U.S. patent application number 15/673675 was filed with the patent office on 2017-12-28 for transfusion registry network providing real-time interaction between users and providers of genetically characterized blood products.
This patent application is currently assigned to BioArray Solutions, Ltd.. The applicant listed for this patent is BioArray Solutions, Ltd.. Invention is credited to Robert DANEHY, Michael SEUL.
Application Number | 20170372015 15/673675 |
Document ID | / |
Family ID | 35541831 |
Filed Date | 2017-12-28 |
![](/patent/app/20170372015/US20170372015A1-20171228-D00000.png)
![](/patent/app/20170372015/US20170372015A1-20171228-D00001.png)
![](/patent/app/20170372015/US20170372015A1-20171228-D00002.png)
![](/patent/app/20170372015/US20170372015A1-20171228-D00003.png)
![](/patent/app/20170372015/US20170372015A1-20171228-D00004.png)
![](/patent/app/20170372015/US20170372015A1-20171228-D00005.png)
![](/patent/app/20170372015/US20170372015A1-20171228-D00006.png)
![](/patent/app/20170372015/US20170372015A1-20171228-D00007.png)
![](/patent/app/20170372015/US20170372015A1-20171228-D00008.png)
United States Patent
Application |
20170372015 |
Kind Code |
A1 |
SEUL; Michael ; et
al. |
December 28, 2017 |
Transfusion Registry Network Providing Real-time Interaction
Between Users and Providers of Genetically Characterized Blood
Products
Abstract
Disclosed is a registry system, including member institutions,
in which transfusion donors and recipients are registered following
genotyping, which would typically take place in a member
institution, or a member institution would have access to the
genotyping information, if performed outside. The registry database
can be accessed and searched by members seeking samples of
particular type(s). Systems are disclosed for maintaining economic
viability of genotyping in connection with transfusions, by
maximizing the number of units placed with the minimal number of
candidate donors typed. Genotyping of potential donors, and product
supply, is matched to forecasted demand. Genotyping can also be
limited to the more clinically relevant markers. The registry
system can also be integrated with one format of assay which
generates an image for analysis, whereby the imaged results can be
analyzed and redacted by experts in a central location, and then
transmitted back to the patient or their representative.
Inventors: |
SEUL; Michael; (Fanwood,
NJ) ; DANEHY; Robert; (Libertyville, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioArray Solutions, Ltd. |
Warren |
NJ |
US |
|
|
Assignee: |
BioArray Solutions, Ltd.
Warren
NJ
|
Family ID: |
35541831 |
Appl. No.: |
15/673675 |
Filed: |
August 10, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14281190 |
May 19, 2014 |
|
|
|
15673675 |
|
|
|
|
11876922 |
Oct 23, 2007 |
|
|
|
14281190 |
|
|
|
|
11092420 |
Mar 29, 2005 |
7363170 |
|
|
11876922 |
|
|
|
|
60621196 |
Oct 22, 2004 |
|
|
|
60586931 |
Jul 9, 2004 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G16H 10/60 20180101;
G16H 40/20 20180101; G06Q 50/22 20130101; Y02A 90/10 20180101; G06Q
10/10 20130101; G16B 40/00 20190201; G16H 20/40 20180101; G06F
19/3481 20130101; G16B 20/00 20190201; G16H 50/70 20180101; G06Q
50/24 20130101; G16B 50/00 20190201 |
International
Class: |
G06F 19/00 20110101
G06F019/00; G06Q 50/24 20120101 G06Q050/24; G06F 19/18 20110101
G06F019/18; G06Q 50/22 20120101 G06Q050/22; G06Q 10/10 20120101
G06Q010/10 |
Claims
1-9. (canceled)
10. A strategy for reducing the cost of genotyping of candidate
donors and maximizing the matching of candidate donors and
recipients, comprising: stratifying prospective donors and
recipients into subpopulations; determining, in each subpopulation,
genetic markers which are associated with clinically significant
adverse events; and matching donors and recipients for those
markers which have a significance greater than a particular
level.
11. The strategy of claim 10 wherein donors and recipients are not
genotypes for markers with a significance below the particular
level.
12-19. (canceled)
20. A method for operating a transfusion registry that matches
donors compatible to recipients of given genotype or phenotype
comprising: estimating anticipated demand for blood products from
transfusion recipients of given genotype or phenotype, wherein the
anticipated demand is estimated using the formula:
.epsilon..about.(N.sup.(Rs)/N.sup.(R))f.sup.(s).SIGMA.(r) wherein
.epsilon. is the probability of logging a request for a specific
genotype, the ratio N.sup.(Rs)/N.sup.(R) represents the relative
proportion of individuals in an ethnic heritage group within a
population at large, f.sup.(s) represents the frequency of
occurrence of a certain allele, and .SIGMA.(r) represents a
function of excess risk for requiring transfusions associated with
the ethnic heritage group relative to the population at large, and
wherein using the formula comprises obtaining values for
N.sup.(Rs)/N.sup.(R), f.sup.(s) and .SIGMA.(r); genotyping a
sufficient number of prospective donors to fulfill the anticipated
demand; and matching donors compatible to recipients of given
genotype or phenotype.
