Sequential Unmasking Research Articles

Utilising linear sequential unmasking to minimise bias in ARCP

Utilising linear sequential unmasking to minimise bias in ARCP

Decision theory and linear sequential unmasking in forensic fire debris analysis: A proposed workflow

The ASTM E1618-19 standard method for fire debris analysis does not endorse the use of statistical analysis to establish error rates or the use of probabilistic statements about the strength of the evidence. The method requires the analyst to report in categorical terms with the possibility of introducing disclaimers. This report introduces a new workflow that extends the data analysis and interpretation methods of ASTM E1618-19. In the new workflow, analysts are asked to assign evidentiary values to fire debris samples. The assigned values are combined with decision theory to determine an optimal decision threshold for ascribing a sample as positive or negative for ignitable liquid residue in categorical terms. The new workflow incorporates linear sequential unmasking with the data analysis methods of ASTM E1618-19, machine learning likelihood ratios and the use of ignitable liquid and substrate databases. The workflow is applied to 20 known ground truth samples by each of three analysts to generate validated personal receiver operating characteristic (ROC) curves and optimal decision thresholds. The ROC curve provides a direct link between perceived evidentiary value and decision thresholds based on a defined ratio of costs for false positive and false negative decisions. The new workflow is applied to casework-relevant large-scale burn data for which the ground truth is unknown.

Cognitive and human factors in legal layperson decision making: Sources of bias in juror decision making.

Juries in adversarial courts are tasked with several responsibilities. They are asked to: 1) assess the credibility and reliability of the evidence presented; 2) deliberate; 3) and then reach a decision. Jurors are expected to evaluate said evidence in a rational/impartial manner, thus allowing the defendant their right to a fair trial. However, psychological research has shown that jurors are not rational and can reach inaccurate decisions by being biased by certain factors. The aim of the current review was to explore the potential sources from which biases are introduced into the jury. Three main sources of bias were focussed upon: 1) pre-trial bias; 2) cognitive bias; 3) bias from external legal actors (expert witnesses). Legal scholars commonly cite deliberations as a method of attenuating individual juror bias, this claim is evaluated in the review. The review concludes that bias is a multifaceted phenomenon introduced from many different elements, and that several sources of bias may interact with one another during a jury trial to cause the effects of bias to snowball. Four recommendations are made: 1) juror selection should be utilised to create heterogenous juries that challenge problematic biases from individual jurors; 2) increase the quality of expert testimony through training; 3) procedures such as Linear Sequential Unmasking should be adopted by expert witnesses to filter out some sources of bias; 4) legal professionals and jurors should be educated about the effects that biases may have on decision making; 5) more research into bias in jurors is needed.

AKEBIA THERAPEUTICS INC v FIBROGEN, INC

Abstract H1 Patents – European patents – Pharmaceuticals – Treatment of anaemia – Revocation – Infringement – Construction – Obviousness – Obvious to try – Reasonable expectation of success – Hindsight – Expert evidence – Sequential unmasking – Insufficiency – Excessive claim breadth – Uncertainty – Identification of technical contribution – Principles of general application – Plausibility – Undue burden – AgrEvo obviousness – Equivalence – File prosecution history – Process limited product claims – Indirect infringement – Means relating to an essential element of the invention – Whether suitable for putting and intended to put invention into effect – “Off-label” use – State of mind of defendants – Intentions of prescribing clinicians – Quia timet claims – Whether stay of infringement claim appropriate

Strategic choice in linear sequential unmasking

Strategic choice in linear sequential unmasking

Abstract 982: Development of homogeneous dual-drug ADCs: Application to the co-delivery of auristatin payloads with complementary antitumor activities

