Opinion ID: 2294040
Heading Depth: 2
Heading Rank: 1

Heading: Frye-Reed Analysis

Text: The essence of the instant case is the application of the Frye-Reed test to the analysis undertaken by an expert where the underlying data and methods for gathering this data are generally accepted in the scientific community but applied to support a novel theory. In reaching his ultimate conclusion that the plaintiffs ... failed in their burden of proving that the bases of the expert witnesses' testimony are generally accepted as reliable within the relevant scientific field, Judge Berger discussed the importance of the threshold determination with which he was vested. He noted that [u]nder Reed, the proponent of an expert witness bears the burden of proving the basis of the witness' opinion is generally accepted as reliable within the relevant scientific field. He also observed that the Frye-Reed test `was deliberately intended to interpose a substantial obstacle to the unrestrained admission of evidence based upon new scientific principles,' quoting Chesson, 399 Md. at 328, 923 A.2d at 946, in turn quoting Reed, 283 Md. at 386, 391 A.2d at 370, that the test posed a minimum threshold for the admissibility of scientific evidence in Maryland, and that trial courts continued to retain discretion to exclude such testimony on other groundssuch as lack of helpfulness or expert qualification. In discerning the factual predicates developed during the hearing, which have not been challenged for clear error, [16] Judge Berger found that [t]himerosal is an organic mercury-based compound, that has been used in various vaccines and other biological and pharmaceutical products since the 1930's, and that it was undisputed that Jamarr had received a diphtheria tetanus and whole-cell pertussis vaccine (DTP), at 2 months, 4 months, 6 months and 18 months, pursuant to the Centers for Disease Control and Prevention's published recommended schedule, as well as a hemophilia influenza type b (Hib) vaccine. According to Judge Beger, [b]oth the DTP vaccine and the Hib vaccine contained 50 micrograms of thimerosal, which results in approximately 25 micrograms of mercury in each vaccination. Judge Berger also found that [i]n July of 1999, the Public Health Service and the American Academy of Pediatrics issued a joint statement recommending the removal of thimerosal from vaccines as a precautionary measure, and that [b]y March of 2001, all vaccines on the recommended childhood immunization schedule were available without thimerosal. Turning to the issue of Jamarr's developmental challenges, Judge Berger found that, autism or autism spectrum disorder (ASD) are pervasive developmental disorders that are characterized by sustained impairments in social interaction, sustained impairments in verbal and nonverbal communication skills, and restricted, repetitive and stereotyped patterns of behaviors or interests, and that [u]nder the American Psychiatric Association's Diagnostic and Statistical Manual . . . the onset of autistic disorder is prior to three years of age. His review of the scientific literature regarding autism's causes, and in particular, the findings of the National Academy of Sciences' Institute of Medicine's (hereinafter IOM) 2001 and 2004 Committees, [17] led him to note that the 2001 IOM Committee, which was tasked with evaluating the alleged connection between thimerosal-containing vaccines and a broad range of neurodevelopmental disorders including autism, ADHD, and speech or language delay, concluded: The hypothesis that thimerosal exposure through the recommended childhood immunization schedule has caused neurodevelopmental disorders is not supported by clinical or experimental evidence.    [T]he evidence is inadequate to accept or reject a causal relationship between thimerosal exposures from childhood vaccines and the neurodevelopmental disorders of autism, ADHD, and speech and language delay. These conclusions were founded upon the following bases: (a) low-dose thimerosal exposure in humans has not been demonstrated to be associated with effects on the nervous system; (b) neurodevelopmental effects have been demonstrated for prenatal but not postnatal exposures to low doses of ethylmercury; (c) the toxicological information regarding ethylmercury, particularly at low doses, is limited; (d) thimerosal exposure from vaccines has not proven to result in mercury levels associated with toxic responses; (e) signs and symptoms of mercury poisonings are not identical to autism, ADHD, or speech or language delay; (f) autism is thought primarily to originate from prenatal injury; and (g) there is no evidence that ethylmercury causes any of the pathophysiological changes known to be associated with autism, such as genetic defects, and there are no well-developed pathological markers of ADHD or delay of speech or language that could be compared to effects of ethylmercury on the nervous system. The 2001 IOM Committee Report was succeeded in 2004 by another IOM Committee, which, Judge Berger found, again attempted to assess whether a causal link between the administration of thimerosal and autism had been proven in the scientific community. To assess causality, the 2004 IOM Committee used the categories of causal conclusions developed by previous