21. The method of claim 20, wherein the genotyping is performed by
an elongation-mediated multiplexed analysis of polymorphisms.
22. The method of claim 21 further comprising collecting samples
from the prospective donors prior to the step of genotyping.
23. The method of claim 20, wherein the genotyping is of one or
more of markers RhCE, Kidd, Kell, Duffy, Dombrock, and MNS.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application Ser. Nos. 60/586,931 and 60/621,196.
BACKGROUND
[0002] The prevailing paradigm of organizing the supply of blood
units available for transfusion relies on routine typing of
transfusion antigens by hemagglutination. Typically, the major
transfusion antigen groups, namely A, B, O and D, are typed at
collection while a select set of minor group antigens such as RhCE,
Kell and Kidd are typed only as needed For blood group antigens
other than ABO and D, source material is diminishing, and the cost
of FDA-approved commercial reagents is escalating. Many antibodies
used for testing for minor blood group antigens (especially when
searching for an absence of a high prevalence antigen) are not
FDA-approved and are characterized to varying degrees by those who
use them. In addition, some antibodies are limited in volume,
weakly reactive, or not available. Collectively, the
labor-intensive approach limits the number of donors one can test;
thereby restricting the supply of antigen-negative RBC products for
patients who have produced the corresponding alloantibody, and,
more recently, restricting the supply of Rh and K matched RBCs for
patients in the Stroke Prevention Trial (STOP) program, which was
designed to prevent immunization of such patients.
[0003] Recipients exposed to foreign transfusion antigens generally
will form antibodies directed against those antigens.
Allo-immunized patients, a subpopulation comprising approximately
2% of transfused patients, and up to 38% of multiply transfused
patients, require red blood cell products which do not contain the
offending antigen. Such units typically must be found either in the
limited available supply or must be found, in real time, by
serological typing of such likely candidate units as may be
available in inventory. The selection of candidate units for "stat"
typing, performed in immunohematology laboratories, is guided
largely by empirical factors. The delay introduced by the search
for matching units can exacerbate emergency situations and
generally will incur substantial cost to hospitals and/or insurance
carriers by delaying in-hospital stay. More generally,
alto-immunization to red blood cell antigens which are also
displayed on other cells (see Table I) and recognized by certain
pathogens such as malaria, can introduce unnecessary health risks
whose elimination would improve the general health.
[0004] The procurement of matched blood to recipients who either
display an uncommon antigen or lack a common antigen, is
particularly problematic. While such incidences are considered
"rare," occurring at a rate of one in 1,000 recipients, the supply
of matched units is very limited. Thus, existing national
collections of special units, including the American Rare Donor
Program (ARDP), register donors encountered in the immunohematology
laboratories of its members: only 30,000 donors have been
registered (see http://www.redcross.org/). In comparison, the
National Marrow Donor Program (NMDP), a national registry of
prospective bone marrow donors who have been genotyped for
polymorphisms in certain loci of the Human Leukocyte Antigen (HLA)
gene complex, in the year 2000, comprised 2.7 million fully
characterized and 4.1 million known donors to supply matching bone
marrow transplants for only .about.2,400 transplantations per year.
See http://www.marrow.org/
[0005] Distribution of the precious few special units available in
the program also leaves substantial room for improvement. At
present, relying primarily on telephone contacts, only 1,000
special units are placed per year, while up to 2% of the
approximately 4-5 million recipients of blood transfusions per
year, that is 100,000 recipients, would benefit from improved
availability.
[0006] In view of this situation, a method of providing a large and
diverse inventory of fully typed blood units, and a method of
instant and efficient distribution of units in response to requests
posted to a central registry would be desirable in order to improve
the public health and to minimize the cost accruing in the health
care system in the form of unnecessarily prolonged hospital stays,
adverse transfusion reactions (see Hillyer et al., Blood Banking
and Transfusion Medicine; published, by Churchill Livingston,
Philadelphia Pa.) and other potential complications arising from
alto-immunization.
[0007] However, absent substantial government or private funding
for such an endeavor, a registry of "critical mass" must be created
and operated in a commercially viable manner. The ARDP operation,
representative of current practice, illustrates the difficulty: In
order to identify a special donor, up to 1,000 donors may have been
typed, and from a collection of 30,000 such special units, only
1,000 were placed. While special units fetch a higher price than do
"vanilla" red blood cell products, the premium does not come close
to covering the cost, in view of the substantial amount of excess
typing required. Commercial viability, under these conditions, is
doubtful.
