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Question: How are thalassemias classified?

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Context 1: Thalassaemia minor | definition of Thalassaemia minor by Medical dictionary
Thalassaemia minor | definition of Thalassaemia minor by Medical dictionary
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Related to Thalassaemia minor: thalassaemia major
Thalassemia describes a group of inherited disorders characterized by reduced or absent amounts of hemoglobin, the oxygen-carrying protein inside the red blood cells  There are two basic groups of thalassemia disorders: alpha thalassemia and beta thalassemia  These conditions cause varying degrees of anemia, which can range from insignificant to life threatening 
All types of thalassemias are considered quantitative diseases of hemoglobin, because the quantity of hemoglobin produced is reduced or absent  Usual adult hemoglobin is made up of three components: alpha globin, beta globin, and heme  Thalassemias are classified according to the globin that is affected, hence the names alpha and beta thalassemia  Although both classes of thalassemia affect the same protein, the alpha and beta thalassemias are distinct diseases that affect the body in different ways 
Beta thalassemia may be the most best-known type of thalassemia and is also called Cooley's anemia  It is caused by a change in the gene for the beta globin component of hemoglobin  Beta thalassemia causes variable anemia that can range from moderate to severe, depending in part on the exact genetic change underlying the disease  Beta thalassemia can be classified based on clinical symptoms  Beta thalassemia major usually causes severe anemia that can occur within months after birth  If left untreated, severe anemia can result in insufficient growth and development, as well as other common physical complications that can lead to a dramatically decreased life-expectancy  Fortunately, in developed countries beta thalassemia is usually identified by screening in the newborn period, before symptoms have developed  Children who are identified early can be started on ongoing blood transfusion therapy as needed  Although transfusion therapy prevents many of the complications of severe anemia, the body is unable to eliminate the excess iron contained in the transfused blood  Over time, the excess iron deposits in tissues and organs, resulting in damage and organ failure  Another medication must be administered to help the body eliminate the excess iron and prevent iron-over-load complications  Beta thalassemia intermedia describes the disease in individuals who have moderate anemia that only requires blood transfusions intermittently, if at all 
Alpha thalassemia is the result of changes in the genes for the alpha globin component of hemoglobin  There are two main types of alpha thalassemia disease: hemoglobin H disease and alpha thalassemia major  The two diseases are quite different from beta thalassemia as well as from one another  Individuals with hemoglobin H disease can experience events of hemolytic anemia—anemia caused by the rapid breakdown of the red blood cells  These events are thought to be triggered by various environmental causes, such as infection and/or exposure to certain chemicals  Hemoglobin H disease is in most cases milder than beta thalassemia  It does not generally require transfusion therapy  Alpha thalassemia major is a very serious disease that results in severe anemia that begins even before birth  Most affected babies do not survive to be born or die shortly after birth 
The thalassemias are among the most common genetic diseases worldwide  Both alpha and beta thalassemia have been described in individuals of almost every ancestry, but the conditions are more common among certain ethnic groups  Unaffected carriers of all types of thalassemia traits do not experience health problems  In fact, the thalassemia trait is protective against malaria, a disease caused by blood-borne parasites transmitted through mosquito bites  According to a widely accepted theory, most genetic changes—mutations—that cause thalassemia occurred multiple generations ago  Coincidentally, these mutations increased the likelihood that carriers would survive malaria infection  Survivors passed the mutation onto their offspring, and the trait became established throughout areas where malaria is common  As populations migrated, so did the thalassemia traits 
Beta thalassemia trait is seen most commonly in people with the following ancestry: Mediterranean (including North African, and particularly Italian and Greek), Middle Eastern, Indian, African, Chinese, and Southeast Asian (including Vietnamese, Laotian, Thai, Singaporean, Filipino, Cambodian, Malaysian, Burmese, and Indonesian)  Alpha-thalassemia trait is seen with increased frequency in the same ethnic groups  However, there are different types of alpha thalassemia traits within these populations  The frequency of hemoglobin H disease and alpha thalassemia major depends on the type of alpha thalassemia trait  The populations in which alpha thalassemia diseases are most common include Southeast Asians and Chinese (particularly Southern Chinese) 
It is difficult to obtain accurate prevalence figures for various types of thalassemia within different populations  This difficulty arises due to testing limitations in determining exact genetic diagnoses, as well as the fact that many studies have focused on small, biased hospital populations 
Two studies reflect prevalence figures that can be helpful counseling families and determining who to screen for beta thalassemia  Between the years of 1990 and 1996, the State of California screened more than 3 1 million infants born in the state for beta thalassemia  Approximately 1 in 114,000 infants had beta thalassemia major, with prevalence rates being highest among Asian Indians (about one in 4,000), Southeast Asians (about one in 10,000), and Middle Easterners (about one in 7,000)  Another type of beta thalassemia disease, E/beta thalassemia, was represented in approximately one in 110,000 births, all of which occurred in families of Southeast Asian ancestry  Among Southeast Asians, the prevalence of E/beta thalassemia was approximately one in 2,600 births  This is in keeping with the observation that hemoglobin E trait carrier rates are relatively high within the Southeast Asian population: 16% in a study of 768 immigrants to California, and up to 25% in some specific Southeast Asian populations such as Cambodians  While these California studies address some of the limitations of earlier population studies, the pattern observed in California is expected to be different in other areas of the United States and the world  For example, Italians are underrepresented in this population when compared to the population of the East Coast of the United States 
Determining prevalence figures for alpha thalassemia is even more difficult due to increased limitations in diagnostic testing  All types of alpha thalassemia disease are most common among people of Southeast Asian and Chinese descent, for reasons that become clearer with an understanding of the underlying genetics of alpha thalassemia  One study of 500 pregnant women in Northern Thailand estimated a frequency of one in 500 pregnancies affected by alpha thalassemia major, for example  Prevalence of alpha thalassemia disease is significantly lower in the United States primarily because of immigration patterns; although at least one state, California, has observed growing hemoglobin H disease incidence rates that are high enough to justify universal newborn screening for the condition 
Humans normally make several types of the oxygen-carrying protein hemoglobin  An individual's stage in development determines whether he or she makes primarily embryonic, fetal, or adult hemoglobins  All types of hemoglobin are made of three components: heme, alpha (or alpha-like) globin, and beta (or beta-like) globin  All types of thalassemia are caused by changes in either the alpha- or beta-globin gene  These changes cause little or no globin to be produced  The thalassemias are, therefore, considered quantitative hemoglobin diseases  All types of thalassemias are recessively inherited, meaning that a genetic change must be inherited from both the mother and the father  The severity of the disease is influenced by the exact thalassemia mutations inherited, as well as other genetic and environmental factors  There are rare exceptions, notably with beta thalassemia, where globin gene mutations exhibit a dominant pattern of inheritance in which only one gene needs to be altered in order to see disease expression  Scientists continue to study the causes  For instance, a new mutation for alpha-thalassemia was discovered for the first time among Iranian patients in 2004 
BETA-THALASSEMIA  Most individuals have two normal copies of the beta globin gene, which is located on chromosome 11 and makes the beta globin component of normal adult hemoglobin, hemoglobin A  There are approximately 100 genetic mutations that have been described that cause beta thalassemia, designated as either beta0 or beta + mutations  No beta globin is produced with a beta0 mutation, and only a small fraction of the normal amount of beta globin is produced with a beta + mutation 
When an individual has one normal beta globin gene and one with a beta thalassemia mutation, he or she is said to carry the beta thalassemia trait  Beta thalassemia trait, like other hemoglobin traits, is protective against malaria infection  Trait status is generally thought not to cause health problems, although some women with beta thalassemia trait may have an increased tendency toward anemia during pregnancy 
When two members of a couple carry the beta thalassemia trait, there is a 25% chance that each of their children will inherit beta thalassemia disease by inheriting two beta thalassemia mutations, one from each parent  The clinical severity of the beta thalassemia disease—whether an individual has beta thalassemia intermedia or beta thalassemia major—will depend largely on whether the mutations inherited are beta0 thalassemia or beta + thalassemia mutations  Two beta0 mutations generally lead to beta thalassemia major, and two beta+ thalassemia mutations generally lead to beta thalassemia intermedia  Inheritance of one beta0 and one beta + thalassemia mutation tends to be less predictable 
