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.

Description of the Invention

BACKGROUND

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.

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, allo-immunization to red blood cell antigens which are also displayed on other cells (see Table I, see Original Patent) and recognized by certain pathogens such as malaria, can introduce unnecessary health risks whose elimination would improve the general health.

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, e.g., the Red Cross Website). 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, e.g., the National Marrow Donor Program Website

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.

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 allo-immunization.

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

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.

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--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.

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.

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.

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.

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).

DETAILED DESCRIPTION

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--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:

N.sup.R the number of requests anticipated (or received); .lamda. the probability of receiving ("logging") a request for a specific genotype; .mu. 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, .lamda..sub.s, for each of multiple constituent homogeneous subpopulations. The population-specific probabilities may be cast in the form: .lamda..sub.s.about.(N.sup.(Rs)/N.sup.(R))f.sup.(s).OMEGA.(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 .OMEGA.(r) represents a function of excess risk associated with a specific subpopulation (relative to the population at large). The function .OMEGA.(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.

The probability, .mu., 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--In accordance with the preferred strategy of registry operation, the supply of registered donors will be adjusted to balance the anticipated demand.

Denote by:

N the number of new donors tested; .epsilon. the fraction of special units encountered in a test population; 0.ltoreq..epsilon.<1; .sigma. the fraction of special units sold. The probability, .sigma., of selling any specific unit is determined, for given unit price, by the probability, .mu., of matching a request for such a unit. Provided that an acceptable price for a unit is agreed upon, then: .sigma.=.mu.

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, e.g., Jewish Virtual Library website), 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 through the National Marrow Donor Program website. 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.

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: .epsilon.=(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)).OMEGA.(r)

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--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:

N.sub.k the number of new donors tested in year k, where k=0, 1, 2, . . . , n; R.sub.k the number of repeat donors (from year k-1) in year k=1, 2, . . . , n; .rho. the fraction of repeat donors; generally R.sub.k<N.sub.k, and thus .rho.<1. .rho..sub.s the fraction of repeat donors among special donors; .rho..sub.s<1. .epsilon. the fraction of special units encountered in a test population; 0.ltoreq..epsilon.<1; c the cost of typing one sample; .sigma. the fraction of special units sold; 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.sub.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.

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.

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.

Claim 1 of 2 Claims

1. A method for reducing the incidence of allo-immunization in recipients transfused by samples obtained from member institutions below that otherwise experienced, where member institutions form a registry which retains a database of genotyped donors, and where certain member institutions perform transfusions to recipients, comprising: requiring that certain member institutions genotype donors for certain molecular markers associated with clinically significant events; maintaining the genetic marker information associated with the genotyped donors and the samples which they donate; requiring that certain member institutions genotype or phenotype recipients for said markers; and transfusing blood, serum or tissues to recipients only if the donor genotype precludes the expression of said molecular markers by said donors.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.