D-Attachment SOW APOE escapees.pdf

Version 11-30-2016-1 FAR Part 11—Describing Agency Needs

STATEMENT OF WORK (SERVICES)

(SOW)

GENERAL INFORMATION

Title of Project:

Investigating the Biology of Cognitive Resilience in WHIMS “APOE e4 Escapees” using machine learning

Statement of Need and Purpose:

In the proposed study, NIA will apply advanced machine learning methods to the analysis of proteomics and metabolomics data from the Women’s Health Initiative Memory Study (WHIMS). NIA will compare APOE e4 carriers with and without cognitive impairment to determine the unique profiles of metabolites and proteins that may render women with an APOE e4 allele resistant to subsequent impairment. NIA will determine whether the profiles of metabolites and proteins are specific to e4 carriers or also distinguish between e3/e3individuals with and without cognitive impairment.

The primary two aims are:

A) To examine whether differences in biomarker profiles exist among APOE e4 women who are cognitively resilient compared to those who are not.

B) To examine whether these differences vary from those seen among e3/e3 women.

NIA will also investigate groups of women with and without the APOE e4 allele who develop cognitive impairment at age 80 and older to allow us to also compare age-matched women with and without cognitive impairment.

Background Information and Objective:

The APOE e4 allele is the most robust genetic risk allele for late onset Alzheimer’s disease (AD) and is associated with a 3 to 4-fold increase in risk and an earlier onset of cerebral amyloid accumulation. Carriers of the e4 allele are also at increased risk for cardiovascular disease, and mortality. However, carriage of an APOE e4 allele or even two copies of the e4 allele is not sufficient for the development of AD and many e4 carriers survive to old age without developing cognitive impairment. Individuals who survive to old age and maintain cognitive health despite the presence of one or two APOE e4 alleles provide a unique opportunity to better understand the demographic, health, behavioral and physiologic characteristics associated with cognitive resilience.

WHIMS investigators are currently investigating demographic, health and lifestyle characteristics of cognitive resilience in APOE e4 carriers but physiologic studies that may provide greater mechanistic insights are lacking.

The aim of the WHIMS Resilience project is to utilize the unique expertise and resources of the NIA Intramural Research Program (IRP) in a coordinated multi-laboratory project to perform deep phenotyping and identify potential physiologic characteristics that promote cognitive resilience. In the WHIMS cohort, NIA has identified 709 women who have APOE e3/e4 (n= 654) or e4/e4 (n=55) genotypes. Of these women, 350 have survived beyond age 80 and remain free of cognitive impairment, 115 developed cognitive impairment at age 80 and younger, and 244 developed cognitive impairment after age 80. NIA has used biospecimens collected at Women’s Health Initiative (WHI) baseline (~20 years ago) to compare the 350 women who remain free of cognitive impairment after age 80 despite carrying an APOE e4 allele with the 115 e4 carriers who developed cognitive impairment at age 80 and younger and with the age comparable sample of women who developed cognitive impairment after age 80. In addition, to determine whether any identified protective factors are specific to e4 carriers, similar comparisons shall be evaluated for women with e3/e3 genotypes who survive and are free of impairment beyond age 80 with those who develop impairment at age 80 and younger and those who develop impairment after age 80. Alzheimer’s disease biomarkers, proteomic and metabolomic assays have been completed. The goal of this project is to support the application of advanced statistical methods, using machine learning, to the completed assay data to accomplish the aims of the overall project.

Period of Performance:

11 months after contract award.

SCOPE OF WORK

General Requirements:

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the Statement of Work below:

Specific Requirements:

Apply machine learning methods to the analysis of proteomics and metabolomics data.

1) Perform classification analyses to evaluate the capability of proteomics to discriminate between WHIMS women who are APOE ɛ4 carriers according to cognitive resilience status. Determine multivariate proteomics signatures predictive of cognitive resilience.

2) Perform classification analyses to evaluate the capability of proteomics to discriminate between WHIMS women who carry APOE genotype ɛ3/ɛ3 according to cognitive resilience. Determine multivariate proteomics signatures predictive of cognitive resilience.

3) Perform survival analyses of incident cognitive impairment using all the available data.

Metabolomics Analyses

4) Similar analyses as described in 1-3.

Combined Analyses

5) Similar analyses as described in 1-3 but based on the concatenation of all markers (proteins, metabolites and blood biomarkers of Alzheimer’s disease).

6) Similar analyses as described in 1-3 but based on concatenating blood AD biomarkers with proteomics and metabolomics signatures determined independently during training.

LEVEL OF EFFORT:

Senior Researcher, 20% effort, 11 months Research Associate, 5% effort, 11 months

GOVERNMENT RESPONSIBILITIES

The government shall provide deidentified WHIMS data for analyses.

DELIVERY OR DELIVERABLES

The Contractor will be responsible for accessing primary WHIMS/WHI data and creation of analysis files to integrate with deidentified data on analytes provided by the Government.

Apply quantitative/targeted metabolomics to assay approximately 500 metabolites within the following classes:

1. Biogenic amines and amino acids

2. Acylcarnitines

3. Glycerophospholipids

4. Sphingomyelins

5. Ceramides

6. Hexoses

7. Di- and triglycerides

8. Cholesteryl esters

Apply quantitative approaches to proteomic data covering 1000-1100 analytes.

1. Detailed reports (WORD document) of analytical methodology applied to the data provided to the contractor.

2. WORD document detailing the key clinical/laboratory variables associated with

APOE genotype and clinical status and the optimal combinations of metabolomic, proteomic, AD biomarker and demographic variables predicting APOE e4 genotype by cognitive status groups.

The timely submission of deliverables is essential to successful completing this requirement. Deliverables are to be submitted in electronic copy.

REPORTING REQUIREMENTS

The contractor is required to provide electronic written progress reports every 3 months during the period of performance. The progress report shall cover all work completed during the specified period and shall present the work to be accomplished during the subsequent period. This report shall also identify any problems that arose and a statement explaining how the problem was resolved. This report shall also identify any problems that have arisen but have not been completely resolved and provide an explanation.

OTHER CONSIDERATIONS

Key Personnel:

Ph.D. with experience in advanced machine learning approaches, biostatistics, neuroimaging, metabolomics and proteomics. Contractor must have access and familiarity with WHIMS/WHI database.

Data Rights:

The National Institute on Aging shall have unlimited rights to and ownership of all deliverables provided under this contract including reports, recommendations, briefings, work plans and all other deliverables. This includes the deliverables provided under the basic contract and any optional task deliverables exercised by the contracting officer. In addition, it includes any additional deliverables required by contract change. The definition of “unlimited rights” is contained in Federal Acquisition Regulation (FAR) 27.401, “Definitions.”

Publications and Publicity:

In collaboration with NIA investigators, the contractor may write and publish articles of data produced as a result of the requirements of the SOW.

Confidentiality of Information:

Contractor will be provided with deidentified information.