SUMMARY
[0008] Described is the efficient organization and operation of a
diverse registry of fully characterized blood units. Preferably,
donors are characterized by DNA typing of the clinically most
relevant genetic markers, including a set of mutations of Human
Erythrocyte Antigens (HEA) including genetic variants of Rh, and
additional antigens such as HLA and HPA. The registry, also
referred to as a Transfusion Network, comprising certain
application programs and databases preferably accessible via a
web-browser interface, offers essentially instant access to linked
inventories of typed units of donor blood ("actual" units) as well
as access to genotyped donors who are available on-call ("callable"
units), along with requisite information relating to donor status.
Inventories of actual units or information relating to callable
units can be held by subscribing member organizations, who also may
participate in the operation and governance of the registry.
[0009] In a preferred embodiment, the registry network comprises an
alliance of dominant regional and national donor centers (such as
New York Blood Center and United Blood Services) which would set
new standards in transfusion medicine. In another embodiment,
regional donor centers and transfusion services are linked so as to
create the critical mass of regional centers (both domestic and
foreign) to decentralize the market by competing with the dominant
national donor centers.
An "Actively Managed" Registry--
[0010] Existing registries such a the ARDP largely operate as
passive repositories of donors encountered per chance during blood
drives. Registries of bone marrow donors operated by the NMDP or
comparable organizations around the world (REF), while in some
cases actively funding bone marrow drives, operate in essentially
the same manner of underwriting the large-scale typing of volunteer
donors and collecting results. TO the extent that the population of
donors and population of recipients are not balanced, this approach
generally will be very inefficient from the point of view of
maximizing the probability of a matching a recipient request.
[0011] To overcome this inefficiency, and to ensure commercial
viability, a preferred strategy is described herein for
constructing and maintaining a registry of genotyped donors which
maximizes the number of units placed with the minimal number of
candidate donors typed. To this end, relevant parameters relating
to managing supply and forecasting demand are identified, and
methods are described to optimize these parameters so as to
maximize revenue and minimize total cost. The registry performs
real-time analysis of supply and demand balance and directs its
subscribing members to balance their respective donor typing
operations.
[0012] A transfusion network, operated as an active registry,
permits near-instant selection of prospective donors matching a
given recipient by way of implementation on a global network such
as the world wide web, thereby also facilitating the efficient
distribution of units in inventory, further supported by
transaction management including order placement and delivery. The
registry will generate revenue from subscription as well as
transaction fees, offering a set of products and services as
described herein. Thus, a commercially viable registry, the first
such in transfusion medicine, is disclosed, to improve clinical
outcomes while enhancing economic efficiency.
[0013] In one embodiment, large-scale, rapid and cost-effective DNA
typing, also herein referred as genotyping, of prospective donors
is performed to permit instant matching of registered donors to
recipients of known phenotype or genotype in a manner improving the
clinical outcome of transfusion while improving economic
efficiencies. To the extent that genotyped donors are retained, the
cost of typing is minimized, as discussed herein.
[0014] The registry server preferably executes a "genetic
cross-matching, gXM" algorithm to identify actual and callable
donors within the registry. A gXM algorithm relating to a selection
of the clinically most relevant human erythrocyte antigen (HEA)
mutations is described in a co-pending application (see Provisional
Application No. 60/621,196, entitled "A Method of Genetic
Cross-Matching of Transfusion Recipients to Registered Donors," as
well as applications to be filed claiming priority to it, all of
which are incorporated by reference).
DESCRIPTION OF THE FIGURES
[0015] FIG. 1 is an illustration of a transfusion registry network
linking multiple donor centers offering blood-derived products to
multiple hospitals requesting blood-derived products for
transfusion to patients. Participating parties can perform donor
genotyping, patient genotyping and patient antibody screening
(using, e.g., BeadChip.TM. assay kits). The registry performs
genetic cross-matching and can offer a variety of additional
products and services.
[0016] FIGS. 2A to 2D is a graphical depiction of the central
components and subsystems of a BeadChip.TM. format for multiplexed
analysis of polymorphisms and profiling of antibodies enabling the
large-scale genotyping of donors and patients, as well as detection
and identification of antibodies circulating in patient serum.
[0017] FIG. 3 is a graphical depiction of a uniform interface for
presentation of data to the registry, preferably by way of a
web-enabled Automated Allele Analysis (AAA) program (as disclosed
in U.S. application Ser. No. 10/909,638, incorporated by
reference), and the connection of the registry to linked
inventories
[0018] FIG. 4 is a graph showing the dependence of cost and revenue
projections for a multiple donation scenario for various values of
the repeat probability, RHO.
[0019] FIG. 5 is an illustration of the concept of optimal
resolution (described in text).