Although relatively uncommon, there are other thalassemia-like mutations that can affect the beta globin gene  Hemoglobin E is the result of a substitution of a single nucleotide  This change results in a structurally altered hemoglobin that is produced in decreased amounts  Therefore, hemoglobin E is unique in that it is both a quantitative (i e  thalassemia-like) and qualitative trait  When co-inherited with a beta thalassemia trait, it causes a disease that is almost indistinguishable from beta thalassemia disease  Large deletions around and including the beta globin gene can lead to delta/beta thalassemia or hereditary persistence of fetal hemoglobin (HPFH)  Interestingly, delta/beta thalassemia trait behaves very similarly to beta thalassemia trait in its clinical manifestations  However, HPFH trait does not tend to cause hemoglobin disease when co-inherited with a second thalassemia or other beta globin mutation 
ALPHA-THALASSEMIA  Most individuals have four normal copies of the alpha globin gene, two copies on each chromosome 16  These genes make the alpha globin component of normal adult hemoglobin, which is called hemoglobin A  Alpha globin is also a component of fetal hemoglobin and the other major adult hemoglobin called hemoglobin A2  Mutations of the alpha globin genes are usually deletions of the gene, resulting in absent production of alpha globin  Since there are four genes (instead of the usual two) to consider when looking at alpha globin gene inheritance, there are several alpha globin types that are possible 
Absence of one alpha globin gene leads to a condition known as silent alpha thalassemia trait  This condition causes no health problems and can be detected only by special genetic testing  Alpha thalassemia trait occurs when two alpha globin genes are missing  This can occur in two ways  The genes may be deleted from the same chromosome, causing the 'cis' type of alpha thalassemia trait  Alternately, they may be deleted from different chromosomes, causing the 'trans' type of alpha thalassemia trait  In both instances, there are no associated health problems, although the trait status may be detected by more routine blood screening 
Hemoglobin H disease results from the deletion of three alpha globin genes, such that there is only one functioning gene  Typically, this can occur when one parent carries the silent alpha thalassemia trait, and the other parent carries the 'cis' type of the alpha thalassemia trait  In this situation, there is a 25% chance for hemoglobin H disease in each of such a couple's children 
Hemoglobin H disease-like symptoms can also be a part of a unique condition called alpha thalassemia mental retardation syndrome  Alpha thalassemia mental retardation syndrome can be caused by a deletion of a significant amount of chromosome 16, affecting the alpha globin genes  This is usually not inherited, but rather occurs sporadically in the affected individual  Affected individuals have mild hemoglobin H disease, mild-to-moderate mental retardation, and characteristic facial features  This syndrome can also occur as a sex-linked form in which a mutation is inherited in a particular gene on the X-chromosome  This gene influences alpha globin production, as well as various other developmental processes  Individuals affected with this form of the syndrome tend to have more severe mental retardation, delayed development, nearly absent speech, characteristic facial features, and genital-urinary abnormalities  The remaining discussion will focus only on aspects of hemoglobin H disease 
Alpha thalassemia major results from the deletion of all four alpha globin genes, such that there are no functioning alpha globin genes  This can occur when both parents carry the 'cis' type of the alpha thalassemia trait  In this situation, there is a 25% chance for alpha thalassemia major in each of such a couple's children 
Beta thalassemia major is characterized by severe anemia that can begin months after birth  In the United States and other developed countries beta thalassemia is identified and treated early and effectively  Therefore, the following discussion of symptoms applies primarily to affected individuals in the past and unfortunately in some underdeveloped countries now  If untreated, beta thalassemia major can lead to severe lethargy, paleness, and delays in growth and development  The body attempts to compensate by producing more blood, which is made inside the bones in the marrow  However, this is ineffective without the needed genetic instructions to make enough functioning hemoglobin  Instead, obvious bone expansion and changes occur that cause characteristic facial and other changes in appearance, as well as increased risk of fractures  Severe anemia taxes other organs in the body—such as the heart, spleen, and liver—which must work harder than usual  This can lead to heart failure, as well as enlargement and other problems of the liver and spleen  When untreated, beta thalassemia major generally results in childhood death, usually due to heart failure  In 2004, the first known heart attack associated with beta thalassemia major was reported  Fortunately, in developed countries diagnosis is usually made early, often before symptoms have begun  This allows for treatment with blood transfusion therapy, which can prevent most of the complications of the severe anemia caused by beta thalassemia major  Individuals with beta thalassemia intermedia have a more moderate anemia that may only require treatment with transfusion intermittently, such as when infections occur and stress the body  As a person with beta thalassemia intermedia gets older, however, the need for blood transfusions may increase to the point that they are required on a regular basis  When this occurs their disease becomes more similar to beta thalassemia major  Other genetic and environmental factors can influence the course of the disease as well  For example, co-inheritance of one or two alpha thalassemia mutations can tend to ameliorate some of the symptoms of beta thalassemia disease, which result in part from an imbalance in the amount of alpha- and beta-globin present in the red blood cells 
Hemoglobin h disease
Absence of three alpha globin genes causes an imbalance of alpha and beta globin proteins in the red blood cells  The excess beta globin proteins tend to come together to form hemoglobin H, which is unable to release oxygen to the tissues  In addition, hemoglobin H tends to precipitate out in the cells, causing damage to the red blood cell membrane  When affected individuals are exposed to certain drugs and chemicals known to make the membrane more fragile, the cells are thought to become vulnerable to breakdown in large numbers, a complication called hemolytic anemia  Fever and infection are also considered to be triggers of hemolytic anemia in hemoglobin H disease  This can result in fatigue, paleness, and a yellow discoloration of the skin and whites of eyes called jaundice  Usually, the anemia is mild enough not to require treatment  Severe anemia events may require blood transfusion, however, and are usually accompanied by such other symptoms as dark feces or urine and abdominal or back pain  These events are uncommon in hemoglobin H disease, although they occur more frequently in a more serious type of hemoglobin H disease called hemoglobin H/Constant Spring disease  Individuals effected with this type of hemoglobin H disease are also more likely to have enlargement of and other problems with the spleen 
Alpha thalassemia major
Because alpha globin is a necessary component of all major hemoglobins and some minor hemoglobins, absence of all functioning alpha globin genes leads to serious medical consequences that begin even before birth  Affected fetuses develop severe anemia as early as the first trimester of pregnancy  The placenta, heart, liver, spleen, and adrenal glands may all become enlarged  Fluid can begin collecting throughout the body as early as the start of the second trimester, causing damage to developing tissues and organs  Growth retardation is also common  Affected fetuses usually miscarry or die shortly after birth  In addition, women carrying affected fetuses are at increased risk of developing complications of pregnancy and delivery  Up to 80% of such women develop toxemia, a disturbance of metabolism that can potentially lead to convulsions and coma  Other maternal complications include premature delivery and increased rates of delivery by cesarean section, as well as hemorrhage after delivery 
Thalassemia may be suspected if an individual shows signs that are suggestive of the disease  In all cases, however, laboratory diagnosis is essential to confirm the exact diagnosis and to allow for the provision of accurate genetic counseling about recurrence risks and testing options for parents and affected individuals  Screening is likewise recommended to determine trait status for individuals of high-risk ethnic groups 
The following tests are used to screen for thalassemia disease and/or trait:
hemoglobin electrophoresis with quantitative hemoglobin A2 and hemoglobin F
free erythrocyte-protoporphyrin (or ferritin or other studies of serum iron levels)
A complete blood count will identify low levels of hemoglobin, small red blood cells, and other red blood cell abnormalities that are characteristic of a thalassemia diagnosis  Since thalassemia trait can sometimes be difficult to distinguish from iron deficiency, tests to evaluate iron levels are important  A hemoglobin electrophoresis is a test that can help identify the types and quantities of hemoglobin made by an individual  This test uses an electric field applied across a slab of gel-like material  Hemoglobins migrate through this gel at various rates and to specific locations, depending on their size, shape, and electrical charge  Isoelectric focusing and high-performance liquid chromatography (HPLC) use similar principles to separate hemoglobins and can be used instead of or in various combinations with hemoglobin electrophoresis to determine the types and quantities of hemoglobin present  Hemoglobin electrophoresis results are usually within the normal range for all types of alpha thalassemia  However, hemoglobin A2 levels and sometimes hemoglobin F levels are elevated when beta thalassemia disease or trait is present  Hemoglobin electrophoresis can also detect structurally abnormal hemoglobins that may be co-inherited with a thalassemia trait to cause thalassemia disease (i e , hemoglobin E) or other types of hemoglobin disease (i e , sickle hemoglobin)  Sometimes DNA testing is needed in addition to the above screening tests  This can be performed to help confirm the diagnosis and establish the exact genetic type of thalassemia 