IOM committees, namely: (1) no evidence; (2) evidence is inadequate to accept or reject a causal relationship; (3) evidence favors rejection of a causal relationship; (4) evidence favors acceptance of a causal relationship; (5) evidence establishes a causal relationship, according to Judge Berger's review. In that context, he continued, the 2004 Committee reviewed a vast body of literature on the subject and considered extensive presentations and submissions made by scientists during an open scientific meeting, ultimately concluding, that the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism. This rejection, Judge Berger found, was in large part, based on [e]pidemiological studies examining [thimerosal] and autism, including three controlled observation studies (Hviid et al., 2003; Miller, 2004; Verstraeten, et al., 2003) and two uncontrolled observational studies (Madsen, et al., 2003; Stehr-Green, et al., 2003), all of which, consistently provided evidence of no association between [thimerosal] and autism, despite the fact that these studies utilized different methods and examined different populations (in Sweden, Denmark, the United States and the United Kingdom). As Judge Berger found, the 2004 IOM Committee ultimately determined that the link between thimerosal and autism was largely speculative: In the absence of experimental or human evidence that vaccination (either the MMR vaccine or the preservative thimerosal) affects metabolic, developmental, immune or other physiological or molecular mechanisms that are causally related to the development of autism, the committee concludes that the hypotheses generated to date are theoretical only.    Given the lack of direct evidence for a biological mechanism and the fact that all well-designed epidemiological studies provide evidence of no association between thimerosal and autism, the committee recommends that cost-benefit assessments regarding the use of thimerosal-containing versus thimerosal-free vaccines and other biological or pharmaceutical products, whether in the United States or other countries, should not include autism as a potential risk. Judge Berger also acknowledged that a plethora of venerable publications reject[] the plaintiffs' theoretical link between thimerosal-containing vaccines and autism, including the Global Advisory Committee on Vaccine Safety, which advises the World Health Organization on health related issues, the Centers for Disease Control and Prevention, the American Academy of Pediatrics, and the National Institutes of Health, all of which have taken the position that thimerosal vaccines do not cause or contribute to autism. He stated that epidemiology, or the science that studies the distribution of diseases within populations, was the single most relevant field of science to the general causation issue presented in this case, i.e., whether thimerosal-containing vaccines can cause autism, and recognized that none of the Blackwells' experts was qualified as an expert in epidemiology. Turning to the opinions rendered by the Blackwells' primary expert, [18] Dr. Mark Geier, Judge Berger looked first at Dr. Geier's analytical framework, whereby he purported to have completed an epidemiological analysis on scientifically accepted data compiled in various third-party databases: the Vaccine Adverse Effect Reporting System (VAERS), the Vaccine Safety Datalink, the Department of Education database, and the California Department of Social Services database. He then subjected Dr. Geier's conclusion, that thimerosal in vaccines causes autism in a small number of genetically susceptible individuals, to Frye-Reed scrutiny. Judge Berger began by observing that the only published epidemiological studies purporting to show a causal link between thimerosal-containing vaccines and autism were the studies undertaken by Dr. Mark Geier and his son, Dr. David Geier, which suggested that the VAERS database could be extrapolated to show a causal connection between thimerosal and autism. He recognized the distinction between the use of data that is scientifically accepted and analysis purportedly based on that data, when the analysis employed is inappropriate to the data produced, which is dependent on the context in which it was produced and the hypothesis under scrutiny: It is significant to this Court that the IOM Committee criticized the technique utilized in [one of the Geier studies] ... expressly noting that: VAERS cannot be used to calculate incidence rates because the VAERS database does not have complete reporting of all adverse events and because many report events lack a confirmed diagnosis or confirmed attribution to vaccine. Admittedly, Dr. Geier acknowledged that [this study] is controversial. Indeed, the American Academy of Pediatrics (AAP), in a May, 2003 posting to their website, strongly denounced the Geier and Geier publication . . . stating: This paper uses data from the [VAERS] inappropriately and contains numerous conceptual and scientific flaws, omissions of fact, inaccuracies, and misstatements . . . . fail[ing] to acknowledge the inherent limitations of the VAERS database when drawing conclusions of adverse event associations . . . [and] [c]omparing the occurrence of late onset, chronic conditions like autism by using acute