DETAILED DESCRIPTION
[0020] In order to maximize the economic efficiency of the
transfusion registry, it will be preferable to adopt a strategy of
minimizing the total number of donors typed for every recipient
request fulfilled. The following exposition refers to a genotype to
represent a combination of marker alleles, where, for each marker,
the possible values of the allele are Normal (1), Homozygous (-1)
or Heterozygous (0), and a specific genotype, representing a
combination of alleles, thus has the form of a ternary string.
Estimating Demand: Requests for Special Units--
[0021] In order to maintain a registry of candidate donors such
that the maximal number of requests from prospective recipients for
special units can in fact be matched while the number of excess
donors typed is kept to a minimum, it will be critical to construct
an estimate of anticipated demand.
Denote by:
[0022] N.sup.R the number of requests anticipated (or
received);
[0023] 8 the probability of receiving ("logging") a request for a
specific genotype;
[0024] : the probability of matching a request (to a pre-determined
level of resolution)
Available evidence indicates that the incidence of certain
genotypes varies substantially between ethnic groups (see G. Hashmi
et al., "A Flexible Array Format for Large-scale, Rapid Blood Group
DNA Typing," Transfusion, in press). Therefore, the probability of
a request for blood from a donor of specific genotype received from
a random sample of a heterogeneous pan-ethnic population in fact
represents a weighted average of probabilities, 8.sub.s, for each
of multiple constituent homogeneous subpopulations. The
population-specific probabilities may be cast in the form:
8.sub.s.about.(N.sup.(Rs)/N.sup.(R))f.sup.(s).SIGMA.(r)
where f.sup.(s) represents the frequency of occurrence of a certain
allele, the ratio (N.sup.(Rs)/N.sup.(R)) represents the relative
proportion of individuals in subpopulation s within the pan-ethnic
population at large, and .SIGMA.(r) represents a function of excess
risk associated with a specific subpopulation (relative to the
population at large). The function .SIGMA.(r), which may assume
positive or negative values, reflects actuarial probabilities which
in turn reflect genetic risk, e.g., the higher than average
incidence of sickle cell anemia in African-Americans, or higher
than average incidence of kidney disease in certain native American
Indian tribes, requiring multiple transfusions, and environmental
risk, e.g., the lower probability of, e.g., the Amish to suffer
trauma in automobile accidents.
[0025] The probability, :, of matching a specific request depends
on the diversity of the registry and its linked inventories of
actual and callable donors.
Managing Supply: Selection of Donors from Stratified
Populations--
[0026] In accordance with the preferred strategy of registry
operation, the supply of registered donors will be adjusted to
balance the anticipated demand.
Denote by:
[0027] N the number of new donors tested;
[0028] , the fraction of special units encountered in a test
population; 0.ltoreq., <1;
[0029] .PHI. the fraction of special units sold.
The probability, .PHI., of selling any specific unit is determined,
for given unit price, by the probability, :, of matching a request
for such a unit. Provided that an acceptable price for a unit is
agreed upon, then:
.PHI.=:
[0030] Preferably, the strategy for balancing the supply of
registered donors will reflect the increased probability of finding
an acceptable match for a prospective recipient of transfusion
within a donor population of similar heritage. The similarity of
genotype among individuals of similar heritage has been established
for a variety of genetic markers such as those for certain
inherited genetic disorders, including so-called Ashkenazi Jewish
Diseases and Cystic Fibrosis (see
http://www.jewishvirtuallibrary.org/), as well as for the highly
variable human leukocyte gene complex which encodes for the human
leukocyte antigens (HLA) determining the compatibility of
recipients and donors of solid organs and bone marrow
(http://www.marrow.org/DONOR/abcs_of_donation.html). For blood
group genotypes, but one example is provided by the high incidence
in individuals of South Chinese heritage of the Miltenberger
mutation within the MNS blood group (see M. Reid, "The Blood Group
Antigen FactsBook" (2003)) which is largely absent in individuals
of Caucasian heritage.
[0031] As with demand estimation, the probability of encountering a
specific genotype in a pan-ethnic and hence genetically
heterogeneous donor population will reflect the existence of
constituent homogeneous subpopulations displaying varying values of
that probability:
,=(N.sup.(1)/N)f.sup.(1)+(N.sup.(2)/N)f.sup.(2)+ . . .
+(N.sup.(s)/N)f.sup.(s)
where, as before, f.sup.(1), f.sup.(2) . . . f.sup.(s) denote
allele frequencies. To balance the supply of registered donors to
anticipated demand, it will be desirable to select, for each
subpopulation, s, shared among donor and recipient populations, the
number of registered donors in accordance with the condition:
(N.sup.(s)/N)=C(N.sup.(Rs))/N.sup.(R)).SIGMA.(r)
[0032] The constant, C, captures factors such as the anticipated
number of units required per recipient. This condition dictates
that the registry, rather then genotyping all corners, would accept
only a certain continent of donors from each subpopulation.