Diagnosis of thalassemia can occur under various circumstances and at various ages  Several states offer thalassemia screening as part of the usual battery of blood tests done for newborns  This allows for early identification and treatment  Thalassemia can be identified before birth through the use of prenatal diagnosis  Chorionic villus sampling (CVS) can be offered as early as 10 weeks of pregnancy and involves removing a sample of the placenta made by the baby and testing the cells  CVS carries a risk of causing a miscarriage that is between 0 5%-1%  Amniocentesis is generally offered between 15 and 22 weeks of pregnancy, but can sometimes be offered earlier  Two to three tablespoons of the fluid surrounding the baby is removed  This fluid contains fetal cells that can be tested  The risk of miscarriage associated with amniocentesis ranges from 0 33-0 5%  Pregnant woman and couples may choose prenatal testing in order to prepare for the birth of a baby that may have thalassemia  Alternately, knowing the diagnosis during pregnancy allows for the option of pregnancy termination  Preimplantation genetic diagnosis (PGD) is a relatively new technique that involves in-vitro fertilization followed by genetic testing of one cell from each developing embryo  Only the embryos unaffected by sickle cell disease are transferred back into the uterus  PGD is currently available on a research basis only and is relatively expensive 
Individuals with beta thalassemia major receive regular blood transfusions, usually on a monthly basis  This helps prevent severe anemia and allows for more normal growth and development  Transfusion therapy does have limitations, however  Individuals can develop reactions to certain proteins in the blood—called a transfusion reaction  This can make locating appropriately matched donor blood more difficult  Although blood supplies in the United States are very safe, particularly relative to the past and to other areas of the world, there remains an increased risk of exposure to such blood-borne infections as hepatitis  Additionally, the body is not able to get rid of the excess iron that accompanies each transfusion  An additional medication called desferoxamine is administered, usually five nights per week over a period of several hours, using an automatic pump that can be used during sleep or taken anywhere the person goes  This medication is able to bind to the excess iron, which can then be eliminated through urine  If desferoxamine is not used regularly or is unavailable, iron overload can develop and cause tissue damage and organ damage and failure  The heart, liver, and endocrine organs are particularly vulnerable  Desferoxamine itself may rarely produce allergic or toxic side effects, including hearing damage  Signs of desferoxamine toxicity are screened for and generally develop in individuals who overuse the medication when body iron levels are sufficiently low  Overall, however, transfusion and desferoxamine therapy have increased the life expectancy of individuals with the most severe types of beta thalassemia major to the 4th or 5th decade  This can be expected to improve with time and increased developments in treatment, as well as for those with more mild forms of the disease 
New treatments offer additional options for some individuals with beta thalassemia major  There are various medications that target the production of red blood cells (i e  erythropoeitin) or fetal hemoglobin (i e  hydroxyurea and butyrate)  Their effectiveness in ameliorating the severity of beta thalassemia is currently being investigated  Another promising new treatment is bone marrow transplantation, in which the bone marrow of an affected individual is replaced with the bone marrow of an unaffected donor  If successful, this treatment can provide a cure  However, there is an approximately 10-15% chance the procedure could be unsuccessful (i e  the thalassemia returns); result in complications (i e  graft-versus-host disease); or result in death  The risk for specific individuals depends on current health status, age, and other factors  Because of the risks involved and the fact that beta thalassemia is a treatable condition, transplant physicians require a brother or sister donor who has an identically matched tissue type, called HLA type  HLA type refers to the unique set of proteins present on each individual's cells, which allows the immune system to recognize "self" from "foreign " HLA type is genetically determined, so there is a 25% chance for two siblings to be a match  Transplant physicians and researchers are also investigating ways to improve the safety and effectiveness of bone marrow transplantation  Using newborn sibling umbilical cord blood—the blood from the placenta that is otherwise discarded after birth but contains cells that can go on to make bone marrow—seems to provide a safer and perhaps more effective source of donor cells  Donors and recipients may not have to be perfect HLA matches for a successful transplant using cord blood cells  Trials are also underway to determine the effectiveness of "partial transplants," in which a safer transplant procedure is used to replace only a percentage of the affected individual's bone marrow  Other possible treatments on the horizon may include gene therapy techniques aimed at increasing the amount of normal hemoglobin the body is able to make 
Hemoglobin H disease is a relatively mild form of thalassemia that may go unrecognized  It is not generally considered a condition that will reduce one's life expectancy  Education is an important part of managing the health of an individual with hemoglobin H disease  It is important to be able to recognize the signs of severe anemia that require medical attention  It is also important to be aware of the medications, chemicals, and other exposures to avoid due to the theoretical risk they pose of causing a severe anemia event  When severe anemia occurs, it is treated with blood transfusion therapy  For individuals with hemoglobin H disease, this is rarely required  For those with the hemoglobin H/Constant Spring form of the disease, the need for transfusions may be intermittent or ongoing, perhaps on a monthly basis and requiring desferoxamine treatment  Individuals with this more severe form of the disease may also have an increased chance of requiring removal of an enlarged and/or overactive spleen 
Anemia — A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values  Common symptoms include paleness, fatigue, and shortness of breath 
Bilirubin — A yellow pigment that is the end result of hemoglobin breakdown  This pigment is metabolized in the liver and excreted from the body through the bile  Bloodstream levels are normally low; however, extensive red cell destruction leads to excessive bilirubin formation and jaundice 
Bone marrow — A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones  Bone marrow is the site of blood cell generation 
Bone marrow transplantation — A medical procedure used to treat some diseases that arise from defective blood cell formation in the bone marrow  Healthy bone marrow is extracted from a donor to replace the marrow in an ailing individual  Proteins on the surface of bone marrow cells must be identical or very closely matched between a donor and the recipient 
Desferoxamine — The primary drug used in iron chelation therapy  It aids in counteracting the life-threatening buildup of iron in the body associated with long-term blood transfusions 
Globin — One of the component protein molecules found in hemoglobin  Normal adult hemoglobin has a pair each of alpha-globin and beta-globin molecules 
Heme — The iron-containing molecule in hemoglobin that serves as the site for oxygen binding 
Hemoglobin — Protein-iron compound in the blood that carries oxygen to the cells and carries carbon dioxide away from the cells 
Hemoglobin A — Normal adult hemoglobin that contains a heme molecule, two alpha-globin molecules, and two beta-globin molecules 
Hemoglobin electrophoresis — A laboratory test that separates molecules based on their size, shape, or electrical charge 
Hepatomegaly — An abnormally large liver 
HLA type — Refers to the unique set of proteins called human leukocyte antigens  These proteins are present on each individual's cell and allow the immune system to recognize 'self' from 'foreign'  HLA type is particularly important in organ and tissue transplantation 
Hydroxyurea — A drug that has been shown to induce production of fetal hemoglobin  Fetal hemoglobin has a pair of gamma-globin molecules in place of the typical beta-globins of adult hemoglobin  Higher-than-normal levels of fetal hemoglobin can ameliorate some of the symptoms of thalassemia 
Iron overload — A side effect of frequent blood transfusions in which the body accumulates abnormally high levels of iron  Iron deposits can form in organs, particularly the heart, and cause life-threatening damage 
Jaundice — Yellowing of the skin or eyes due to excess of bilirubin in the blood 
Mutation — A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring 
Placenta — The organ responsible for oxygen and nutrition exchange between a pregnant mother and her developing baby 
Red blood cell — Hemoglobin-containing blood cells that transport oxygen from the lungs to tissues  In the tissues, the red blood cells exchange their oxygen for carbon dioxide, which is brought back to the lungs to be exhaled 
Screening — Process through which carriers of a trait may be identified within a population 
Splenomegaly — Enlargement of the spleen 
