PONE-D-23-25666Computerized decision support is an effective approach to select memory clinic patients for amyloid-PETPLOS ONE

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"Research of the Alzheimer’s Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Vrije Universiteit Medical Center Alzheimer Center is supported by the Stichting Alzheimer Nederland and Stichting Vrije Universiteit Medical Center Fonds. The clinical database structure was developed with funding from Stichting Dioraphte. For development of the PredictAD tool, VTT Technical Research Centre of Finland has received funding from European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreements601055 (VPH-DARE@IT) ), 224328 (PredictAD), and 611005 (PredictND). The collaboration project DAILY (project number LSHM19123-HSGF) is co-funded by the PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. The ABIDE clinical utility study is funded by the PPP Allowance made available by health-Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships and co-funded by Life Molecular Imaging GmbH (grant no.: LSHM18075). HR is recipient of the Memorabel Dementia Fellowship 2021 (ZonMw projectnumber 10510022110004) and Alzheimer Nederland InterACT grant (projectnumber WE.08-2022-06). LC is supported by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115952. This Joint Undertaking receives the support from the European Union’s Horizon 2020 research and innovation program and EFPIA. FB is supported by the NIHR biomedical research centre at UCLH. The chair of WF is supported by the Pasman Stichting. WF is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (number 73305095007) and Health-Holland, Top Sector Life Sciences and Health (public–private partnership allowance; number LSHM20106), WF and HR are recipient of the Horizon 2022 project PROMINENT (project number 101112145). We thank Mahnaz Shekari for her significant contribution to the processing of the amyloid-PET images."

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"We have read the journal's policy and the authors of this manuscript have the following competing interests: Hanneke FM Rhodius- Meester performs contract research for Combinostics, all funding is paid to her institution. Ingrid van Maurik received a consultancy fee (paid to the university) from Roche. Lyduine E Collij has received consultancy fees from GE Healthcare, all funding is paid to her institution. Aniek M van Gils reports no disclosures. Juha Koikkalainen and Jyrki Lötjönen report that VTT Technical Research Centre of Finland owns the following IPR related to the paper: 1. J. Koikkalainen and J. Lotjonen. A method for inferring the state of a system, US7,840,510 B2, PCT/FI2007/050277. 2. J. Lotjonen, J. Koikkalainen and J. Mattila.State Inference in a heterogeneous system, PCT/FI2010/050545. FI20125177. Koikkalainen and Lötjönen are shareholders in Combinostics Oy. Antti Tolonen reports no disclosures. Yolande AL Pijnenburg has received funding from Dioraphte Foundation, Zabawas Foundation, JPND, ZonMW, NWO, Team Alzheimer and the Dutch Brain Foundation. Johannes Berkhof reports no disclosures. Frederik Barkhof is member of the Steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena. FB is consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics. FB has research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD. Elsmarieke van de Giessen has received research support from NWO, ZonMw, Hersenstichting and KWF. EvdG has performed contract research for Heuron Inc., Roche and 1st Biotherapeutics. EvdG has a consultancy agreement with IXICO for the reading of PET scans. Wiesje M van der Flier performs contract research for Biogen. Research programs of WF have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Pasman stichting, stichting Alzheimer & NeuroPsychiatry Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Combinostics. WF has performed contract research for Biogen MA Inc, and Boehringer Ingelheim. WF has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), Springer Healthcare. WF is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. WF participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain"

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Additional Editor Comments :

In addition to the reviewers’ comments, this editor considers that several parts in the manuscript need to be clarified or explained in more details, as follows.

1 p8 line 230-233 They cite ref13 but citing this ref. is insufficient. Please explain about AUC in more details.

2 Subjects in page 4 and Discussion

They included patients with AD, FTD, VaD, and SCD. Please explain why they did not include those with other dementia disorders such as DLB and AGD. In ordinary clinical practice, these non-AD dementia disorders are relatively common and should not be neglected. Clearly, this is a limitation of this study and should also be discussed.

3 Page 7, Ref 37 A correct ref should be described.

4 Fig.2 This figure should be corrected as it does not cover the whole graphs. Fig 3 Is it possible to change the background color from blue to white?

5 Discussion page 14 line 403-405 “Our computerized approach even outranked performing 404 amyloid-PET in all patients” Please explain about the reasons for this result more clearly.

6. Discussion page 15 line 418-431

This editor judges that this part is not a balanced view and should be shortened or more carefully revised. It can only be said that a data-driven approach will be a supportive tool in the future clinical practice in which disease-modifying treatments become widely available. In addition, in the clinical practice, differential diagnosis of MCI patients (MCI due to AD or MCI not due to AD) is also important but this issue is not discussed in the manuscript. Why not include some discussion about this point?

7 Abstract line 48 “AUC” Please include statement about what AUC means.

8 Abstract the last sentence “ supports clinicians in making a balanced decision in ordering additional amyloid PET during the dementia workup” This does not reflect the real situation, and should be corrected.