Factors Determining Profitability--
[0033] A key aspect of operating a transfusion registry network
with an acceptable profit margin concerns the pricing for a test
permitting the genotyping a donor sample for a designated number of
genetic markers, preferably by invoking elongation-mediated
multiplexed analysis of polymorphisms ("eMAP"; as disclosed in U.S.
application Ser. No. 10/271,602, incorporated by reference).
Denote by:
[0034] N.sub.k the number of new donors tested in year k, where
k=0, 1, 2, . . . , n;
[0035] R.sub.k the number of repeat donors (from year k-1) In year
k=1, 2, . . . , n;
[0036] .DELTA. the fraction of repeat donors; generally
R.sub.h<N.sub.k, and thus .DELTA.<1.
[0037] .DELTA..sub.s the fraction of repeat donors among special
donors; .DELTA..sub.s<1.
[0038] , the fraction of special units encountered in a test
population; 0.ltoreq., <1;
[0039] c the cost of typing one sample;
[0040] .PHI. the fraction of special units sold;
[0041] s the excess revenue (over the "vanilla" unit) of a special
unit of product.
The cost of screening in year k is: C.sub.k=cN.sub.k-g(R.sub.k,
R.sup.k-1, . . . ), that is, in any year but the first (k=0), the
total cost of typing N.sub.k donor samples will be reduced by a
certain portion reflecting the number of repeat donors from
previous years. Various assumptions--manifesting themselves in
specific forms of the function g(R.sub.k, R.sub.k-1, . . . )--are
possible. To the cost of typing must be added the cost of operating
the registry--including transaction costs.
[0042] The revenue in year k reflects the sale of special units
accumulated in inventory, that is: S.sub.k=h(N.sub.k, N.sub.k-1, .
. . ). Various assumptions--manifesting themselves in specific
forms of the function h(N.sub.k, N.sub.k-1, . . . )--are
possible.
[0043] The profit in year k is given by P.sub.k=S.sub.k-C.sub.k.
Break-even, P.sub.k=0, is attained at a certain k.
Example 1: Single Repeat Donations
[0044] Assume that a certain constant total number of donors, say
N.sub.0, is screened every year, and that a (constant) fraction of
donors repeat, but repeat only once, namely in the year following
their initial donation. Then R.sub.k=.DELTA.N.sub.k-1, and:
TABLE-US-00001 Yr0 Yr1 Yr2 New donors N.sub.0 N.sub.1 = N.sub.0 -
R.sub.1 N.sub.2 = N.sub.0 - R.sub.2 Repeat donors R.sub.1 =
.DELTA.N.sub.0 R.sub.2 = .DELTA.N.sub.1 where R.sub.2 =
.DELTA.N.sub.1 = .DELTA.(N.sub.0 - R.sub.1) = .DELTA.N.sub.0 -
.DELTA..sup.2N.sub.0 and N.sub.2 = N.sub.0 - .DELTA.N.sub.0 +
.DELTA..sup.2N.sub.0 = N.sub.0(1 - .DELTA. + .DELTA..sup.2).
Generalizing, one finds the expression for N.sub.k to be
N.sub.k=N.sub.0 (1-.DELTA.+.DELTA..sup.2-.DELTA..sup.3+ . . . );
the alternating series reflects the fact that, as repeat donors
stay away, a greater number of new donors must be screened in every
even year. For n sufficiently large so that .DELTA..sup.2n=<1,
this expression turns out to be N.sub.k=N.sub.0/(1+.DELTA.),
independent of n; for example, with .DELTA.=1/2,
.DELTA..sup.2n=(1/2).sup.2n= 1/256 for n=4.
[0045] Assume further that revenue in any given year reflects the
sale of a certain fraction, .PHI., of the total units, N.sub.0,
available that year, at an excess sales price, s, per sample, and
that the population of repeat donors within the special population
equals that within the general population. Then
TABLE-US-00002 Yr0 Yr1 Yr2 S.sub.0 = .phi.(,N.sub.0)s S.sub.1 =
.phi.(,N.sub.0)s S.sub.2 = .phi.(,N.sub.0)s
Then P.sub.n=S.sub.n-C.sub.n=[,.PHI.s-c/(1+.DELTA.)]N.sub.0,
independent of n. Under these assumptions, to attain break-even,
P.sub.n=0, or c/s=(1+.DELTA.),.PHI., the cost per unit screened
must not exceed a certain fraction of the excess revenue in each
year.
[0046] For example, with reported numbers of .DELTA.=1/2 (see
Schreiber, G. B. et al., "Targeting Repeat Blood Donors Can
Increase Supply," Transfusion 43: 591-97 (2003)), ,=0.001
(percentage of "rare" units in pan-ethnic population) and
.PHI.=1/5, reflecting the placement of 1,000 "rare" units (from a
stock of 30,000), with approximately 5,000 new rare units acquired
per year (See http://www.marrow.org/), one obtains
c/s=3/2*0.001*1/5=0.0003. Since s will likely not exceed $1,000,
the price per test will have to be negligibly small, not a scenario
for a profitable large-scale screening operation. In fact, this is
near the worst case scenario in which, along with the low abundance
of special samples, and low percentage of placement, donors do not
repeat (.DELTA.=0).