vaccine reactions like fever, pain and vomiting (presumably attributable to other vaccine components) as controls makes no sense as a measure of relative adverse event rates. Dr. Geier presented several additional publications that also contained studies in which the Geiers compared adverse event reports filed with VAERS with regard to thimerosal-containing and thimerosal-free vaccines. In each of the studies, Geier and Geier continued assigning (despite the absence of total mercury exposive data), a higher cumulative thimerosal total to one group of children (those who filed a VAERS report regarding a TCV) than the other group (those who filed a VAERS report regarding a thimerosal-free vaccine.) As a result, Geier and Geier concluded that the greater the total exposure to mercury from thimerosal, the greater the risk of neurological disorders. Critically, with regard to the pre-2004 published Geier and Geier VAERS database studies, the [IOM] opined: (1) [t]he three studies have serious methodological limitations that make their results uninterpretable; (2) [t]he results of their studies are likewise improbable; (3) [t]he articles also lack a complete and transparent description of their methods and underlying data, making it difficult to confirm or evaluate their findings. Accordingly, the 2004 IOM Committee concluded that the Geier and Geier VAERS studies were not helpful with regard to the causation issue it considered, that is, whether thimerosal-containing vaccines can cause autism or autistic spectrum disorders. The 2004 IOM Committee Report concluded: As a result of these significant methodological limitations, the committee finds the results of [Geier and Geier's] studies to be uninterpretable and, as such, they are noncontributory with respect to causality. In addition, Geier and Geier analyzed the VSP database on no less than two occasions. The Geiers presented to the 2004 IOM Committee an unpublished analysis of USD data, but did not describe the basis for their calculation or their methods leading the 2004 IOM Committee to conclude that it found the results of their analysis using VSP data uninterpretable, primarily due to the lack of a complete description of their methods. Finally, the 2004 IOM Report reviewed Geier and Geier's Department of Education database and found that [t]hese studies are characterized by serious methodological problems. Judge Berger concluded that, as a result of flawed analysis of acceptable data, Dr. Geier's epidemiological studies did not pass scrutiny under Frye-Reed: In sum, the plaintiffs rely on Dr. Geier's six epidemiological studies that purport to find an association between thimerosal in vaccines and autism. However, this Court finds that Dr. Geier's epidemiological studies do not constitute generally accepted bases for plaintiffs' causation opinions inasmuch as those studies have been rejected by the relevant scientific community due to severe methodological flaws that render them unreliable. Indeed, the venerable IOM Committee concluded that Dr. Geier's studies were not only flawed methodologically, but uninterpretable. and therefore noncontributory.     As a result, this Court finds expressly that Dr. Geier's epidemiological studies are not generally accepted in the scientific community because they utilize a methodology that is fundamentally flawed.    For the purposes of the Frye-Reed test, the relevant scientific community includes the full community of scientists with sufficient training and expertise to permit them to comprehend novel scientific methods, and may not properly be restricted to those who practice or otherwise adhere to the methods at issue. Reed v. United States [State], supra, 283 Md. at 444, 391 A.2d 364. For the reasons stated in this Memorandum Opinion, the plaintiffs have failed to satisfy their burden of proof under Frye-Reed, because they have failed to show that the methodologies underlying their expert witness' opinions are generally accepted to be reliable in the relevant scientific community. The consensus of the scientific community with expertise relevant to the issue of general causation in this case is reflected by the comprehensive and venerable report published by the Institute of Medicine in 2004. Moreover, other organizations have issued statements that comport with the comprehensive analysis supplied in the 2004 IOM Committee Report.    It is well established that where an expert witness offers a novel medical theory of causation, the bases of the expert's opinion, including the theory of causation, and the methodologies, must all be generally accepted or reliable in the relevant scientific community. See Montgomery Mut. Ins. Co. v. Chesson, supra, 399 Md. at 327, 923 A.2d 939 (2007). This Court finds that it is generally accepted in the relevant scientific community that autism is genetic in origin except in rare instances of prenatal exposures to certain substances at defined periods during pregnancy. Further, for the reasons explicated in this Memorandum Opinion, this Court notes that it is generally accepted in the relevant scientific community that thimerosal in vaccines does not cause or contribute to neurodevelopmental disorders such as autism. Critical to this Court's analysis is the 2004 IOM Report. IOM Reports are highly