Due in part to shortages of health care professionals with expertise in genetics, primary care ph... more Due in part to shortages of health care professionals with expertise in genetics, primary care physicians will assume a greater role in providing frontline genetic services as genetic tests for more diseases become available. I report some preliminary findings from a national survey of primary care physicians, psychiatrists, medical geneticists and genetic counselors. As expected, no group of nongenetics specialists had as much knowledge as geneticists. Nongeneticist physicians with the greatest exposure to patients with genetic problems had more knowledge than physicians without such exposure. Non-geneticist physicians were more likely to be directive in counseling than geneticists. Problems for future research are enumerated.
September 30, 2014, marks the 50th anniversary of the Children’s Bureau recommendation for “the s... more September 30, 2014, marks the 50th anniversary of the Children’s Bureau recommendation for “the screening of all newborn infants for PKU [phenylketonuria] on a routine basis.”1 By 1968, 43 states had made screening for PKU mandatory.1 As a result of technological advances, newborn screening in the United States has been extended to as many as 37 core conditions in some states.2 As reported by Kwan and colleagues3 in this issue of JAMA, newborn screening for severe combined immunodeficiency (SCID) has been undertaken in 23 states and the Navajo Nation, beginning in Wisconsin in January 2008. The authors present data on more than 3 million newborns screened with a T-cell receptor excision circle (TREC) assay followed by confirmatory flow cytometry from 11 of these programs (10 states and the Navajo Nation). Have these programs absorbed lessons from the first 50 years of newborn screening? In 1975, a committee of the National Academy of Sciences considered the lessons of the first 10 years. The committee noted: “Screening was started, frequently under mandatory laws, when questions regarding diagnosis, prognosis, and optimal management were unanswered.”1 Each of these questions with regard to SCID screening deserves examination. Diagnosis. Because tests that diagnose a disorder with perfect validity are often expensive and sometimes lengthy to perform, screening tests suitable for entire populations almost always yield false-positive test results requiring costly recall of healthy infants, perturbing them and their parents unnecessarily. This wide net is cast to ensure that infants who have the disorder and whose initial screening test result can vary are not missed by screening (false negatives). In the study by Kwan et al,3 of the 11 programs providing data on SCID screening, the cutoff in the TREC assay was set at less than 40 TREC/μL in 8 programs and less than 252 TREC/μL in 3 programs. Excluding the Navajo Nation, in which a founder effect mutation in the DCLRE1C gene increased the incidence of SCID to 1 in 3500, the data reported by Kwan et al yield a ratio of total TREC-positive results to SCID infants detected by confirmatory tests to be 91.1 (291.7 referrals for flow cytometry per 100 000 screened/3.2 mean SCID diagnosed per 100 000 screened) in the 7 programs with the most stringent cutoffs (<40 TREC/μL) compared with 170.5 (255.8 referrals/ 1.5 diagnosed) in the 3 programs with the more inclusive cutoffs (<252 TREC/μL). In the study, no infants with SCID were missed by screening. However, the authors did not report the actual TREC results of the infants diagnosed with SCID, so the extent to which lowering the cutoffs will reduce the number of false-positive infants without missing infants with SCID cannot be ascertained. The data are currently under analysis in the R4S project, which incorporates factors in addition to the TREC result to identify “presumptive positive” infants for referral for definitive diagnosis.4 This method should reduce the number of false positives for SCID without increasing the number of false negatives (Piero Rinaldo, Mayo Clinic College of Medicine, written communication, July 4, 2014). The TREC assay, based on real-time polymerase chain reaction to detect the small piece of DNA that is excised from lymphocytes when they become T cells, resulted in the detection of 52 infants with SCID involving 11 different genes. In 8 of the 52, no known SCID mutation was found. Thus, the phenotypic TREC assay has proven more efficient than single-gene assays and is much less costly than whole-genome sequencing, which might miss mutations previously unknown to cause SCID. The observed SCID incidence of 1 in 58 000 births reported by Kwan et al3 is greater than the previously assumed incidence based on clinical detection and exceeds the criterion of a US panel that a condition should have an incidence of greater than 1 in 100 000 to qualify for inclusion in newborn screening.5 Prognosis. The ability to improve outcomes is a cardinal criterion for screening and there is no doubt that newborn SCID screening has saved lives and improved their quality. In the report by Kwan et al,3 of the 52 SCID infants diagnosed, 49 received immunity restoring therapies, of whom 45 survived (92%). The early deaths of 3 infants who were not treated were attributable to other conditions. Without early detection by screening, some of the survivors most likely would have died, some of them without a diagnosis. Of the 411 infants with nonSCID T-cell lymphopenia, only 4 were treated. This small proportion justifies the authors’ conclusion that the “usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.” Optimal Management. For disorders like SCID that may be fatal in the first months of life, early screening and prompt diagnosis are essential. The authors observed that 175 infants with “a nonnormal TREC... died before further testing could be done.” They…