[0047] It is anticipated that proper demand projection and
inventory management, combined with providing instant access to
such inventories by way of a transfusion registry network, as
disclosed herein, will provide a basis to attain an operating
regime of, .fwdarw.0.1 and .PHI..fwdarw.1 so that, even with
.DELTA.=1/2, c/s=3/2*0.1*1=0.15.
Example 2: Multiple Repeat Donations
[0048] In contrast to the previous Example 1, assume that of the
total number of donors, say N.sub.0, screened in the first year, a
(constant) fraction of donors, once recruited, repeat every year.
Given that each donor is genotyped only once, this will have a
cumulative effect on cost reduction.
[0049] To illustrate the effect, assume first that the same
fraction of general donors and special donors repeat, that is:
.DELTA.=.DELTA..sub.s, and that this fraction is constant.
TABLE-US-00003 Yr0 Yr1 Yr2 Cost C.sub.0 = cN.sub.0 C.sub.1 =
c(N.sub.0 - R.sub.1) C.sub.2 = c(N.sub.0 - R.sub.2 - R.sub.1) =
cN.sub.0(1 - .DELTA.) = cN.sub.0(1 - .DELTA.).sup.2 Revenue S.sub.0
= .phi.(,N.sub.0)s S.sub.1 = .phi.(,N.sub.0)s S.sub.2 =
.phi.(,N.sub.0)s
Then P.sub.n=S.sub.n-C.sub.n=[,.PHI.s-c(1-.DELTA.).sup.n]N.sub.0.
The contrast to the model of Example 1 is dramatic: the requisite
cost of typing required to attain the same revenue, decreases
geometrically with n, the slope of the decrease being set by
.DELTA.. Break-even corresponds to c/s=,.PHI./(1-.DELTA.).sup.n,
and profit grows rapidly thereafter.
[0050] FIG. 4 illustrates the evolution of projected cost and
excess revenue for different values of the repeat probability,
.DELTA.. Precedents for relatively high repeat probabilities exist,
especially in donors who are aware of their special status. It will
be desirable to provide incentives to such donors, as described
below.
Mutually Beneficial interaction of Registry and Reagent
Manufacturer--
[0051] Provided that the large-scale genotyping of donors and
patients is enabled by an efficient methodology, preferably
invoking the eMAP-HEA design in conjunction with the BeadChip.TM.
format (U.S. Provisional Application Ser. No. 60/586,931, entitled
"Encoded Probe Pairs for Molecular Blood Group Antigen Molecular
Typing and Identification of New Alleles" and applications claiming
priority thereto (incorporated by reference); G. Hashmi et al., "A
Flexible Array Format for Large-scale, Rapid Blood Group DNA
Typing," Transfusion, in press; see also: FIG. 2), the cost of
genotyping is reduced by the use of the multiplexed format of
analysis and delivery of the assay in a parallel processing format,
thereby permitting automation and uniform data management for a
large menu of applications, Including the typing of multiple
antigen groups (FIG. 3).
[0052] In the initial stage, while building its initial donor
reservoir, the registry, to the extent that it bears the cost of
recruiting and genotyping donors, either directly, or indirectly,
by way of subscribing member donor centers, will operate at a loss
(FIG. 4). It will be beneficial for the registry to partner with a
reagent manufacturer who would underwrite the operations in the
initial stage, for example by providing kits at reduced or at no
cost to the registry. To the extent that the registry is successful
in retaining special donors, and hence reduces Its cost of typing,
the market opportunity for the reagent manufacturer declines. To
compensate the reagent manufacturer, the registry could, for
example, grant the manufacturer participation in a jointly
controlled entity along with a profit sharing arrangement.
Example 3: Expanding the Registry
[0053] The scenario of Example 2 offers several modes of operation.
For example, the registry might operate in a "non-profit" regime by
setting the ratio c.sub.n/s.sub.n so as to ensure P.sub.n=0. That
is, the diagnostic reagent manufacturer, in return for obtaining a
designated share of profits after break-even, can subsidize the
initial ramp-up of the registry by accepting a lower price per
test, corresponding to the condition P.sub.n
(c.sub.n/s.sub.n)=0.
[0054] Alternatively, the registry, having attained breakeven, may
decide to expand operations by expanding the number of donors
screened per year, for example, such that the number of new donors
is set by the available profit. This provides a mechanism to
compensate the participating reagent manufacturer for the declining
sales of tests arising from the successful retention of repeat
donors.