Abstract A common theme in treating cancer is the use of combination chemotherapy, where multiple drugs with different mechanisms of action are combined to elicit synergistic activity or overcome differential drug sensitivities. Antibody-drug conjugates (ADCs) have emerged as a powerful approach for treating cancer, combining the tumor targeting specificity of monoclonal antibodies with the potent cell-killing activity of cytotoxic drugs. Like other therapies, these agents are increasingly being tested in combination with unconjugated, clinically approved anticancer agents. In addition, emerging data demonstrates that insensitivity to a particular ADC can be overcome through delivery of a different payload using the same antibody. For these reasons, the development of ADCs that can deliver two complementary payloads to a tumor would likely be a significant advancement in ADC technology. To enable dual-drug conjugation, we utilized a multiplexing drug carrier that contains cysteine residues with orthogonal protecting groups and identified novel conditions for utilization of these protecting groups on a folded protein. Sequential cysteine unmasking enables discrimination between conjugation sites to allow for site-specific drug conjugation. This strategy provides homogeneous ADCs bearing 16 total drugs per antibody, split evenly between the two drug linkers. Importantly, this strategy is flexible, as it does not require engineered antibodies or custom enzymes for drug-linker conjugation. To demonstrate the potential benefits of ADC dual drug delivery, this strategy was applied to the construction of ADCs bearing two classes of auristatin drug linkers that have different physiochemical properties and complementary anti-cancer activities. Dual-auristatin ADCs were tested in cell line and xenograft models that have differential sensitivities to the individual auristatin components, including those with heterogeneous antigen expression or high levels of drug efflux transporters. The data from these studies demonstrate that the dual-auristatin ADCs were active on cells and tumors that are refractory to treatment with either of the individual component drugs. This work highlights the potential for delivering two synergistic or complementary payloads on a single ADC and presents a flexible method for constructing dual-drug ADCs with site-specific and homogeneous drug loading. Citation Format: Matthew R. Levengood, Xinqun Zhang, Kim K. Emmerton, Joshua H. Hunter, Peter D. Senter. Development of homogeneous dual-drug ADCs: Application to the co-delivery of auristatin payloads with complementary antitumor activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 982. doi:10.1158/1538-7445.AM2017-982

Addressing potential observer effects in forensic science: a perspective from a forensic scientist who uses linear sequential unmasking techniques

The linear sequential unmasking (LSU) protocol is a protocol intended to reduce the effects of potentially biasing information that may affect a forensic scientist during his/her examinations. This paper explores two central themes. The first theme is that the institution of LSU, and thus the control of information possessed by the case analyst, can affect the outcome. Some interesting case examples are offered to emphasize this point. The second theme is the exploration of the practical costs and benefits of employing an LSU approach. These issues will be explored from both the perspective of a scientist in a large, publicly-funded crime laboratory, but also from the perspective of a small, private consultant.

Orthogonal Cysteine Protection Enables Homogeneous Multi‐Drug Antibody–Drug Conjugates

AbstractA strategy for the preparation of homogeneous antibody–drug conjugates (ADCs) containing multiple payloads has been developed. This approach utilizes sequential unmasking of cysteine residues with orthogonal protection to enable site‐specific conjugation of each drug. In addition, because the approach utilizes conjugation to native antibody cysteine residues, it is widely applicable and enables high drug loading for improved ADC potency. To highlight the benefits of ADC dual drug delivery, this strategy was applied to the preparation of ADCs containing two classes of auristatin drug‐linkers that have differing physiochemical properties and exert complementary anti‐cancer activities. Dual‐auristatin ADCs imparted activity in cell line and xenograft models that are refractory to ADCs comprised of the individual auristatin components. This work presents a facile method for construction of potent dual‐drug ADCs and demonstrates how delivery of multiple cytotoxic warheads can lead to improved ADC activities. Lastly, we anticipate that the conditions utilized herein for orthogonal cysteine unmasking are not restricted to ADCs and can be broadly utilized for site‐specific protein modification.

Orthogonal Cysteine Protection Enables Homogeneous Multi-Drug Antibody-Drug Conjugates.

A strategy for the preparation of homogeneous antibody–drug conjugates (ADCs) containing multiple payloads has been developed. This approach utilizes sequential unmasking of cysteine residues with orthogonal protection to enable site‐specific conjugation of each drug. In addition, because the approach utilizes conjugation to native antibody cysteine residues, it is widely applicable and enables high drug loading for improved ADC potency. To highlight the benefits of ADC dual drug delivery, this strategy was applied to the preparation of ADCs containing two classes of auristatin drug‐linkers that have differing physiochemical properties and exert complementary anti‐cancer activities. Dual‐auristatin ADCs imparted activity in cell line and xenograft models that are refractory to ADCs comprised of the individual auristatin components. This work presents a facile method for construction of potent dual‐drug ADCs and demonstrates how delivery of multiple cytotoxic warheads can lead to improved ADC activities. Lastly, we anticipate that the conditions utilized herein for orthogonal cysteine unmasking are not restricted to ADCs and can be broadly utilized for site‐specific protein modification.