Because alpha thalassemia major is most often a condition that is fatal in the prenatal or newborn period, treatment has previously been focused on identifying affected pregnancies in order to provide appropriate management to reduce potential maternal complications  Pregnancy termination provides one form of management  Increased prenatal surveillance and early treatment of maternal complications is an approach that is appropriate for mothers who wish to continue their pregnancy with the knowledge that the baby will most likely not survive  In recent years, there have been a handful of infants with this condition who have survived long-term  Most of these infants received experimental treatment including transfusions before birth, early delivery, and even bone marrow transplantation before birth, although the latter procedure has not yet been successful  For those infants that survive to delivery, there seems to be an increased risk of developmental problems and physical effects, particularly heart and genital malformations  Otherwise, their medical outlook is similar to a child with beta thalassemia major, with the important exception that ongoing, life-long blood transfusions begin right at birth 
As discussed above, the prognosis for individuals with the most serious types of thalassemia has improved drastically in the last several years following recent medical advances in transfusion, chemo-, and transplantation therapy  Advances continue and promise to improve the life expectancy and quality of life further for affected individuals 
"First Known Heart Attack Associated With Beta-thalassemia Major Reported " Heart Disease Weekly February 22, 2004: 10 
"Novel Alpha-thalassemia Mutations Identified " Hematology Week January 26, 2004: 19 
Children's Blood Foundation  333 East 38th St , Room 830, New York, NY 10016-2745  (212) 297-4336  cfg@nyh med cornell edu 
Cooley's Anemia Foundation, Inc  129-09 26th Ave  #203, Flushing, NY 11354  (800) 522-7222 or (718) 321-2873  http://www thalassemia org 
March of Dimes Birth Defects Foundation  1275 Mamaroneck Ave , White Plains, NY 10605  (888) 663-4637  resourcecenter@modimes org  http://www modimes org 
National Heart, Lung, and Blood Institute  PO Box 30105, Bethseda, MD 20824-0105  (301) 592-8573  nhlbiinfo@rover nhlbi nih gov  http://www nhlbi nih gov 
National Organization for Rare Disorders (NORD)  PO Box 8923, New Fairfield, CT 06812-8923  (203) 746-6518 or (800) 999-6673  Fax: (203) 746-6481  http://www rarediseases org 
Bojanowski J  "Alpha Thalassemia Major: The Possibility of Long-Term Survival " Pamphlet from the Northern California Comprehensive Thalassemia Center  (1999) 
Children's Hospital Oakland, Northern California Comprehensive Thalassemia Center website  http://www thalassemia com 
Cooley's Anemia Foundation, Inc  website  http://www thalassemia org/gohome html 
Joint Center for Sickle Cell and Thalassemic Disorders website  http://cancer mgh harvard edu/medOnc/sickle htm 
[thal″ah-se´me-ah]
a heterogeneous group of hereditary hemolytic anemias marked by a decreased rate of synthesis of one or more hemoglobin polypeptide chains, classified according to the chain involved (α, β, δ); the two major categories are α- and β-thalassemia 
α-thalassemia (alpha-thalassemia) that caused by diminished synthesis of alpha chains of hemoglobin  The homozygous form is incompatible with life, the stillborn infant displaying severe hydrops fetalis  The heterozygous form may be asymptomatic or marked by mild anemia 
β-thalassemia (beta-thalassemia) that caused by diminished synthesis of beta chains of hemoglobin  The homozygous form is called t  major and the heterozygous form is called t  minor 
thalassemia ma´jor the homozygous form of β-thalassemia, in which hemoglobin A is completely absent; it appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia; hepatosplenomegaly; skeletal deformation; mongoloid facies; and cardiac enlargement 
thalassemia mi´nor the heterozygous form of β-thalassemia; it is usually asymptomatic, but there may be mild anemia 
sickle cell–thalassemia a hereditary anemia involving simultaneous heterozygosity for hemoglobin S and thalassemia 
thal·as·se·mi·a
, thalassanemia (thal'ă-sē'mē-ă, thă-las-ă-nē'mē-ă),
Any of a group of inherited disorders of hemoglobin metabolism in which there is impaired synthesis of one or more of the polypeptide chains of globin; several genetic types exist, and the corresponding clinical picture may vary from barely detectable hematologic abnormality to severe and fatal anemia 
[G  thalassa, the sea, + haima, blood]
/thal·as·se·mia/ (thal″ah-se´me-ah) a heterogeneous group of hereditary hemolytic anemias marked by a decreased rate of synthesis of one or more hemoglobin polypeptide chains, classified according to the chain involved (α, β, δ); the two major categories are α- and β-thalassemia 
α-thalassemia that caused by diminished synthesis of alpha chains of hemoglobin  The homozygous form is incompatible with life, the stillborn infant displaying severe hydrops fetalis  The heterozygous form may be asymptomatic or marked by mild anemia 
β-thalassemia that caused by diminished synthesis of beta chains of hemoglobin  The homozygous form is called t  major and the heterozygous form is called t  minor 
thalassemia ma´jor the homozygous form of &#x03B2;, in which hemoglobin A is completely absent; it appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia, hepatosplenomegaly, skeletal deformation, mongoloid facies, and cardiac enlargement 
thalassemia mi´nor the heterozygous form of &#x03B2;, usually asymptomatic, although there is sometimes mild anemia 
(thăl′ə-sē′mē-ə)
An inherited form of anemia occurring chiefly among people of Mediterranean descent, caused by faulty synthesis of part of the hemoglobin molecule  Also called Mediterranean anemia 
thal′as·se′mic adj 
[thal′əsē′mē·ə]
Etymology: Gk, thalassa, sea, a + haima, without blood
production and hemolytic anemia characterized by microcytic, hypochromic red blood cells  Thalassemia is caused by inherited deficiency of alpha- or beta-globin synthesis  See also hemochromatosis, hemosiderosis 
Beta thalassemia, clinical thalassemia, Cooley's anemia, Mediterranean anemia, thalassemia major Hematology A group of genetic diseases by underproduction of hemoglobin due to mutations in the beta globin gene, which is more common in Mediterraneans Heredity Parents are carriers–heterozygotes; one in 4 children is homozygous for the mutation and thus has full-blown disease Clinical See Anemia  Cf Sickle cell anemia 
α-thalassemia
Hemoglobin Barts Hematology An inherited condition caused by a defect in the synthesis of the Hb α chain; Hb Barts hemoglobinopathy is characterized by the presence of 4 gamma chains; it is more common in southeast Asians; the most severe form of alpha thalassemia causes stillbirth due to hydrops fetalis Heredity Parents are carriers–heterozygotes; one in 4 children is homozygous for the mutation and thus has full-blown disease Clinical Pallor, fatiguability, FTT, fever, infections, diarrhea Management Transfusions
Thalassemia major Hematology A hemoglobinopathy caused by a defect in the synthesis of Hb β chain Clinical Pallor, fatigability, FTT, fever due to infections, diarrhea, bone deformities, hepatosplenomegaly Management Transfusions, but iron overload can damage the heart, liver, and endocrine systems, ergo iron chelation–early use of deferiprone, deferoxamine ↓ transfusion-related iron overload and may protect against DM, cardiac disease, early death
δ-thalassemia
Hematology A condition characterized by a defect of Hb A2–α2δ2; because Hb A2 comprises only 3% of the circulating Hb, even its complete absence; δ-thalassemia has little clinical or hematologic impact
γ-thalassemia
Hematology A condition characterized by a defect of gamma–γ Hb chains found in Hb F–α2γ2; because Hb F is present primarily in the fetus and newborns, it is rarely seen outside of the neonatal period, but may cause transient neonatal hemolytic anemia 
, thalassanemia (thal'ă-sē'mē-ă, -ă-să-nē'mē-ă)
Any of a group of inherited disorders of hemoglobin metabolism in which there is impaired synthesis of one or more of the polypeptide chains of globin; several genetic types exist, and the corresponding clinical picture may vary from barely detectable hematologic abnormality to severe and fatal anemia  People of Mediterranean, extraction are more often affected than others by this type of anemia 
Synonym(s): thalassaemia, thalassanaemia 
Any of a group of inherited disorders of hemoglobin metabolism with impaired synthesis of one or more polypeptide chains of globin; several genetic types exist 
<a href="https://medical-dictionary thefreedictionary com/Thalassaemia+minor">thalassemia</a>
Barts hemoglobin
beta hemoglobinopathy
beta-delta thalassemia
beta-thalassaemia
Bite Cell
black gallstone
I know of a couple, totally unrelated and unbeknownst to them, who are silent carriers of Thalassaemia minor 
Pakistan: Genetic factor: All in the genes
But, unfortunately, when one person with thalassaemia minor carrier happens to marry another with the same diagnosis, there is a strong possibility that their child would be thalassaemia major, as happened in the case of Taneja 
' My life depends upon a monthly blood transfusion '
0] thalassaemia demonstrates variable severity, ranging from a condition similar to [beta] thalassaemia minor to something approaching thalassaemia major 
A retrospective review of homozygous haemoglobin E patients
Thal, Alan P 
thalame
thalamencephalic
thalamencephalon
thalamic
thalamic fasciculus
thalamic nucleus
thalamic pain syndrome
thalamic peduncle
thalamic radiation
thalamo-
thalamocoele
thalamocortical
thalamocortical fibers
thalamogeniculate artery
thalamolenticular
thalamoperforating artery
thalamostriate radiation
thalamotuberal artery
Thalassaemia minor
thalassaemiaor Cooley's disease
thalassemic facies
thalasso-
Thalassobacter
Thalassobacter utilis
thalassoplankton
thalassoposia
thalidomide neuropathy
Thalidomider
thallium poisoning
Thalarctos
THALAS
Thalasaemia
Thalassaemia Association of Malaysia
thalassaemia major
Thalassaemias
thalassaemic
thalassanaemia
Thalassemia Action Group
Thalassemia Clinical Research Network
thalassemia syndrome
Context 3: Paper Info