regarded in the relevant scientific community, and their reliability has been recognized by numerous courts.... After careful consideration by this Court, the 2004 Committee's finding that the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism is generally accepted in the relevant scientific community. After reviewing the testimony and evidence, this Court finds that the fields of epidemiology and toxicology and genetics are central to many of the issues in this case, including the causation issues that have been presented in this proceeding. For the reasons stated in this Memorandum Opinion, Dr. Geier's epidemiological studies purporting to show an association between thimerosal-containing vaccines and autism were not conducted in accordance with generally accepted epidemiological methods. (Emphasis added). Although we have not in the past had occasion to scrutinize the analytical phase of a scientific process underlying a novel scientific opinion, where the underlying data may otherwise be generally accepted in the scientific community, various federal courts have had occasion to scrutinize the reliability of the analytical framework utilized by an expert in formulating a novel theory of science, and to them we turn, recognizing that they utilized the Daubert standard rather than Frye. [19] We explore what they have opined, nevertheless, when they are speaking about reliability. The Supreme Court in General Electric Company v. Joiner, 522 U.S. 136, 118 S.Ct. 512, 139 L.Ed.2d 508 (1997), recognized that the analysis employed by an expert must be reliable. In Joiner, an electrician, alleging that his small cell lung cancer was caused by exposure to polychlorinated biphenyls (PCBs) and to furans and dioxins (PCB derivatives), sued the manufacturers of the products and attempted to introduce expert testimony linking his exposure to the chemicals to his small cell lung cancer. The trial judge excluded the testimony, reasoning that the expert's conclusions did not rise above subjective belief or unsupported speculation, Joiner v. General Electric Co., 864 F.Supp. 1310, 1326 (N.D.Ga.1994), and then granted summary judgment in favor of the manufacturer. The Court of Appeals for the Eleventh Circuit reversed, Joiner v. General Electric Co., 78 F.3d 524, 533 (11th Cir.1996), holding that the District Court should not have excluded expert testimony that merely drew different conclusions from the research than did each of the experts, and that the court should have permitted the jury to decide the correctness of competing expert opinions. The Supreme Court reversed the Eleventh Circuit and excluded the expert's testimony. The Court recognized that the analysis of data or extrapolation requires more than mere conjecture to pass reliability scrutiny: [Joiner] claims that because the District Court's disagreement was with the conclusion that the experts drew from the studies, the District Court committed legal error and was properly reversed by the Court of Appeals. But conclusions and methodology are not entirely distinct from one another. Trained experts commonly extrapolate from existing data. But nothing in either Daubert or the Federal Rules of Evidence requires a district court to admit opinion evidence that is connected to existing data only by the ipse dixit of the expert. A court may conclude that there is simply too great an analytical gap between the data and the opinion proffered. Joiner, 522 U.S. at 146, 118 S.Ct. at 519, 139 L.Ed.2d at 518-19, citing Turpin v. Merrell Dow Pharmaceuticals, Inc., 959 F.2d 1349, 1360-61 (6th Cir.1992) (When [t]he analytical gap between the evidence presented and the inferences to be drawn on the ultimate issue of human birth defects is too wide . . . . a jury should not be asked to speculate on the issue of causation.). In calling attention to the analytical gap between existing data and the opinion proffered by an expert, the Court admonished against reliance solely on an expert's word that his conclusion is appropriate to the underlying data and methods. Id. This concept of analytical gap had been employed by federal courts before Joiner, see Lust v. Merrell Dow Pharmaceuticals, Inc., 89 F.3d 594, 598 (9th Cir. 1996) (When a scientist claims to rely on a method practiced by most scientists, yet presents conclusions that are shared by no other scientist, the [trial] court should be wary that the method has not been faithfully applied.), and even before Daubert. See Christophersen v. Allied-Signal Corp., 939 F.2d 1106, 1115 (5th Cir.1991) (en banc) (When analyzing the validity of an expert's methodology, we seek to determine whether it connects the facts to the conclusion in a scientifically valid way. We answer this question by applying the Frye test: whether the methodology or reasoning that the expert uses to connect the facts to his conclusion is generally accepted within the relevant scientific community.). Since Joiner, the concept of the analytical gap also has been applied by numerous federal appellate courts. See, e.g., Bland v. Verizon Wireless, L.L.C., 538 F.3d 893, 898 (8th Cir.2008) (affirming a trial judge's exclusion of expert testimony from plaintiff's treating physician, who linked plaintiff's exercised-induced asthma to her inhalation and ingestion of freon that