Recruiting and Retaining Special Donors--
[0055] The single repeat and multiple repeat scenarios indicate the
critical role of the effect of the repeat probability on the
profitability of the registry.
[0056] As with the recruitment of HLA donors for national
registries, genotyping of blood group antigens will permit the
identification of prospective future donors--that is, donors who do
not have to donate blood until called upon. For example, analysis
of DNA extracted from buccal swabs would enable "self-collection"
in targeted communities such as churches and synagogues, and simple
submission processes, e.g., by mail, to a designated member
laboratory (not necessarily a donor center), for DNA analysis. This
aspect not only allows the extension of the universe of known
special donors, but also would be invaluable in registry
management, in order to match the volume of donor typing to
projected demand within individual subpopulations.
[0057] To refine this model toward a "best case" scenario,
retention efforts would be directed to special donors, not the
general donor population. The total number of special donors in
each designated subpopulation would be matched to demand
projections, as described above. Special donors would be given
Incentive to repeat by granting them, and donating family members,
authorized direct emergency access to the registry.
Clinical Benefit Vs. Cost of Genotyping: "Optimal" Panel Size--
[0058] The clinical outcome of transfusion generally would improve
with increasing resolution, that is, with the number of genetic
markers included in the determination of patient and donor
genotypes. The greatest benefit would derive from matching alleles
encoding the clinically most significant blood group antigens (see
M. Reid, "The Blood Group Antigen FactsBock" (2003)), and the
incremental benefit of matching additional alleles would decrease,
Ignoring cost, a reasonable criterion for the determining the
optimal resolution would be to select this point of diminishing
incremental benefit.
[0059] However, significant economic considerations also apply.
Thus, the higher the degree of resolution required for genetic
cross-matching of a donor genotype to that of a patient, the higher
the risk to the registry of not being able to place that unit, and
the higher the cost of typing that unit. That is, c, the cost of
genotyping, generally will increase with the number, m, of genetic
markers included in the set, while the probability, :, of matching
a request and selling a specific unit will decrease. For example,
denoting by f.sub.First, f.sub.Second, f.sub.Third, . . .
f.sub.Last the relative allele frequencies of markers included in
cross-matching, in the order of decreasing clinical significance,
:.about.f.sub.Firstf.sub.Secondf.sub.Third, . . . f.sub.Last, thus
:.about.1/m.sup.x, where x denotes an exponent, while
c.about.c.sub.0+a*m.sup.y, where c.sub.0 denotes a constant, namely
the initial cost of genotyping the first marker, a denotes a
constant related to the marginal cost of genotyping additional
markers, and y denotes an exponent reflecting the rate of increase
in cost: for example, using a single-marker method of genotyping
such as Restriction Fragment Length Polymorphism (RFLP) or
Allele-specific PCR, one would anticipate cost to increase
linearly, y=1, while using the preferred embodiment of
elongation-mediated multiplexed analysis of polymorphisms (eMAP),
one would anticipate cost to increase in a sublinear form, y<1.
In either case, from the cost-benefit point of view, there exists
an "optimal" resolution. Unless the market would compensate the
registry for the higher cost of matching a donor unit to high
resolution, in which case clinical benefit will set the optimal
resolution, m*, that value otherwise will be determined by the
intersection of the two functions :=:(m) and c=c(m), as illustrated
in FIG. 5.
Implementation of Registry--
[0060] A co-pending application (U.S. application Ser. No.
10/909,638, incorporated by reference) discloses algorithms and
implementations for automated allele analysis, and these methods
are useful in connection with genetic cross-matching (gXM)
generally, as disclosed in a further co-pending application
(Provisional Application No. 60/621,196, noted above, incorporated
by reference).
[0061] Using standard software engineering technologies such as
MicroSoft.net ("dot-net"), these methods can be implemented in a
manner permitting their use in an application-server modality using
a standard web browser such as Microsoft Explorer.TM.. Preferably,
such an implementation, wAAA.TM., will invoke an SQL server and
provide a uniform interface to Array Imaging Systems generating
data for a variety of applications such as multiplex HEA, HLA and
HPA analysis as well as patient and donor antibody identification.
As disclosed in a co-pending application (Ser. No. 10/714,203),
data records will be uploaded--preferably using transaction
protocols preserving donor and patient anonymity--to the wAAA
application on a central server permitting review and redaction by,
and delivery to authorized users.
Establishing an Efficient Market: Management of Real-time
Transactions--Disclosed is a mode of operating a commercially
viable registry in the form a real-time transaction network
offering instant access to a diverse collection of characterized
donors, that is, both actual donor-derived blood products in linked
inventories, and callable candidate donors of desirable genotype.