Title: An CUSUM Test with Observation-Adjusted Control Limits in Change Detection
Publish Date: March 9, 2023
Author List: Fuquan Tang (from Department of Statistics, Shanghai Jiao Tong University), Dong Han (from Department of Statistics, Shanghai Jiao Tong University)

Figure

exp{−cg(µ)(θ − x Hv (θ) + o(1))} for 1 ≤ k ≤ ac − 1, bc ≤ n ≤ m, where Zi = −g ′ (µ)(Z i − µ)/a and Hv (θ) = ln hv (θ) + ( ac k − 1) ln ĥv (θ), ĥv (θ) = E v (e θ Zi ) 
i < cg(µ)(1 + o(1))) exp{−cg(µ)θ * v (1 + o(1))} (A  5) for ac ≤ k ≤ bc − 1, bc ≤ n ≤ m,andP v (
i + g ′ (µ)a −1 Tc(g)−1 i=Tc(g)−ac (Z i − µ)] −→ µas c → ∞ By the uniform integrability of {T c (g)/c} and using Theorem A 1 1 in Gut's book(1988), we haveE v (T c (g)) = (1 + o(1)) cg(µ) µfor a large c This completes the proof of Theorem 2 Proof of Theorem 4  Since g(x) < 0 for x > a * , a * ≤ µ * and µ * ≥ 0, it follows thatP v m Ẑm < cg( Ẑm ), Ẑm > a * ≤ P v ( Ẑm < µ * )andP v (T c (g) > m) = P v n i=n−k+1 Z i < cg( Ẑn ), 1 ≤ k ≤ n, 1 ≤ n ≤ m ≤ P v m Ẑm < cg( Ẑm ) = P v m Ẑm < cg( Ẑm ), Ẑm ≤ a * + P v m Ẑm < cg( Ẑm ), Ẑm > a * ≤ 2P v ( Ẑm < µ * ) Furthermore,P v ( Ẑm < µ * ) = P v ( m i −Z i > −mµ * ) = P v ( m i (µ − Z i ) > m(µ − µ * )) = P v (e θ m i (µ−Z i ) > e θm(µ−µ * ) ) ≤ e −m[θ(µ−µ * )−ln M (θ)] ,whereM(θ) = E v (e θ(µ−Z 1 )) and the last inequality follows from Chebychev's inequality Note thath(θ) = θ(µ − µ * ) − ln M(θ) attains its maximum value h(θ * ) = θ * (µ − µ * ) − ln M(θ * ) > 0 at θ = θ * > 0, where h ′ (θ * ) = 0  So, E v (T c (g)) = 1 + ∞ m=1 P v (T c (g) > m) ≤ 1 + m=1 −m[θ * (µ−µ * )−ln M (θ * )] = e θ * (µ−µ * )−ln M (θ * ) + 1 e θ * (µ−µ * )−ln M (θ * ) − Let k > 1 It follows that E vk (T c (g) − k + 1) + = ∞ m=1 P vk (T c (g) > m + k − 1, T c (g) > k − 1) ≤ (a 0 + 1)(k − 1)P 0 (T c (g) > k − 1) + ∞ m≥(a 0 +1)(k−1) P vk (T c (g) > m + k − 1) Similarly, we haveP vk (T c (g) > m + k − 1) = P vk n i=n−k+1 Z i < cg( Ẑn ), 1 ≤ k ≤ n, 1 ≤ n ≤ m + k − 1 ≤ 2P vk ( Ẑm+k−1 < µ * ) − Z i ) > m(µ − µ * ) + (k − 1)(µ 0 − µ * ) ≤ 2 exp{−m θ * (µ − µ * ) − ln M(θ * ) + k − 1 m [µ 0 − µ * − ln M 0 (θ * )] } ≤ e −mb for m ≥ (a 0 + 1)(k − 1), since θ * (µ − µ * ) − ln M(θ * ) + k − 1 m [µ 0 − µ * − ln M 0 (θ * )] ≥ b for m ≥ (a 0 + 1)(k−1) Thus, E vk (T c (g) − k + 1) + ≤ (a 0 + 1)(k − 1)P 0 (T c (g) ≥ k) + m≥(a 0 +1)(k−1) e −mb ≤ (a 0 + 1)(k − 1)P 0 (T c (g) >≥ k) + 2e −(a 0 +1)(k−1)b 1 − e −b  
Simulation of E τ i ,v and J ACE for detecting two mean shifts v = 0 1, v = 1 The parameters for T * M are k1=1, k2=150, r 1 = 5 2 * 10 −5 , r 2 = 1 1 * 10 −5 , and the expectation and standard deviation in both cases are 1717 06with 13459 80 and 3918 33 with 16893 25,respectively 

abstract

In this paper, we not only propose an new optimal sequential test of sum of logarithmic likelihood ratio (SLR) but also present the CUSUM sequential test (control chart, stopping time) with the observation-adjusted control limits (CUSUM-OAL) for monitoring quickly and adaptively the change in distribution of a sequential observations 
Two limiting relationships between the optimal test and a series of the CUSUM-OAL tests are established  Moreover, we give the estimation of the in-control and the out-of-control average run lengths (ARLs) of the CUSUM-OAL test  The theoretical results are illustrated by numerical simulations in detecting mean shifts of the observations sequence 