Context Effects in Forensic Entomology and Use of Sequential Unmasking in Casework.

Context effects are pervasive in forensic science, and are being recognized by a growing number of disciplines as a threat to objectivity. Cognitive processes can be affected by extraneous context information, and many proactive scientists are therefore introducing context-minimizing systems into their laboratories. Forensic entomologists are also subject to context effects, both in the processes they undertake (e.g., evidence collection) and decisions they make (e.g., whether an invertebrate taxon is found in a certain geographic area). We stratify the risk of bias into low, medium, and high for the decisions and processes undertaken by forensic entomologists, and propose that knowledge of the time the deceased was last seen alive is the most potentially biasing piece of information for forensic entomologists. Sequential unmasking is identified as the best system for minimizing context information, illustrated with the results of a casework trial (n = 19) using this approach in Victoria, Australia.

Do Observer Effects Matter? A Comment on Langenburg, Bochet, and Ford

ABSTRACTWe identify methodological problems in Langenburg et al. (2014), which undermine its conclusions about the size of the observer effect problem and the importance of sequential unmasking as a solution. The scoring method of Langenburg et al. (2014) appears to be subjective. The classification of cases is not congruent with the three keys to observer effects in forensic science: the analyst's state of expectation, the analyst's state of desire, and the degree of ambiguity in the evidence being examined. Nor does the paper adequately support its claim, “[I]t has been asserted that the high context/high interaction cases are essentially where there is the most danger of bias.” While the paper tends to minimize concern over observer effects, the evidence in it seems to support the view that fingerprint analysts look to contextual information to help them make decisions.

ChemInform Abstract: Synthesis of (+)‐ and (—)‐Phaselic Acid.

Abstract The syntheses of both enantiomers of phaselic acid (2-O-caffeoylmalate) are described. The previously unreported acetate-protected caffeic acid anhydride was used with appropriately protected malic acid derivatives as coupling partners to provide fully protected phaselic acid. Sequential unmasking of the protecting groups afforded phaselic acid in an acceptable overall yield. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

Synthesis of (+)- and (−)-Phaselic Acid

The syntheses of both enantiomers of phaselic acid (2-O-caffeoylmalate) are described. The previously unreported acetate-protected caffeic acid anhydride was used with appropriately protected malic acid derivatives as coupling partners to provide fully protected phaselic acid. Sequential unmasking of the protecting groups afforded phaselic acid in an acceptable overall yield. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

Commentary on: Authors’ Response [J Forensic Sci 2009;54(2):501] to Wells’ comments [J Forensic Sci 2009;54(2):500] regarding Krane DE, Ford S, Gilder JR, Inman K, Jamieson A, Koppl R, Kornfield IL, Risinger DM, Rudin N, Taylor MS, Thompson WC. Sequential unmasking: a means of minimizing observer effects in forensic DNA interpretation.

Journal of Forensic SciencesVolume 54, Issue 6 p. 1498-1499 Commentary on: Authors’ Response [J Forensic Sci 2009;54(2):501] to Wells’ comments [J Forensic Sci 2009;54(2):500] regarding Krane DE, Ford S, Gilder JR, Inman K, Jamieson A, Koppl R, Kornfield IL, Risinger DM, Rudin N, Taylor MS, Thompson WC. Sequential unmasking: a means of minimizing observer effects in forensic DNA interpretation. Brent Ostrum B.A. (Hons), Brent Ostrum B.A. (Hons) Senior Forensic Document Examiner, Canada Border Services Agency, 79 Bentley Avenue, Ottawa, ON, Canada K2E 6T7.Search for more papers by this author Brent Ostrum B.A. (Hons), Brent Ostrum B.A. (Hons) Senior Forensic Document Examiner, Canada Border Services Agency, 79 Bentley Avenue, Ottawa, ON, Canada K2E 6T7.Search for more papers by this author First published: 23 October 2009 https://doi.org/10.1111/j.1556-4029.2009.01191.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume54, Issue6November 2009Pages 1498-1499 RelatedInformation

Painting the target around the matching profile: the Texas sharpshooter fallacy in forensic DNA interpretation

Forensic DNA analysts tend to underestimate the frequency of matching profiles (and overestimate likelihood ratios) by shifting the purported criteria for a ‘match’ or ‘inclusion’ after the profile of a suspect becomes known-a process analogous to the well-known Texas sharpshooter fallacy. Using examples from casework, informal and naturalistic experiments, and analysts’ own testimony, this article demonstrates how post hoc target shifting occurs and how it can distort the frequency and likelihood ratio statistics used to characterize DNA matches, making matches appear more probative than they actually are. It concludes by calling for broader adoption of more rigorous analytical procedures, such as sequential unmasking, that can reduce the sharpshooter fallacy by fixing the target before the shots are taken.