This study demonstrates the feasibility of a randomized controlled investigation of terminating t... more This study demonstrates the feasibility of a randomized controlled investigation of terminating the phenylalanine-restricted diet in four-year-old children with phenylketonuria. The parents of 14 of 16 children gave informed consent, knowing their children would be randomly assigned to either a diet-continuation or a diet-termination group. Compared with the continuation group, the mean serum phenylalanine of the termination group was 15.1 mg per dl higher (P less than 0.005) one year, and 9.2 mg per dl higher (P less than 0.025) two years after diet termination. Mean weight gain between four and six years of age was 3.4 kg greater in the terminated than in the continued group (P less than 0.01). There were no significant differences in mean head circumferences, height or performances on psychologic tests. At age six, mean I.Q. in the terminated group was 99.8, in those continuing the diet 103.6. Children in both groups showed some subtest scatter in memory and concentration. Thus, no harmful effects of diet termination were noted, but a longer period of observation in a larger number of subjects is needed.
The presented book we offer here is not kind of usual book. You know, reading now doesn't mea... more The presented book we offer here is not kind of usual book. You know, reading now doesn't mean to handle the printed book in your hand. You can get the soft file of backdoor to eugenics in your gadget. Well, we mean that the book that we proffer is the soft file of the book. The content and all things are same. The difference is only the forms of the book, whereas, this condition will precisely be profitable.
In the guidance to its ‘Code of Practice on Human Genetic Testing Services Supplied Direct to the... more In the guidance to its ‘Code of Practice on Human Genetic Testing Services Supplied Direct to the Public’, the United Kingdom’s Advisory Committee on Genetic Testing allows the public to obtain carrier testing for inherited recessive disorders direct from suppliers, including commercial laboratories. For other types of genetic testing, involvement of a medical practitioner is needed. Thus the Committee creates two spheres of genetic testing, the first for which it maintains that there are ‘no significant direct health implications for the customer’ and the second for which there are. This is an unwarranted distinction. By permitting people who can afford to pay for the test the opportunity to obtain it direct from the supplier, the Code contributes to two tiers of access to carrier testing. The first tier is available to those who can afford the supplier’s price. Everyone else falls into the second tier, being able to obtain the test only through the National Health Service (NHS). At present, the NHS covers carrier testing for relatives of patients with cystic fibrosis, not for the general public. In this situation, a two-tier system could widen disparities in health between rich and poor.
In many infants with phenylketonuria (PKU) the concentration of blood phenylalanine rises only mi... more In many infants with phenylketonuria (PKU) the concentration of blood phenylalanine rises only minimally during the first three days of life and infants of both sexes may be missed by screening. During this period the rate of rise of blood phenylalanine is slower in females than in males and, on the fourth day of life, significantly more males than females are discovered by screening. The ratio of males to females who are screened on the fourth day is not higher than on the previous days. The large proportion of all infants who were screened on the fourth day of life probably accounts for the previously described excess of males; females are being missed. In 12 states providing data 44.4% of all infants were screened on one of the first three days of life and 25% on the fourth day.
This book describes the methods of recombinant DNA analysis and outlines its uses in the diagnosi... more This book describes the methods of recombinant DNA analysis and outlines its uses in the diagnosis, treatment, and prevention of genetic diseases, hinting also at applications in diagnosis and prevention of the common disorders of adult life. Sections are also devoted to the products of the biotechnology companies and the impact of their uses.