INTRODUCTION

In order to quickly detect a change in distribution of observations sequence without exceeding a certain false alarm rate, a great variety of sequential tests have been proposed, developed and applied to various fields since proposed a control chart method, see, for example, , , One of popular used sequential tests is the following upper-sided CUSUM test which was proposed by  
where c > 0 is a constant control limit, Z i = log[p v 1 (X i )/p v 0 (X i )], p v 0 (x) and p v 1 (x) are prechange and post-change probability density functions respectively for a sequence of mutually independent observations {X i , i ≥ 1}, that is, there is a unknown change-point τ ≥ 1 such that X 1 ,    , X τ −1 have the probability density function p v 0 , whereas, X τ , X τ +1 ,     have the probability density function p v 1  
By the renewal property of the CUSUM test T C we have , where E 1 (T C ) is the out-of-control average run length (ARL 1 ), P k and E k denote the probability and expectation respectively when the change from p v 0 to p v 1 occurs at the change-point τ = k for k ≥ 1  Though we know that the CUSUM test is optimal under Lorden's measure (see Moustakides 1986 and Ritov 1990), the out-of-control ARL 1 of the CUSUM test is not small, especially in detecting small mean shifts ( see Table in Section 4) 
In other words, the CUSUM test is insensitive in detecting small mean shifts  Then, how to increase the sensitivity of the CUSUM test ? Note that the control limit in the CUSUM test is a constant c which does not depend on the observation samples  Intuitively, if the control limit of the CUSUM test can become low as the samples mean of the observation sequence increases, then the alarm time of detecting the increasing mean shifts will be greatly shortened 
Based on this idea, by selecting a decreasing function g(x) we may define the ( upper-sided ) CUSUM chart T C (cg) with the observation-adjusted control limits cg( Ẑn ) ( abbreviated to the CUSUM-OAL chart ) in the following where c > 0 is a constant and Ẑn = n i=1 Z i /n  In other words, the control limits cg( Ẑn ) of the CUSUM-OAL test can be adjusted adaptively according to the observation information { Ẑn } 
Note that the control limits cg( Ẑn ) may be negative  In the special case, the CUSUM-OAL chart T C (cg) becomes into the conventional CUSUM chart T C (c) in (1) when g ≡ 1  Similarly, we can define a down-sided CUSUM-OAL test  In this paper, we consider only the upper-sided CUSUM-OAL test since the properties of the down-sided CUSUM-OAL test can be obtained by the similar method 
The main purpose of the present paper is to show the good detection performance of the CUSUM-OAL test and to give the estimation of its the in-control and out-of-control ARLs  The paper is organized as follows  In Section 2, we first present an optimal SLR sequential test, then define two sequences of the CUSUM-OAL tests and prove that one of the two sequences of CUSUM-OAL tests converges to the optimal test, another sequences of CUSUM-OAL tests converges to a combination of the optimal test and the CUSUM test 
The estimation of the in-control and out-of-control ARLs of the CUSUM-OAL tests and their comparison are given in Section 3  The detection performances of the three CUSUM-OAL tests and the conventional CUSUM test are illustrated in Section 4 by comparing their numerical out-ofcontrol ARLs  Section 5 provides some concluding remarks 
Proofs of the theorems are given in the Appendix



ground_truth: According to the globin that is affected (alpha or beta).

prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: How is the function beta(r) determined in the derivation?

Read the following text and answer briefly.

Context 2: \section{Introduction}
The Schwarzschild solution plays a key role in teaching about general relativity: It describes the simplest version of a black hole  By Birkhoff's theorem, it more generally describes the gravitational field around any spherical mass distribution, such as the Sun in our own Solar system  As one of two particularly simple, yet physically relevant examples of a non-trivial metric (the other being the FLRW spacetime of an expanding universe), it is particularly well-suited for teaching about general techniques of ``reading'' and interpreting a spacetime metric 

Consider undergraduate courses where students are introduced to selected concepts and results from general relativity without exposing them to the full mathematical formalism  Such courses have the advantage of introducing students to one of the two great fundamental theories of 20th century physics early on (the other being quantum mechanics); they also profit from subject matter that meets with considerable interest from students \cite{Hartle2006} Using the terminology of Christensen and Moore,\cite{Christensen2012} in the ``calculus only'' approach pioneered by Taylor and Wheeler,\cite{Taylor2001,Taylor2018} spacetime metrics are not derived, but taken as given, and the focus is on learning how to interpret a given spacetime metric  Similar presentations can be found in the first part of the ``physics first'' approach exemplified by Hartle's text book,\cite{Hartle2003} where the concepts of the metric and of geodesics are introduced early on, and their physical consequences explored, while the mathematics necessary for the Einstein equations is only introduced at a later stage  

Whenever the approach involves an exploration of simple metrics such as the Schwarzschild solution, but stops short of the formalism required for the full tensorial form of Einstein's equations, access to a simple derivation of the Schwarzschild solution that does not make use of the advanced formalism can be a considerable advantage 

Simplified derivations of the Schwarzschild solution have a long tradition within general relativity education,\cite{Schiff1960,Harwit1973} although specific simplifications have met with criticism \cite{Rindler1968} This article presents a derivation which requires no deeper knowledge of the formalism of differential geometry beyond an understanding of how to interpret a given spacetime metric $\mathrm{d} s^2$  The derivation avoids the criticism levelled at attempts to derive the Schwarzschild solution from the Einstein equivalence principle in combination with a Newtonian limit,\cite{Gruber1988} relying as it does on a simplified version of the vacuum Einstein equation 

More specifically, I combine the restrictions imposed by the symmetry with the simple form of Einstein's equations formulated by Baez and Bunn \cite{BaezBunn2005} That same strategy was followed by Kassner in 2017,\cite{Kassner2017} but in this text, I use the ``infalling coordinates'' that are commonly associated with the Gullstrand-Painlev\'e form of the Schwarzschild metric,\cite{Martel2001,Visser2005,HamiltonLisle2008} not the more common Schwarzschild coordinates  That choice simplifies the argument even further  In the end, what is required is no more than the solution of an ordinary differential equation for a single function, which yields to standard methods, to obtain the desired result 

\section{Coordinates adapted to spherical symmetry and staticity}
\label{SymmetriesCoordinates}