Sequential Unmasking: A Means of Minimizing Observer Effects in Forensic DNA Interpretation

Journal of Forensic SciencesVolume 53, Issue 4 p. 1006-1007 Sequential Unmasking: A Means of Minimizing Observer Effects in Forensic DNA Interpretation Dan E. Krane Ph.D., Dan E. Krane Ph.D. Department of Biology, Wright State University, Dayton, OHSearch for more papers by this authorSimon Ford Ph.D., Simon Ford Ph.D. Lexigen Science and Law Consultants, Inc., San Francisco, CASearch for more papers by this authorJason R. Gilder Ph.D., Jason R. Gilder Ph.D. Forensic Bioinformatics, Inc., Fairborn, OHSearch for more papers by this authorKeith Inman M.Crim., Keith Inman M.Crim. Forensic Analytical Sciences, Inc., Hayward, CASearch for more papers by this authorAllan Jamieson Ph.D., Allan Jamieson Ph.D. The Forensic Institute, Glasgow, U.K.Search for more papers by this authorRoger Koppl Ph.D., Roger Koppl Ph.D. Institute for Forensic Science Administration, Fairleigh Dickinson University, Madison, NJSearch for more papers by this authorIrving L. Kornfield Ph.D., Irving L. Kornfield Ph.D. Department of Biology and Molecular Forensics, University of Maine, Orono, MESearch for more papers by this authorD. Michael Risinger J.D., D. Michael Risinger J.D. Seton Hall University School of Law, South Orange, NJSearch for more papers by this authorNorah Rudin Ph.D., Norah Rudin Ph.D. Private forensic DNA consultant, Mountain View, CASearch for more papers by this authorMarc Scott Taylor, Marc Scott Taylor Technical Associates, Inc., Ventura, CASearch for more papers by this authorWilliam C. Thompson J.D., Ph.D., William C. Thompson J.D., Ph.D. Department of Criminology, Law and Society, University of California, Irvine, CASearch for more papers by this author Dan E. Krane Ph.D., Dan E. Krane Ph.D. Department of Biology, Wright State University, Dayton, OHSearch for more papers by this authorSimon Ford Ph.D., Simon Ford Ph.D. Lexigen Science and Law Consultants, Inc., San Francisco, CASearch for more papers by this authorJason R. Gilder Ph.D., Jason R. Gilder Ph.D. Forensic Bioinformatics, Inc., Fairborn, OHSearch for more papers by this authorKeith Inman M.Crim., Keith Inman M.Crim. Forensic Analytical Sciences, Inc., Hayward, CASearch for more papers by this authorAllan Jamieson Ph.D., Allan Jamieson Ph.D. The Forensic Institute, Glasgow, U.K.Search for more papers by this authorRoger Koppl Ph.D., Roger Koppl Ph.D. Institute for Forensic Science Administration, Fairleigh Dickinson University, Madison, NJSearch for more papers by this authorIrving L. Kornfield Ph.D., Irving L. Kornfield Ph.D. Department of Biology and Molecular Forensics, University of Maine, Orono, MESearch for more papers by this authorD. Michael Risinger J.D., D. Michael Risinger J.D. Seton Hall University School of Law, South Orange, NJSearch for more papers by this authorNorah Rudin Ph.D., Norah Rudin Ph.D. Private forensic DNA consultant, Mountain View, CASearch for more papers by this authorMarc Scott Taylor, Marc Scott Taylor Technical Associates, Inc., Ventura, CASearch for more papers by this authorWilliam C. Thompson J.D., Ph.D., William C. Thompson J.D., Ph.D. Department of Criminology, Law and Society, University of California, Irvine, CASearch for more papers by this author First published: 04 July 2008 https://doi.org/10.1111/j.1556-4029.2008.00787.xCitations: 117Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume53, Issue4July 2008Pages 1006-1007 RelatedInformation