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: With the insurance coverage of Lecanemab and other therapeutic agents against amyloid-β, there is growing interest in testing for amyloid-β detection. As the authors state in their introduction, PET scans are too expensive to be used for screening, raising the question of which patients should be aggressively screened for PET.

The purpose of this study is to "develop a computerized decision support approach to select patients for amyloid PET," but the study targets AD, FTLD, and VaD, and is more focused on disease type diagnosis rather than DMT target selection. Therefore, the study is disappointing to those who expect it to be a supportive approach to narrow down the target population for treatment of amyloid-β.

At the method of study, the following details should be considered.

1. the final classification result (likelihood of diagnosis) seems to be obtained by combining binary classification by DSI, but the rationale for "we considered that patients had a sufficiently reliable diagnosis if the PCC was 0.75 or higher" is not provided. Presumably, there is a valid basis, but it is not clear how many false positives or false negatives this may include.

2. it says that DSI "can handle missing data," but it is not clear how much missingness is actually allowed or how much it affects accuracy.

3. Figure 3 is helpful in understanding this study. For example, in Patient B, FTD is suspected and an amyloid PET scan is recommended as a result. However, without presentation of the present illness, symptoms, results of psychological testing, and MRI findings, the usefulness of DSI cannot be realized for readers. Wouldn't ordinary clinical diagnostic methods have been sufficient to suspect FTD?

4. it is stated that "the strength of this study is the use of a control group and an unselected memory clinic cohort consisting of AD, FTD, and VaD patients, which reflects clinical practice," but it is not stated how PD, epilepsy, and other illness were excluded to get there.

First of all, I would like to express my utmost respect for the results of this study. In general, the study would have been more interesting if it had been conducted with DMT in mind. In understanding the utility of DSI, which requires the input of a variety of clinical data, what is its advantage over the diagnoses we clinicians make in our daily clinical practice? If we could understand how DSI differs from and is superior to the diagnosis that we clinicians usually make in daily clinical practice, it would be more convincing.

Reviewer #2: The article of Hanneke et al. affirms that a computerized decision support approach to select patients from the Memory Clinic for amyloid-PET increase the diagnostic certainty, being useful for the doctor requesting. The approach applies The Disease State Index (DSI) classifier, already tested with proven high diagnostic accuracy [references 35 and 36 of the authors] . The DSI suggests a diagnosis with a probability of correct class (PCC), based on demographics, neuropsychology, and MRI data. Thereafter, the hypothetical positive and negative amyloid-PET PCC’s values are calculated to evaluate the influence in the diagnostic certainty. The authors point out that this starting point makes the difference to other models that predict positive or negative amyloid-PET [references 40-42 of the authors]. Afterwards, an amyloid PET scan is order only if an increase to >0.75 of the PCC. Finally, the real amyloid-PET values are added to the model and PCC is evaluated.

This approach is compared with three control scenarios: without amyloid- PET using demographics, APOE, neuropsychology, and MRI; applying amyloid-PET based on The Appropriate Use Criteria (AUC) [reference 12 of the authors]; and performing amyloid-PET in all patients. Using visual PET reads and Centiloid values submit similar results to support the affirmation as a meaningful conclusion.

This proposed tool is quite relevant for the clinics, as the authors justify well in the introduction and discussion, considering nowadays there is conclusive evidence on the clinical usefulness of amyloid-PET, in the in vivo diagnosis of Alzheimer's disease (AD), as shown the results of two large international series [the American project IDEAS: reference 4 of the authors; and the European AMYPAD: reference 7 of the authors and Altomare et al. 2023]. Furthermore, even if the amyloid-PET is prescribed regarding the AUC there are other situations in which the added certainty of amyloid-PET could be helpful [reference 13 of the authors and Altomare et al. 2018]. Moreover, an increasing demand [Verger et al. 2023] is predictably because of its contribution to AD diagnosis, AD treatment (the search and introduction of possible modifying therapies [Garnier-Crussard A et al. 2023] and is the gold standard for investigating disease mechanisms [Bao et al. 2021]) and to screening improvement for clinical trials [Rabinovici et al. 2019].In words of the authors: amyloid-PET is costly and limitedly available, so intelligent and efficient use of our resources is already needed.

The statistics, with a large sample size (N=286) including controls (N=135), and other analyses (v.g. amyloid-PET procedure, Centiloid), are well conducted with a high technical standard and are described to enable reproduce. Results are exposed with sufficient detail (including mean and standard deviation) represented with clear figures and tables. The manuscript is properly presented and is written in standard English. The research meets all applicable experimentation ethics standards and integrity (blinding etc.). The article adheres to appropriate reporting guidelines and community standards for data availability.