was allegedly sprayed into her water bottle by a Verizon employee, and holding that there was simply too great an analytical gap between the data identified and [the expert's] proffered opinion because the expert lacked knowledge regarding what level of exposure to freon constitutes an appreciable risk of causing asthma and the specific concentration and degree of [plaintiff's] exposure to the freon); Ruggiero v. Warner-Lambert Co., 424 F.3d 249, 254-255 (2d Cir.2005) (excluding expert testimony that medication was capable of causing or exacerbating cirrhosis because the expert's failure to consider other causes when employing differential diagnosis created too great an analytical gap between the data and the opinion proffered); United States v. Mamah, 332 F.3d 475, 478 (7th Cir.2003) (discussing the analytical gap when holding, [t]he problem with the proposed testimony in this case does not lie in the quality of [the experts'] research .... [but in] the absence of an empirical link between that research and the opinion that [defendant] likely gave a false confession). The analytical gap concept also has been employed by some of our sister states in a Frye analysis. In Goeb v. Tharaldson, 615 N.W.2d 800, 816 (Minn.2000), for example, the Minnesota Supreme Court upheld the exclusion of expert testimony because the methodology was unreliable and the conclusions proffered exhibited too great a leap from the data gathered. The Goebs had sued a pesticide applicator, Tharaldson, and Dow Chemical, the manufacturer, alleging that exposure to the insecticide Dursaban, after it was sprayed in the house into which they were moving, caused injury to them and their child. The Goebs offered the testimony of two experts, both of whom would have testified, based on the Goebs' medical records referring to adverse health affects, as well as on the toxic levels of the chemical chlorpyifos in their bodies, [20] that the Goebs were suffering from organophosphate [21] poisoning caused by their exposure to Dursaban. Id. at 806-08. Dow had argued that the experts' conclusion should be excluded under Frye because the Goebs' level of exposure was not factored into their analysis. After the expert testimony was excluded, the Goebs sought review, arguing that the experts' testimony had been based upon generally accepted methodologies. The court affirmed, accepting the contention that the experts had used generally accepted methods in completing their tests, but rejecting the experts' analysis when affirming the trial judge's conclusion that [the expert] made too great a leap to get from `mere exposure of an unquantified amount of Dursban' to his conclusions about appellants' illnesses. Id. at 816. See also Kane v. Motorola, Inc., 335 Ill.App.3d 214, 221-22, 268 Ill. Dec. 688, 779 N.E.2d 302 (2002) (discussing Joiner and the analytical gap concept when applying a Frye analysis). Generally accepted methodology, therefore, must be coupled with generally accepted analysis in order to avoid the pitfalls of an analytical gap. Dr. Geier's faulty extrapolation from VAERS data, a potentially reliable source, manifests the ipsa dixit identified in the Joiner opinion because his conclusion is ethereal. The conclusion is ethereal because the bases of the expert's opinion, including the theory of causation, and the methodologies, are not generally accepted as reliable within the expert's particular scientific field, see Chesson, 399 Md. at 327, 923 A.2d at 947, and the data he relies upon was not tested nor gathered for the purpose of testing the hypothesis that thimerosal in vaccines causes autism. None of Dr. Geier's research aimed at establishing a link between thimerosal and autism, moreover, is based upon sound methodology. See, e.g., Mark R. Geier & David A. Geier, Neurodevelopmental Disorders after Thimerosal-Containing Vaccines: A Brief Communication, 228 Experimental Biology and Med. 660, 660-64 (2003) (relying on VAERS data); Mark R. Geier & David A. Geier, Thimerosal in Childhood Vaccines, Neurodevelopment Disorders, and Heart Disease in the United States, 8 J. Am. Physicians and Surgeons, Spring 2003, at 6-11 (relying on VAERS data); David A. Geier & Mark R. Geier, An Assessment of the Impact of Thimerosal on Childhood Neurodevelopmental Disorders, 6 Pediatric Rehabilitation, Apr.-June 2003, at 97-102 (relying on VAERS data); David A. Geier & Mark R. Geier, A Comparative Evaluation of the Effects of MMR Immunization and Mercury Doses from Thimerosal-Containing Childhood Vaccines on the Population Prevalence of Autism, 10 Med. Sci. Monitor, Mar. 2004, at P133-39 (relying on Department of Education data); David A. Geier & Mark R. Geier, Neurodevelopmental Disorders Following Thimerosal-Containing Childhood Immunizations: A Follow-Up Analysis, 23 Int'l J. of Toxicology 369, 369-376 (2004) (relying on VAERS data); Mark R. Geier & David A. Geier, The Potential Importance of Steroids in the Treatment of Autism Spectrum Disorders and Other Disorders Involving Mercury Toxicity, 64 Med. Hypotheses 946, 946-954 (2005) (merely suggesting a series of experiments that need to be conducted to potentially develop steroid treatments to reduce the affects of mercury poisoning); David A. Geier & Mark R. Geier, A Two Phased Population Epidemiological Study of the Safety of Thimerosal-Containing Vaccines: A Follow-Up Analysis, 11 Med. Sci. Monitor, Apr. 2005, at CR160-70 (relying on VAERS data); David A. Geier & Mark R. Geier, An Assessment of Downward Trends in Neurodevelopmental Disorders in the United States Following Removal of Thimerosal from Childhood Vaccines, 12 Med. Sci. Monitor, June 2006, at CR231-39 (relying on VAERS data); David A. Geier & Mark R. Geier, An Evaluation of the Effects of Thimerosal on Neurodevelopmental Disorders Reported Following DTP and Hib Vaccines in Comparison to DTPH Vaccine in the United States, 69 J. Toxicology and Envtl. Health 1481, 1481-95 (2006) (relying on VAERS data); David A. Geier & Mark R. Geier, A Meta Analysis Epidemiological Assessment of Neurodevelopmental Disorders Following Vaccines Administered from 1994 through 2000 in the United States, 27 Neuroendocrinology Letters, May 2006, at 401-13 (relying on VAERS data); David A. Geier & Mark R. Geier, A Clinical and Laboratory Evaluation of Methionine Cycle-Transsulfuration and Androgen Pathway Markers in Children with Autistic Disorders, 66 Hormone Research 182, 182-188 (2006) (studying 16 pre-pubertal children, 11 and under, with previously diagnosed autism and suggesting a possible interaction between a particular alpha-amino acid cycle, the methionine cycle-transsulfuration, and androgen pathways in some children with autism); David A. Geier & Mark R. Geier, A Prospective Assessment of Porphyrins in Autistic Disorders: A Potential Marker for Heavy Metal Exposure, 10 Neurotoxicity Research, Aug. 2006, at 57, 62 (studying urine samples of 37 children age-7 and under and concluding, [t]his study provides the first clinical evidence from Americans with [autism] that associates them with specific urinary porphyrin markers known to be associated with heavy metals.... The results ... provide insights into the apparent dose-response effect mercury exposure may have in some children with [autism], and suggest that additional research should be conducted to evaluate mercury exposure in [autism] ) (emphasis added); David A. Geier & Mark R. Geier, A Clinical Trial of Combined Anti-Androgen and Anti-Heavy Metal Therapy in Autistic Disorders, 27 Neuroendocrinology Letters, Oct. 2006, at 833-38 (administering the drugs LUPRON and CHEMET to 11 children to lower their androgen levels or heavy-metal levels respectively, and observing amelioration of autistic symptoms in some of those children obtaining reduced androgen levels). In attempting to avoid the pitfalls of postulating a direct causal link between thimerosal and autism, which would require accountability for those children who had been vaccinated without becoming autistic, Dr. Geier postulated an alternative hypothesisthat thimerosal in vaccines cause autism in certain genetically susceptible individuals. According to Judge Berger's findings, this hypothesis was apparently inspired by statements made in the 2001 and 2004 IOM Report that a link is biologically plausible, and that it is well settled that even a large well-designed epidemiological study might fail to detect the possibility that vaccines contribute to autism in some small subset of cases or very unusual circumstances. Two predicates of Dr. Geier's alternative theory are that (1) autism is associated with certain genesthe A1298C polymorphism in the MTHFR gene, the null polymorphism of the GSTMI gene, the I105V polymorphism of the GSTPI gene, the I114T, R197Q, and K268R polymorphisms in the NATZ gene, and an unspecified variant in the CYP3A4 gene; and (2) based on a differential diagnoses analysis, [22] Jamarr's neurological disorders were caused or exacerbated by his exposure to thimerosal because of his genetic susceptibility. We shall first address Judge Berger's factual findings with respect to these predicates, as well as the Blackwells' challenges thereto, under the clear error standard, [23] and then shall evaluate de novo Judge Berger's ultimate conclusionthat neither the genetic susceptibility theory nor the tests used to determine if Jamarr's autism was due to genetic susceptibility were generally accepted in the relevant scientific field. See Wilson, 370 Md. at 201-02 n. 5, 803 A.2d at 1040 n. 5. In rejecting the association of autism with certain gene polymorphisms identified by Dr. Geier, Judge Berger found that, although [t]he 2004 IOM Committee found that a genetic susceptibility could indeed constitute a `theoretical explanation' for the fact that reliable epidemiological studies have not found any association between thimerosal exposure and autism, it, nevertheless, found no corroborating data in the laboratory, in animals, or in humans, linking vaccines or vaccine components for autism based on genetic susceptibility. He also found that there is no evidence that the presence of these polymorphisms impairs the body's ability to excrete mercury. During oral argument before us, the Blackwells' attorney specifically challenged Judge Berger's generalized factual finding, that there is no evidence that any of the polymophisms identified by Dr. Geier are associated with autism, arguing that the Blackwells submitted three studies that provided such evidence: Steven Buyske, et al., Analysis of Case-Parent Trios at a Locus with a Deletion Allele: Association of