Assume that the spacetime we are interested in is spherically symmetric and static  In general relativity, a symmetry amounts to the possibility of being able to choose coordinates that are adapted to the symmetry, at least within a restricted sub-region of the spacetime in question  That the spacetime is static is taken to mean that we can introduce a (non-unique) time coordinate ${t}$ so that our description of spacetime geometry does not depend explicitly on ${t}$, and that space and time are completely separate --- in the coordinates adapted to the symmetry, there are no ``mixed terms'' involving $\mathrm{d} {t}$ times the differential of a space coordinate in the metric  If we use ${t}$ to slice our spacetime into three-dimensional hyperplanes, each corresponding to ``space at time ${t}$,'' then each of those 3-spaces has the same spatial geometry  A mixed term would indicate that those slices of space would need to be shifted relative to another in order to identify corresponding points  The mixed term's absence indicates that in adapted coordinates, there is no need for such an extra shift  In those coordinates, we can talk about the 3-spaces as just ``space,'' without the need for specifying which of the slices we are referring to 

In the case of spherical symmetry, we can introduce spherical coordinates that are adapted to the symmetry: a radial coordinate $r$ and the usual angular coordinates $\vartheta,\varphi$, so that the spherical shell at constant $r$ has the total area $4\pi r^2$  In consequence, the part of our metric involving $\mathrm{d}\vartheta$ and $\mathrm{d}\varphi$ will have the standard form
\begin{equation}
r^2(\mathrm{d}\vartheta^2+\sin^2\theta\mathrm{d}\varphi^2) \equiv r^2\mathrm{d}\Omega^2,
\end{equation}
where the right-hand side defines $\mathrm{d}\Omega^2$, the infinitesimal solid angle corresponding to each particular combination of $\mathrm{d}\vartheta$ and $\mathrm{d}\varphi$ 

The radial coordinate slices space into spherical shells, each corresponding to a particular value $r=const $ The rotations around the origin, which are the symmetry transformations of spherical symmetry, map each of those spherical shells onto itself, and they leave all physical quantities that do not explicitly depend on $\vartheta$ or $\varphi$ invariant 

In what follows, we will use the basic structures introduced in this way --- the slices of simultaneous ${t}$, the radial directions within each slice, the angular coordinates spanning the symmetry--adapted spherical shells of area $4\pi r^2$ --- as auxiliary structures for introducing spacetime coordinates  For now, let us write down the shape that our metric has by simple virtue of the spherical symmetry, the requirement that the spacetime be static, and the adapted coordinates, namely
\begin{equation}
\mathrm{d} s^2 = -c^2F(r) \mathrm{d} {t}^2 + G(r) \mathrm{d} r^2 + r^2\:\mathrm{d}\Omega^2  
\label{StaticForm}
\end{equation}
Students familiar with  ``reading'' a spacetime metric will immediately recognize the sign difference between the parts describing space and describing time that is characteristic for spacetime, and the speed of light $c$ that gives us the correct physical dimensions  That there is no explicit dependence on $\varphi$ and $\vartheta$ in the remaining functions $F$ and $G$ is a direct consequence of spherical symmetry  That the factor in front of $\mathrm{d}\Omega^2$ is $r^2$ is a consequence of our coordinate choice, with spherical angular coordinates so that the area of a spherical surface of constant radius $r$ is $4\pi r^2$  That there is no explicit dependence on ${t}$ is one consequence of the spacetime being static; the absence of the mixed term $\mathrm{d} {t}\cdot \mathrm{d} r$ is another  We are left with two unknown functions $F(r)$ and $G(r)$  In the following, let us call ${t}$ and $r$ the {\em static coordinates}  
 
Note that, since $G(r)$ is as yet undefined, we have not yet chosen a specific physical meaning for the length measurements associated with our $r$ coordinate  But because of the $\mathrm{d}\Omega^2$ part, it is clear that whatever choice we make, the locally orthogonal lengths $r\cdot\mathrm{d}\vartheta$ and $r\cdot\sin\vartheta\cdot\mathrm{d}\varphi$ will have the same physical interpretation as for the length measurement corresponding to $\mathrm{d} r$ 

\section{Infalling observer coordinates}
\label{Sec:InfallingObservers}

Now that we know what the radial directions are, at each moment of time ${t}$, we follow Visser\cite{Visser2005} as well as Hamilton and Lisle\cite{HamiltonLisle2008} in defining a family of radially infalling observers   Observers in that family are in free fall along the radial direction, starting out at rest at infinity: In mapping each observer's radial progression in terms of the static coordinate time ${t}$, we adjust initial conditions, specifically: the choice of initial speed at some fixed time ${t}$, in just the right way that the radial coordinate speed goes to zero for each observer in the same way as $r\to\infty $

It is true that talking about ``infalling'' observers already reflects our expectation that our solution should describe the spacetime of a spherically symmetric mass   As we know from the Newtonian limit, such a mass attracts test particles in its vicinity  It should be noted, though, that all our calculations would also be compatible with the limit of no mass being present  In that case, ``infalling'' would be a misnomer, as our family of observers would merely hover in empty space at unchanging positions in $r$  

We can imagine infinitesimal local coordinate systems associated with our observers --- think of the observer mapping out space and time by defining three orthogonal axes, and by measuring time with a co-moving clock  We assume all such little coordinate systems to be non-rotating --- otherwise, we would break spherical symmetry, since rotation would locally pick out a plane of rotation that is distinguishable from the other planes  The radial direction is a natural choice for the first space axis of those little free-falling systems  The other directions, we take to point to observers falling side by side with our coordinate-defining observer --- and to remain pointed at a specific such other observer, once the choice of direction is made 

We assume our infalling observers' clocks to be synchronised at some fixed radius value $r$  By spherical symmetry, those clocks should then be synchronised at {\em all} values of $r$  Anything else would indicate direction-dependent differences for the infalling observers and their clocks, after all  Hence, at any given static time ${t}$, all the infalling observers who are at radius value $r$ show the same proper time $T$ on the ideal clocks travelling along with them  

Once our definition is complete, our static, spherically symmetric spacetime is filled with infalling observers from that family: Whenever we consider an event $\cal E$, there will be an observer from that family passing by at that time, at that location  

Now, consider the coordinate speed of those infalling observers  If we position ourselves at some constant radius value $r$ and watch the falling observers fly by, then we can express both their proper time rate and their coordinate speed in the $r$ direction in terms of $r$ and ${t}$  We can combine the two pieces of information to obtain the rate of change in radial position $r$ with proper time $T$ for those infalling observers  But since the initial conditions for those observers are the same, and since our spacetime is, by assumption, static, the resulting function can only depend on $r$, and not explicitly on ${t}$  Let us rescale that function with the speed of light to make it dimensionless, give it an overall minus sign to make it positive for infalling particles, and call it $\beta(r)$,
\begin{equation}
\beta(r)\equiv -\frac{1}{c}\frac{\mathrm{d} r}{\mathrm{d} T}(r) 
\label{betaDefinition}
\end{equation}

Recall from section \ref{SymmetriesCoordinates} that we also still have the freedom to decide on the physical meaning of $r$  We make the choice of making $\mathrm{d} r$ the physical length measured by one of our infalling observers at the relevant location in spacetime, at constant time $T$  Via our angular coordinates, that implies that length measurements orthogonal to the radial direction, $r\cdot\mathrm{d}\vartheta$ and $r\cdot\sin\vartheta\:\mathrm{d}\varphi$ inherit the same physical interpretation 

As a next step, we transform our metric (\ref{StaticForm}) from the static form into the form appropriate for our coordinate choice $r$ and $T$  We do so by writing the static time coordinate as a function ${t}(T,r)$ in terms of infalling observer time and radius value  In consequence,
\begin{equation}
\mathrm{d} {t} = \frac{\partial{t}}{\partial T}\cdot\mathrm{d} T+ \frac{\partial {t}}{\partial r}\cdot\mathrm{d} r,
\end{equation}
and our new metric now has the form
\begin{align}
 \mathrm{d} s^2 = {} & -c^2 F(r)\left(\frac{\partial t}{\partial T}\right)^2\mathrm{d} T^2 \nonumber \\[0 2em]
 & -2c^2F(r)\left(\frac{\partial t}{\partial T}\right)\left(\frac{\partial t}{\partial r}\right)\mathrm{d} T\:\mathrm{d} r \nonumber \\[0 2em]
 & +\left[G(r)-c^2F(r)\left(\frac{\partial t}{\partial r}\right)^2\right]\mathrm{d} r^2+r^2\:\mathrm{d}\Omega^2 
 \end{align}
At face value, this looks like we are moving the wrong way, away from simplification, since we now have more functions, and they depend on two variables instead of one 