In this work, a real-life cohort is studied (recruiting in a tertiary memory clinic) in contradistinction to the computerized decision support approach applied by the author of correspondence et al. in the cohort of Alzheimer’s Disease Neuroimaging Initiative (ADNI2) that can be consulted at Alzheimer’s Dement. 2020;16(Suppl. 5):e042687).Therefore, it cannot be considered as a replication study. The data were collected during routine care and the amyloid-PET is interpreted visually by an imaging specialist from the local hospital setting, as often do in practice and in the IDEAS project [reference 4 of the authors], and no by centralizing reading. Agreeing to the authors, this naturalistic setting features, far from being a limitation, represent an advantage due to its immediate applicability in clinical practice in the dementia workup. The strengths and limitations are well exposed.

Some aspects that may weaken the quality of the manuscript and that the authors could clarify so readers better understand could be: DSI is not included in the abstract, the data of the patients correctly classified presented in the flow chart (Figure 1) seems no be present or explained in the text. Also review: line 283 doubt about the 180 patients (66%)¿is it maybe 188 (66%)?, line 293-297 review typographical errors and also doubt about 1654 (54%).%)¿is it maybe 154(54%)?, line 638: 37. !!! INVALID CITATION !!! [20, 36]. Please, take as a kind suggestion the possibility of including the refrence of AMYPAD 2023 in the introduction and update the reference 44. Maybe will be interesting a brief mention about the availability of the computerized decision support approach created by the authors for use in other centers.

References:

Altomare D, Barkhof F, Caprioglio C, Collij LE, Scheltens P, Lopes Alves I, et al. Clinical effect of early vs late amyloid positron emission tomography in Memory Clinic patients: The AMYPAD-DPMS randomized clinical trial. JAMA Neurology [Internet]. 2023 May 8 Available from: https://jamanetwork.com/journals/jamaneurology/fullarticle/2804755

Altomare D, Ferrari C, Festari C, Guerra UP, Muscio C, Padovani A, et al. Quantitative appraisal of the Amyloid Imaging Taskforce Appropriate Use Criteria for amyloid‐PET. Alzheimers Dement. 2018;14(8):1088-98.

Verger A, Yakushev I, Albert NL, Van Berckel B, Brendel M, Cecchin D, et al. FDA approval of lecanemab: the real start of widespread amyloid PET use? — the EANM Neuroimaging Committee perspective. Eur J Nucl Med Mol Imaging. 2023;50(6):1553-5.

Garnier-Crussard A, Flaus A. Positive opinion of the French National Authority for Health on the reimbursement of amyloid tracer (Flutemetamol). Eur J Nucl Med Mol Imaging. 2023;50(2):253-4.

Bao W, Xie F, Zuo C, Guan Y, Huang YH. PET Neuroimaging of Alzheimer’s Disease: radiotracers and their utility in clinical research. Front Aging Neurosci. 2021; 13:624330.

Rabinovici GD, Gatsonis C, Apgar C, Chaudhary K, Gareen I, Hanna L, et al. Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia. JAMA. 2019;321(13):1286.

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PONE-D-23-25666R1Computerized decision support is an effective approach to select memory clinic patients for amyloid-PETPLOS ONE

Dear Dr. Rhodius-Meester,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

This editor judges that some parts of the revised manuscript still need to be clarified, as noted in the comments of the editor. 

Please submit your revised manuscript by Apr 19 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Wataru Araki

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

In the revised manuscript, the authors have addressed almost all the criticisms of the reviewers. However, this editor thinks that some parts are not well explained or clarified and still need to be amended as indicated below. Especially, the authors should be careful to make the manuscript more comprehensible in general.

1) Response to Editor comment 5

L405-406, L428-430? L523?

These revisions are not enough to clarify the question raised by the editor.

2) Response to Reviewer #1 comment 4 and Editor comment 2

L119 is not enough. Please explain about the reason for this point.

3) Discussion L427-429

As such, -----testing [45]. This sentence seems to be an overstatement. Please change the expression.

Discussion L431-438 It is better to move this paragraph after the first paragraph in Discussion.

Discussion L455-463 This paragraph is too superficial and may be omitted.

Discussion L478-500 This paragraph should be revised so that readers can understand what the limitations of this work are. Please list the limitations in order (First, second, third ----)

Line 482 a MCI should be MCI

Line 483-485 Recruiting in ----- value. This sentence is not understandable and should be rephrased.

Conclusion Line 510-511 “to funnel patient through the diagnostic pathway,” This expression is not grammatically correct and should be corrected.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

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Reviewer #2: Yes: RAQUEL SÁNCHEZ VAÑÓ

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Computerized decision support is an effective approach to select memory clinic patients for amyloid-PET

PONE-D-23-25666R2

Dear Dr. Rhodius-Meester,

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Kind regards,

Wataru Araki

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have responded to all the criticisms very appropriately.

Reviewers' comments: