• Information on the stratification or lack of stratification over vehicles, sex etc. (as detailed in above question) "]
["Comments"]
["How often are HCDs updated?","• Yearly \n• Bi-annual \n• After ‘x’ number of experimental occasions (Please include number of experimental occasions to ‘Comments’ section below)\n• After ‘x’ number of data points (Please include number of data to ‘Comments’ section below)\n• Changes to the experimental protocol (Please comment below) \n• Dependent on the frequency of experimental occasions (Please comment below)\n• Continuously / After each experiment"]
["Comments"]
["Do you determine HCDs for both vehicle control and positive controls?","• Vehicle control HCDs only \n• Both vehicle and positive HCDs are generated "]
["Comments"]
["Do vehicle control HCDs and positive control HCD overlap? (If these data overlap, please add further details in ‘Comments’ on whether this is expected or triggers any action.)","• Yes, observed ranges overlap \n• Yes, observed range and calculated distributions overlap \n• No\n• Not applicable"]
["Comments"]
["Use of HCDs in Study Acceptance Criteria"]
["Are HCDs used as part of the study acceptance criteria?","• Yes\n• No (if no add further details in ‘Comments’) "]
["Comments"]
["What historical vehicle control ranges are used as part of acceptance criteria? ","• The observed range (i.e. the highest and lowest observed values) \n• A calculated range (If different from method described above please state what method is used in the ‘Comments’ below) "]
["Comments"]
["How are vehicle control HCDs used as part of study evaluation criteria? (Several answers can be selected)","(Note: Vehicle HCDs are generated from group mean values or individual replicate values have been indicated above, however, this can be further clarified in the comments section below, i.e. whether comparing mean to mean or mean to individual, for example) \n• All individual replicate vehicle control values must fall within the upper and lower values of / fall within the upper value of / be consistent with the observed range (min/max) \n• All individual replicate vehicle control values must fall within the upper and lower values of / fall within the upper value of / be consistent with the calculated distribution   \n• The mean vehicle control value must fall within the upper and lower values of / fall within the upper value of / be consistent with the observed range (min/max)?\n• The mean vehicle control value must fall within the upper and lower values of / fall within the upper value of / be consistent with the calculated distribution \n• Concurrent study positive control values must exceed the upper value (range or calculated distribution) of the HCD\n• Other (State in ‘Comments’ section)"]
["Comments"]
["Are positive control ranges used as part of the study data acceptance criteria? ","• Yes\n• No"]
["Which positive control ranges are used for acceptance criteria? ","• Observed ranges (min-max values) \n• Calculated distribution\n• Statistical significance over concurrent control used, no comparison to historical controls "]
["How are positive control HCDs used as part of study acceptance criteria? ","• Not used as part of study data acceptance criteria \n• Positive control values must fall within the positive control HCD  \n• Positive control values must be close /comparable to the positive control HCD  "]
["Evaluation Criteria"]
["Are HCDs used as part of the study evaluation criteria?","• The observed range (i.e. the highest and lowest observed values) \n• A calculated range (If different from method described above please state what method is used in the ‘Comments’ below) "]
["Which vehicle control HCD is used as part of study evaluation criteria?","• The observed range (i.e. the highest and lowest observed values) \n• A calculated range (If different from method described above please state what method is used in the ‘Comments’ below) "]
["Comments"]
["How are vehicle control HCDs used as part of study evaluation criteria?","• All individual replicate values for a test article treated concentration are compared individually against the vehicle control HCD \n• The mean value of replicates for the test article concentration is compared against the vehicle control HCD \n• 1 / 2 / 3 / 4 / etc. individual replicate values for a test article treated concentration are compared against the vehicle control HCD \n• Other (State in ‘Comments’ section) "]
["Comments"]