Due in part to shortages of health care professionals with expertise in genetics, primary care ph... more Due in part to shortages of health care professionals with expertise in genetics, primary care physicians will assume a greater role in providing frontline genetic services as genetic tests for more diseases become available. I report some preliminary findings from a national survey of primary care physicians, psychiatrists, medical geneticists and genetic counselors. As expected, no group of nongenetics specialists had as much knowledge as geneticists. Nongeneticist physicians with the greatest exposure to patients with genetic problems had more knowledge than physicians without such exposure. Non-geneticist physicians were more likely to be directive in counseling than geneticists. Problems for future research are enumerated.
September 30, 2014, marks the 50th anniversary of the Children’s Bureau recommendation for “the s... more September 30, 2014, marks the 50th anniversary of the Children’s Bureau recommendation for “the screening of all newborn infants for PKU [phenylketonuria] on a routine basis.”1 By 1968, 43 states had made screening for PKU mandatory.1 As a result of technological advances, newborn screening in the United States has been extended to as many as 37 core conditions in some states.2 As reported by Kwan and colleagues3 in this issue of JAMA, newborn screening for severe combined immunodeficiency (SCID) has been undertaken in 23 states and the Navajo Nation, beginning in Wisconsin in January 2008. The authors present data on more than 3 million newborns screened with a T-cell receptor excision circle (TREC) assay followed by confirmatory flow cytometry from 11 of these programs (10 states and the Navajo Nation). Have these programs absorbed lessons from the first 50 years of newborn screening? In 1975, a committee of the National Academy of Sciences considered the lessons of the first 10 years. The committee noted: “Screening was started, frequently under mandatory laws, when questions regarding diagnosis, prognosis, and optimal management were unanswered.”1 Each of these questions with regard to SCID screening deserves examination. Diagnosis. Because tests that diagnose a disorder with perfect validity are often expensive and sometimes lengthy to perform, screening tests suitable for entire populations almost always yield false-positive test results requiring costly recall of healthy infants, perturbing them and their parents unnecessarily. This wide net is cast to ensure that infants who have the disorder and whose initial screening test result can vary are not missed by screening (false negatives). In the study by Kwan et al,3 of the 11 programs providing data on SCID screening, the cutoff in the TREC assay was set at less than 40 TREC/μL in 8 programs and less than 252 TREC/μL in 3 programs. Excluding the Navajo Nation, in which a founder effect mutation in the DCLRE1C gene increased the incidence of SCID to 1 in 3500, the data reported by Kwan et al yield a ratio of total TREC-positive results to SCID infants detected by confirmatory tests to be 91.1 (291.7 referrals for flow cytometry per 100 000 screened/3.2 mean SCID diagnosed per 100 000 screened) in the 7 programs with the most stringent cutoffs (<40 TREC/μL) compared with 170.5 (255.8 referrals/ 1.5 diagnosed) in the 3 programs with the more inclusive cutoffs (<252 TREC/μL). In the study, no infants with SCID were missed by screening. However, the authors did not report the actual TREC results of the infants diagnosed with SCID, so the extent to which lowering the cutoffs will reduce the number of false-positive infants without missing infants with SCID cannot be ascertained. The data are currently under analysis in the R4S project, which incorporates factors in addition to the TREC result to identify “presumptive positive” infants for referral for definitive diagnosis.4 This method should reduce the number of false positives for SCID without increasing the number of false negatives (Piero Rinaldo, Mayo Clinic College of Medicine, written communication, July 4, 2014). The TREC assay, based on real-time polymerase chain reaction to detect the small piece of DNA that is excised from lymphocytes when they become T cells, resulted in the detection of 52 infants with SCID involving 11 different genes. In 8 of the 52, no known SCID mutation was found. Thus, the phenotypic TREC assay has proven more efficient than single-gene assays and is much less costly than whole-genome sequencing, which might miss mutations previously unknown to cause SCID. The observed SCID incidence of 1 in 58 000 births reported by Kwan et al3 is greater than the previously assumed incidence based on clinical detection and exceeds the criterion of a US panel that a condition should have an incidence of greater than 1 in 100 000 to qualify for inclusion in newborn screening.5 Prognosis. The ability to improve outcomes is a cardinal criterion for screening and there is no doubt that newborn SCID screening has saved lives and improved their quality. In the report by Kwan et al,3 of the 52 SCID infants diagnosed, 49 received immunity restoring therapies, of whom 45 survived (92%). The early deaths of 3 infants who were not treated were attributable to other conditions. Without early detection by screening, some of the survivors most likely would have died, some of them without a diagnosis. Of the 411 infants with nonSCID T-cell lymphopenia, only 4 were treated. This small proportion justifies the authors’ conclusion that the “usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.” Optimal Management. For disorders like SCID that may be fatal in the first months of life, early screening and prompt diagnosis are essential. The authors observed that 175 infants with “a nonnormal TREC... died before further testing could be done.” They…