GSTM1 with Autism, 7 BMC Genetics, Feb. 2006, at 1-16; G.A. Westphal, et al., Homozygous Gene Deletions of the Glutathione S-Transferases M1 and T1 Are Associated with Thimerosal Sensitization, 73 Inter. Archives of Occupational Health, 384, 384-88 (2000); and S. Jill James, et al., Metabolic Endophenotype and Related Genotypes Are Associated with Oxidative Stress in Children With Autism, 26 Am. J. of Med. Genetics 947, May 2006, at 947-56. Judge Berger made the contested statement in the following paragraph where he discussed his general findings with respect to Dr. Geier's identified polymorphisms: Autism is likely to involve multiple genes. Dr. Geier testified that the following genes are associated with autism: the A1298C polymorphism in the MTHFR gene; the null polymorphism of the GSTMI gene; the 1105V polymorphism of the GSTPI gene; the I114T, R197Q, and K268R polymorphisms in the NATZ gene; and an unspecified variant in the CYP3A4 gene. There is no evidence that any of the polymorphisms identified by Dr. Geier are associated with autism. None of the polymorphisms is generally accepted among clinical geneticists to be causes of autism. Further, despite the theories advanced by Dr. Geier, there is no evidence that the presence of these polymorphisms impairs the body's ability to excrete mercury. Judge Berger subsequently supported these general findings with specific findings: first, he found that there is no evidence that the A1298C polymorphism in the MTHFR gene is associated with autism, based on [a] 2004 study by Boris, et al., and a follow-up study by one of the co-authors of that 2004 study, Jill James (among others), both showed no statistically significant association between the MTHFR 1298A/C polymorphism and autism. See Marvin Boris et al., Association of MTHFR Gene Variants with Autism, 9 J. of Am. Physicians and Surgeons, Winter 2004, at 106, 107; James, supra at 951. Judge Berger next found that it is well established that common genetic polymorphisms that vary across ethnic groups, such as the MTHFR 1298A/C polymorphism, are not considered by geneticists to be candidates for causation of a disease, such as autism, that has equal prevalence among ethnic groups, observing that the MTHFR 1298A/C polymorphism exhibited this variance according to a Single Nucleotide Polymorphism Cluster Report database. [24] Judge Berger then addressed Dr. Geier's identification of the null polymorphism, finding: The GSTMI null polymorphism refers to a condition in which the GSTMI gene is missing. The purported association between the GSTMI polymorphism and autism has been investigated and rejected in several studies. No study has found an association between the GSTMI null polymorphism and autism. Further, there is no evidence that the absence of the GSTMI gene is associated with autism. He based this determination primarily on studies by James, supra, at 947-56, and Buyske, supra, at 1-16. The existence of articles from Buyske, Westphal and James, proffered by the Blackwells, do not contradict, with any significance, Judge Berger's specific factual findings: Buyske's article, Analysis of Case-Parent Trios at a Locus with a Deletion Allele: Association of GSTM1 with Autism, defines what he considers to be the appropriate methodology to test for a possible association of a specific genotype with autism. Buyske, supra, at 1. Westphal's article, Homozygous Gene Deletions of the Glutathione S-Transferases M1 and T1 are Associated with Thimerosal Sensitization, discusses a study that he conducted, in which he tested allergic reactions to thimerosal in men and women over the age of 38, none of whom was identified as autistic; autism was not being studied. Westphal, supra, at 385. The James article, Metabolic Endophenotype and Related Genotypes are Associated with Oxidative Stress in Children With Autism, recognized its own limitation, [g]iven the relatively small number of cases and controls in the present study, and suggested that abnormal metabolic profile observed in a significant proportion of autistic children suggests the provocative possibility that some autistic behaviors could be a neurologic manifestation of a genetically based systemic metabolic derangement. James, supra, at 954 (italics in original). Clearly, this article suggests a hypothesis for further testinga hypothesis which does not bear on any purported relationship between thimerosal and autism. Judge Berger supported his general finding that there was, no evidence that any of the polymorphisms identified by Dr. Geier are associated with autism, with articles specifically addressing polymorphisms identified by Geier; he did not err in his finding. In rejecting the methodology utilized by Dr. Geier of differential diagnosis to arrive at a genetic susceptibility thesis, Judge Berger recognized that differential diagnosis is a methodology by which the cause of a medical problem is identified by considering and then ruling out the potential causes until the most probable cause remains. According to Judge Berger, Dr. Geier had performed urinary porphyrin, [25] mercury toxicity, testosterone and genetic polymorphism [26] tests, but that none of them is generally accepted by the medical community, including clinical geneticists and pediatricians, as appropriate