["How is the positive control HCD applied for evaluation criteria?","• Not applied? \n• Other (State in ‘Comments’ section) "]
["Comments"]

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["Scoring Method"]
["Manual scoring"]
["Image analysis"]
["Flow cytometry"]
[]
["Experience"]
["<1 year"]
["1 - 2 years"]
["2 -5 years"]
["5 - 10 years"]
[">10 years"]
[]
["Experiments per year"]
["<10"]
["11 to 20"]
["21 to 40"]
[">40"]
[]
[]
["Yes"]
["No"]
[]
["Monitoring HCD",null,null,"Group mean values include",null,null,"Why are mean/individual values used",null,null,null,"How many data points",null,null,"Criteria used to exclude"]
["Point values (means, limits, ranges) of specified time ranges",null,null,"Individual replicate values",null,null,"Historically done this way ",null,null,null,"Based on number of data points",null,null,"Data does not fall within the current laboratory calculated laboratory historical control distribution "]
["Graphical methods of time ranges",null,null,"Mean values",null,null,"Acceptance / evaluation criteria",null,null,null,"Based on time",null,null,"Data falls outside ‘k’ standard deviations (SDs) of current laboratory HCD mean "]
["Graphical methods continuously over time/c-charts",null,null,"Both",null,null,"Benefits discussion of results",null,null,null,null,null,null,"Data is an unusual/extreme value"]
[null,null,null,null,null,null,"Other: (use comment space below)",null,null,null,null,null,null,"There is a clear, valid and scientifically justified reason to do so"]
[null,null,null,null,null,null,null,null,null,null,null,null,null,"Statistical methods are used to exclude data from HCD"]
[null,null,null,null,null,null,null,null,null,null,null,null,null,"All data is included "]
[null,null,null,null,null,null,null,null,null,null,null,null,null,"All data included if no technical reason to exclude "]
[]
[]
["HCDs"]
["Range",null,"HCD split in vivo",null,"HCD split in vivo",null,"Info in study report",null,"HCD updates",null,"Vehicle positive controls",null,null,"Overlap"]
["The observed range (i.e., the min/max)",null,"Per species ",null,"Cell type ",null,"Number of experiments ",null,"Yearly ",null,"Vehicle control HCDs only ",null,null,"Yes, observed ranges overlap "]
["A calculated distribution (e.g., point estimates such as parametric limits [confidence/tolerance/prediction interval/etc.] or non-parametric limits such as empirical percentiles))",null,"Per strain ",null,"Per strain (Ames) ",null,"Number of individual replicates ",null,"Bi-annual ",null,"Both vehicle and positive HCDs are generated",null,null,"Yes, observed range and calculated distributions overlap "]
[null,null,"Per sex ",null,"Plate incorporation v’s pre-incubation (Ames) ",null,"Mean ",null,"After ‘x’ number of experimental occasions (Please include number of experimental occasions to ‘Comments’ section below)",null,null,null,null,"No"]
[null,null,"Per tissue ",null,"Per treatment regimen ",null,"Median ",null,"After ‘x’ number of data points (Please include number of data to ‘Comments’ section below)",null,null,null,null,"Not applicable"]
[null,null,"Per vehicle ",null,"w/ and w/o S-9 ",null,"95% confidence intervals",null,"Changes to the experimental protocol (Please comment below) "]
[null,null,"All data for the endpoint is included in one HCD ",null,"Source of S-9 (i.e. Aroclor v’s Phenobarbital/5,6-Benzoflavone induced, species, etc. Please state in Comments; below) ",null,"Standard Deviation (Please state in ‘Comments’ how SD is generated, e.g. excel, control chart, etc.) ",null,"Dependent on the frequency of experimental occasions (Please comment below)"]
[null,null,null,null,"Per vehicle ",null,"Observed Range (min/max) ",null,"Continuously / After each experiment"]
[null,null,null,null,"All data for the endpoint is included in one HCD ",null,"Calculated distribution (as stated above) "]
[null,null,null,null,null,null,"Date of HCD generation "]
[null,null,null,null,null,null,"Date range of study data included in the HCD "]
[null,null,null,null,null,null,"Information on the stratification or lack of stratification over vehicles, sex etc. (as detailed in above question) "]
[]
["HCD in Study Acceptance Criteria"]
["Use","historical Ranges",null,"How are vehicle HCDS used",null,null,null,"Positive control ranges",null,null,null,"How are positive controls used"]