Such a registry will increase demand by extending its reach to a
global base of potential customers by providing access to its
products and services by way of a standard web browser and
permitting applications, notably automated allele analysis, gXM and
selection of candidate donors to be performed automatically, in
real time. By offering instant transactions, under a variety of
pricing arrangements including contracts, notably futures
contracts, as well as real-lime pricing, for example by way of
bid-ask matching (currently available in the context of
web-auctions as well as Electronic Communications Networks (ECNs)
such as InstiNet (http://www.island.com), the registry will create
an efficient market for the global procurement and distribution of
matched donor units.
Collection of Samples, Assay Performance, Analysis of Assay
Results, Patient Counseling and Reporting Results to Patients--
[0062] Also disclosed herein is a model of implementing molecular
diagnostics in a mode of "virtual centralization" which permits the
the steps of actually performing assays, preferably in a standard
and universal format such as the Random Encoded Array Detection
(READ.TM.) format, and the steps of analyzing, interpreting and
reporting assay results including communicating outcomes to the
patient or referring physician, to be performed in different
locations, such that experts or groups of experts have access, by
way of a standard web browser to the wAAA environment to review
data generated in a location different from their own physical
location.
[0063] Virtual centralization of the data is accomplished by
uploading of data relating to assay results, and
interpretation/analysis thereof, to a server or other accessible
database. It can then be accessed by or securely transmitted to
authorized parties to perform additional interpretation or
analysis, or to view or report the results. User identification can
be secured at all stages of the process so as to preserve
confidentiality, such that, for example, only the patient and
perhaps his physician will be aware of the patient identity
associated with particular results.
[0064] This model is particularly well-suited to the analysis and
interpretation of results produced by genetic tests, including,
results which can be processed for initial analysis by the
web-based AAA program (discussed above) or where these results are
in the form of images for which standard formats of network
transmission now exist. Assay formats producing suitable images
invoke, for example, spatially encoded "dot blot" or "reverse dot
blot" formats, including "spotted" probe or protein arrays; arrays
of oligonucleotide probes synthesized in-situ on a substrate; or
probes (or proteins) associated with encoded beads; see U.S. Pat.
No. 6,797,524; U.S. application Ser. No. 10/204,799, filed on Aug.
23, 2002 "Multianalyte Molecular Analysis Using
Application-Specific Random Particle Arrays," (incorporated by
reference).
[0065] Networking allows the different parties involved in
different steps of the process to perform their respective
functions such as collecting samples, performing the assay, or
analyzing the results, at the same location, or at different
locations. Performing separate functions by different parties at
different locations can provide a significant advantage in terms of
cost and speed of analysis, as parties do not need to travel to a
location to carry out their function. It also allows better control
over the confidentiality of the results, as results do not need to
be physically transported, by non-secure means, to different
locations.
[0066] After sample collection, or self-collection by the patient
(e.g., by using a buccal swab), an assay on a patient sample can be
performed at a first location. The initial assay results, which may
be encoded (see U.S. Pat. No. 8,797,524; U.S. application Ser. No.
10/204,799, filed on Aug. 23, 2002 "Multianalyte Molecular Analysis
Using Application-Specific Random Particle Arrays," both being
Incorporated herein by reference) or in the form of an assay image
(see "Analysis, Secure Access to and Transmission of Array Images,"
Ser. No. 10/714,203, filed Nov. 14, 2003, incorporated herein by
reference), can be uploaded to a server or transmitted to an
analysis site (which may be the site which sold the assay kit to
the remote location). The identity of the patient can be associated
with the sample, using, e.g., methods set forth in the co-pending
application "Genetic Analysis and Authentication," Ser. No.
10/238,439 (incorporated herein by reference). The analysis site
decodes or interprets or performs a preliminary analysis of the
results (and/or the assay image), and may also obtain assistance in
interpretation from experts or consultants, who may either be
on-site or may transmit an image from the assay, or who have access
to the server with such images or results. The analyzed results can
then be accessed by, or transmitted to, the patient's physician, or
the patient, or the laboratory where the assay was conducted, which
in turn provides them to the patient's physician and/or the
patient. It is possible to keep the patient identity separated from
the results at all stages, so that only the physician and the
patient, or even only the patient, can correlate results with a
particular patient. This secures the confidentiality of assay
information, as is desirable in the case of genetic information,
given the growing concern over maintaining confidentiality of
Individual's genetic data.
[0067] In this manner, the "front-end" of laboratory practice is
standardized, preferably by adoption of a BeadChip.TM. format of
performing multiplexed nucleic acid and protein analysis while the
"back end", generally requiring specialized expertise, is moved to
a network, preferably by implementation of an application service
which provides network protocols to transmit assay results, perform
analysis, authorize access to databases for review and result
certification, and manage communication between multiple
participants in the process.
[0068] It should be understood that the terms and expressions
herein are exemplary only, and not limiting, and that the invention
is defined only in the claims which follow, and includes all
equivalents of the claimed subject matter.
* * * * *
References