tests for either the work-up of a patient with autism or to determine the underlying cause of autism. Noting as well that Dr. Geier's differential diagnosis methodology fail[ed] to even consider the single most important alleged cause of autismunknown geneticsJudge Berger concluded that causation opinions on the etiology of autism cannot be based on a differential diagnosis that includes thimerosal as a potential cause of autism because the science does not support the plaintiffs' purported theory of a causal connection between thimerosal-containing vaccines and autism: Further, Dr. Geier performed a differential diagnosis in this proceeding. It is generally accepted in the relevant scientific community that differential diagnosis is a methodology by which the cause of a medical problem is identified [by] considering and then ruling out the potential causes until the most probable cause remains. It is well settled that [g]enerally, it is not appropriate to rely on a differential diagnosis to prove general causation. See Doe v. Ortho-Clinical Diagnostics, Inc., 440 F.Supp.2d 465, 477 (M.D.N.C.2006), citing, Riggiero [Ruggiero] v. Warner-Lambert Co., 424 F.3d 249, 254 (2d Cir.2005). Indeed, [a] differential diagnosis that fails to take serious account of other potential causes may be so lacking that it cannot provide a reliable basis for an opinion. Doe v. Ortho-Clinical Diagnostics, Inc., supra, 440 F.Supp.2d at 471, quoting Roche v. Lincoln Property Co., 278 F.Supp.2d 744, 751 (E.D.Va.2003), aff'd 175 Fed.Appx. 597, 603 (4th Cir.2006). It is noteworthy that other courts have acknowledged that Dr. Geier's methodology of differential diagnosis is fundamentally flawed, because he improperly rules in thimerosal as a potential cause of autism, and he cannot rule out the high likelihood that autism in any given individual was caused purely by genetic factors that do not require an environmental trigger. See e.g. Doe v. Ortho-Clinical Diagnostics, Inc., supra, 440 F.Supp.2d [465] 405 (M.D.N.C.2006) (excluding Dr. Geier's differential diagnosis); Redfoot v. [B.F.] Ascher [& Co.], No. C 05 2045 PJH, 2007 WL 1593239 at 11. (Emphasis added). The Blackwells contest Judge Berger's finding of fact that Dr. Geier failed even to consider the single most important alleged cause of autism[unknown genetics]when conducting differential diagnosis, arguing that Dr. Geier addressed genetics as a possible cause and that it is not generally accepted in the relevant scientific community that unknown genetics is the single most important alleged cause of this disorder. The Blackwells assert that Dr. Geier considered genetics and genetic interactions, but that, according to Dr. Geier, unknown genetics account for less than 5% of autism cases, and he need not discount all possible causes. Conversely, Wyeth's expert, Dr. Yeboa, opined that unknown genetics constitutes the most cases of autism, a premise supported by the 2004 IOM Report (Autism is a very complex disorder. A strong genetic component clearly exists. . . . As yet a biological marker specific for autism has not been defined. It is possible that Autism encompasses a spectrum of disease subtypes that have different etiologies.), as well as other articles proffered to Judge Berger by both the Blackwells and Wyeth. See, e.g., Boris, supra, at 106-07 (Autism is a complex neurodevelopment disorder with numerous possible genetic and environmental influences. . . . A search for additional genomic and environmental risk factors should be undertaken. . . . It is unlikely that any single polymorphism accounts for the majority of autistic risk factors.); Fatema J. Serajee et al., Polymorphisms in Xenobiotic Metabolism Genes and Autism, 19 J. of Child Neurology, June 2004, at 413, 413 (2004) (Although there is an underlying genetic predisposition, the etiology of autism is currently unknown.); A. Bailey, et al., Autism as a Strongly Genetic Disorder: Evidence from a British Twin Study, 25 Psychological Med. 63, 63 (1995); Lorna Wing & David Potter, The Epidemiology of Autistic Spectrum Disorders: Is the Prevalence Rising?, 8 Mental Retardation and Developmental Disabilities Res. Rev. 151, 152 (2002) (As a result of the ever growing list of studies, autism is now seen as a disorder of the developing brain, mainly genetic in origin and part of a wider spectrum of disorders.). Judge Berger did not err in finding that a gene or series of interacting genes that have not yet been identified is the most prevalent alleged cause of autism, based upon our review of the record. We agree that Dr. Geier did not sufficiently consider genetics in his differential diagnosis equation. This conclusion is similar to that reached in Wilson, in which we recognized that the State's expert, in applying the product rule, did not account for a genetic linkage between siblings, who may have died of SIDS, rather than been murdered by their father. Based on Judge Berger's rejection of Dr. Geier's underlying hypothesis and methodology, i.e. the identification of specific genes and differential diagnosis, we hold that Judge Berger's ultimate determinationthat Dr. Geier's genetic susceptibility theory is no more than hypothesis and conjecture, devoid of a generally accepted methodology to support itshould not be disturbed by us.