This study demonstrates the feasibility of a randomized controlled investigation of terminating t... more This study demonstrates the feasibility of a randomized controlled investigation of terminating the phenylalanine-restricted diet in four-year-old children with phenylketonuria. The parents of 14 of 16 children gave informed consent, knowing their children would be randomly assigned to either a diet-continuation or a diet-termination group. Compared with the continuation group, the mean serum phenylalanine of the termination group was 15.1 mg per dl higher (P less than 0.005) one year, and 9.2 mg per dl higher (P less than 0.025) two years after diet termination. Mean weight gain between four and six years of age was 3.4 kg greater in the terminated than in the continued group (P less than 0.01). There were no significant differences in mean head circumferences, height or performances on psychologic tests. At age six, mean I.Q. in the terminated group was 99.8, in those continuing the diet 103.6. Children in both groups showed some subtest scatter in memory and concentration. Thus, no harmful effects of diet termination were noted, but a longer period of observation in a larger number of subjects is needed.
The presented book we offer here is not kind of usual book. You know, reading now doesn't mea... more The presented book we offer here is not kind of usual book. You know, reading now doesn't mean to handle the printed book in your hand. You can get the soft file of backdoor to eugenics in your gadget. Well, we mean that the book that we proffer is the soft file of the book. The content and all things are same. The difference is only the forms of the book, whereas, this condition will precisely be profitable.
In the guidance to its ‘Code of Practice on Human Genetic Testing Services Supplied Direct to the... more In the guidance to its ‘Code of Practice on Human Genetic Testing Services Supplied Direct to the Public’, the United Kingdom’s Advisory Committee on Genetic Testing allows the public to obtain carrier testing for inherited recessive disorders direct from suppliers, including commercial laboratories. For other types of genetic testing, involvement of a medical practitioner is needed. Thus the Committee creates two spheres of genetic testing, the first for which it maintains that there are ‘no significant direct health implications for the customer’ and the second for which there are. This is an unwarranted distinction. By permitting people who can afford to pay for the test the opportunity to obtain it direct from the supplier, the Code contributes to two tiers of access to carrier testing. The first tier is available to those who can afford the supplier’s price. Everyone else falls into the second tier, being able to obtain the test only through the National Health Service (NHS). At present, the NHS covers carrier testing for relatives of patients with cystic fibrosis, not for the general public. In this situation, a two-tier system could widen disparities in health between rich and poor.
In many infants with phenylketonuria (PKU) the concentration of blood phenylalanine rises only mi... more In many infants with phenylketonuria (PKU) the concentration of blood phenylalanine rises only minimally during the first three days of life and infants of both sexes may be missed by screening. During this period the rate of rise of blood phenylalanine is slower in females than in males and, on the fourth day of life, significantly more males than females are discovered by screening. The ratio of males to females who are screened on the fourth day is not higher than on the previous days. The large proportion of all infants who were screened on the fourth day of life probably accounts for the previously described excess of males; females are being missed. In 12 states providing data 44.4% of all infants were screened on one of the first three days of life and 25% on the fourth day.
This book describes the methods of recombinant DNA analysis and outlines its uses in the diagnosi... more This book describes the methods of recombinant DNA analysis and outlines its uses in the diagnosis, treatment, and prevention of genetic diseases, hinting also at applications in diagnosis and prevention of the common disorders of adult life. Sections are also devoted to the products of the biotechnology companies and the impact of their uses.
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