["Yes","The observed range (i.e. the highest and lowest observed values) ",null,"All individual replicate vehicle control values must fall within the upper and lower values of / fall within the upper value of / be consistent with the observed range (min/max) ",null,"Fall within ",null,"Observed ranges (min-max values) ",null,null,null,"Not used as part of study data acceptance criteria  "]
["No (if no add further details in ‘Comments’) ","A calculated range (If different from method described above please state what method is used in the ‘Comments’ below) ",null,"All individual replicate vehicle control values must fall within the upper and lower values of / fall within the upper value of / be consistent with the calculated distribution   ",null,"Fall within upper value",null,"Calculated distribution ",null,null,null,"Positive control values must fall within the positive control HCD   "]
[null,null,null,"The mean vehicle control value must fall within the upper and lower values of / fall within the upper value of / be consistent with the observed range (min/max)?",null,"Be consistent with",null,"Statistical significance over concurrent control used, no comparison to historical controls",null,null,null,"Positive control values must be close /comparable to the positive control HCD"]
[null,null,null,"The mean vehicle control value must fall within the upper and lower values of / fall within the upper value of / be consistent with the calculated distribution "]
[null,null,null,"Concurrent study positive control values must exceed the upper value (range or calculated distribution) of the HCD"]
[null,null,null,"Other (State in ‘Comments’ section)"]
[]
["Evaluation Criteria"]
["Which used",null,"Vehicle control use",null,null,"Positive control applied"]
["The observed range (i.e. the highest and lowest observed values) ",null,"All individual replicate values for a test article treated concentration are compared individually against the vehicle control HCD ",null,null,"Not applied?"]
["A calculated range (If different from method described above please state what method is used in the ‘Comments’ below) ",null,"The mean value of replicates for the test article concentration is compared against the vehicle control HCD ",null,null,"Other (State in ‘Comments’ section"]
[null,null,"1 / 2 / 3 / 4 / etc. individual replicate values for a test article treated concentration are compared against the vehicle control HCD "]
[null,null,"Other (State in ‘Comments’ section) "]
[]
[]
["General Questions"]
["What do you consider HCDs to be",null,null,"what limits use",null,null,"Handle statistics",null,null,"Inclusion"]
["A reference interval / range to flag outliers during study data evaluation ",null,null,"Insufficient information on the criteria for selecting historical control data (e.g. number of studies, number of replicates, study conditions, etc.) ",null,null,"Study directors are responsible for statistical analyses, and their resources are primarily SOPs and scientific literature",null,null,"GLP"]
["A measure of the biological noise for the assay ",null,null,"Insufficient level of details in reporting historical control data ",null,null,"We outsource for statistical guidance and specific analyses as necessary",null,null,"non-GLP"]
["A measure of the normal background variability for the assay ",null,null,"Insufficient number of studies to source historical control data ",null,null,"In-house statistician(s) provide guidance and oversee analyses related to genotoxicity studies",null,null,"both"]
["Used for comparison to study controls to assess study reliability ",null,null,"Insufficient number of replicate values included in the historical control data set "]
["Used for comparison to study controls to identify drift in data / species / strain ",null,null,"Lack of consistent terminology "]
["A replacement for concurrent control data ",null,null,"Lack of consistent format "]
["Used alongside statistical analysis of study results for overall evaluation of study data (such as pairwise comparison or trend tests)",null,null,"Lack of guidance on how to use, report and interpret historical control data "]
["An indication of how well the laboratory is performing the assay",null,null,"Lack of information related to the methods and settings used to collect the data "]
["Used for assessment of the biological relevance of statistically significant increases in study data ",null,null,"Lack of information on how HCDs are generated "]
["Never consider HCDs",null,null,"Nothing "]
["Other purpose than listed, please specify in ‘Comments’",null,null,"Other, please specify in ‘Comments’ below. "]