But in fact, this new formulation paves the way for an even simpler form of the metric  Consider a specific event, which happens at given radius value $r$  In a small region around that event, we will introduce a new coordinate $\bar{r}$ to parametrize the radial direction  We want this coordinate to be co-moving with our infalling observers at $r$; each such observer then has a position $\bar{r}=const $ that does not change over time  

Key to our next step is that we {\em know} the metric for the local length and time measurements made by any one of our free-falling observers  By Einstein's equivalence principle, the metric is that of special relativity  Locally, namely whenever tidal effects can be neglected, spacetime geometry for any non-rotating observer in free fall is indistinguishable from Minkowski spacetime as described by a local inertial system 

Since we have chosen both the time coordinate $T$ and the physical meaning of the radial coordinate $r$ so as to conform with the measurements of the local infalling observer, the transformation between $\bar{r}$ and $r$ is particularly simple: It has the form of a Galilei transformation
\begin{equation}
\mathrm{d}\bar{r}= \mathrm{d} r + \beta(r)c\:\mathrm{d} T 
\label{barRshift}
\end{equation}
In that way, as it should be by definition, radial coordinate differences at constant $T$ are the same in both systems, while for an observer at constant $\bar{r},$ with $\mathrm{d} \bar{r}=0$, the relation between $\mathrm{d} r$ and $\mathrm{d} T$ is consistent with the definition of the function $\beta(r)$ in (\ref{betaDefinition}) 

Are you surprised that this is not a Lorentz transformation, as one might expect from special relativity? Don't be  We are not transforming from one local inertial coordinate system to another  The $T$ is already the time coordinate of the infalling observers, so both coordinate systems have the same definition of simultaneity, and time dilation plays no role in this particular transformation  Also, we have chosen $r$ intervals to correspond to length measurements of the infalling observers, so there is no Lorentz contraction, either  It is the consequence of these special choices that gives the relation (\ref{barRshift}) its simple form 

Last but not least, when we analyse specifically an infinitesimal neighbourhood of the point $r,\vartheta,\varphi$, let us make the choice that directly at our point of interest, we make $\bar{r}$ coincide with $r$  Since before, we had only fixed the differential $\mathrm{d} \bar{r}$, we do have the remaining freedom of choosing a constant offset for $\bar{r}$ that yields the desired result 

By Einstein's equivalence principle, the metric in terms of the locally co-moving coordinates $T,\bar{r},\vartheta,\varphi$ is the spherical-coordinate version of the Minkowski metric,
\begin{equation}
\mathrm{d} s^2 = -c^2\mathrm{d} T^2 + \mathrm{d}\bar{r}^2 + \bar{r}^2\mathrm{d}\Omega 
\end{equation}
This version can, of course, be obtained by taking the more familiar Cartesian-coordinate version
\begin{equation}
\mathrm{d} s^2=-c^2\mathrm{d} T^2 + \mathrm{d} X^2 + \mathrm{d} Y^2 + \mathrm{d} Z^2,
\label{CartesianMinkowski}
\end{equation}
applying the definition of Cartesian coordinates $X,Y,Z$ in terms of spherical coordinates $\bar{r},\vartheta,\varphi$
\begin{equation}
x= \bar{r}\:\sin\vartheta\:\cos\varphi, \;\;
y= \bar{r}\:\sin\vartheta\:\sin\varphi, \;\;
z= \bar{r}\:\cos\vartheta,
\end{equation}
to express $\mathrm{d} X, \mathrm{d} Y, \mathrm{d} Z$ in terms of $\mathrm{d} \bar{r}, \mathrm{d}\vartheta, \mathrm{d}\varphi$, and substitute the result into (\ref{CartesianMinkowski}) 

By noting that we have chosen $\bar{r}$ so that, at the specific spacetime event where we are evaluating the metric, $\bar{r}=r$, while, for small radial coordinate shifts around that location, we have the relation (\ref{barRshift}), we can now write down the same metric in the coordinates $T, r, \vartheta,\varphi$, namely as
\begin{equation}
\mathrm{d} s^2 = -c^2\left[
1-\beta(r)^2
\right] \mathrm{d} T^2+2c\beta(r)\mathrm{d} r\:\mathrm{d} T
+\mathrm{d} r^2+r^2\mathrm{d}\Omega^2 
\label{preMetric}
\end{equation}
Since we can repeat that local procedure at any event in our spacetime, this result is our general form of the metric, for all values of $r$  This, then is the promised simplification: By exploiting the symmetries of our solutions as well as the properties of infalling observers, we have reduced our metric to a simple form with no more than one unknown function of one variable, namely $\beta(r)$ 

So far, what I have presented is no more than a long-form version of the initial steps of the derivation given by Visser in his heuristic derivation of the Schwarzschild metric \cite{Visser2005} In the next section, we will deviate from Visser's derivation 

\section{$\beta(r)$ from tidal deformations}
\label{TidalSection}

In the previous section, we had exploited symmetries and Einstein's equivalence principle  In order to determine $\beta(r)$, we need to bring in additional information, namely the Einstein equations, which link the matter content with the geometry of spacetime  For our solution, we only aim to describe the spacetime metric outside whatever spherically-symmetric matter distribution resides in (or around) the center of our spherical symmetry  That amounts to applying the {\em vacuum Einstein equations} 

More specifically, we use a particularly simple and intuitive form of the vacuum Einstein equations, which can be found in a seminal article by Baez and Bunn:\cite{BaezBunn2005} Consider a locally flat free-fall system around a specific event $\cal E$, with a time coordinate $\tau$, local proper time, where the event we are studying corresponds to $\tau=0$  In that system, describe a small sphere of freely floating test particles, which we shall call a {\em test ball}  The particles need to be at rest relative to each other at $\tau=0$  Let the volume of the test ball be $V(\tau)$  Then the vacuum version of Einstein's equations states that
\begin{equation}
\left \frac{\mathrm{d}^2 V}{\mathrm{d}\tau^2}\right|_{\tau=0} = 0 
\label{EinsteinVacuum}
\end{equation}
In words: If there is no matter or energy inside, the volume of such a test ball remains constant in the first order (those were our initial conditions) and the second order (by eq ~[\ref{EinsteinVacuum}])  

If you are familiar with Wheeler's brief summary of Einstein's equations, ``spacetime grips mass, telling it how to move'' and ``mass grips spacetime, telling it how to curve'',\cite{Wheeler1990} you will immediately recognise that this is a specific way for the structure of spacetime telling the test ball particles how to move  The calculation later in this section provides the second part: It will amount to using (\ref{EinsteinVacuum}) to determine the structure of spacetime, namely the still missing function $\beta(r)$, and that is the way for mass, in this case: for the absence of mass, to tell spacetime how to curve 

Note that equation (\ref{EinsteinVacuum}) also holds true in Newtonian gravity  So in a way, this version of Einstein's equation can be seen as a second-order extension of the usual Einstein equivalence principle: Ordinarily, the equivalence principle is a statement about physics in the absence of tidal forces  Equation (\ref{EinsteinVacuum}) adds to this that the lowest-order correction for tidal forces in a freely falling reference frame is that specified by Newtonian gravity  This makes sense, since by going into a free-fall frame, and restricting our attention to a small spacetime region, we have automatically created a weak-gravity situation  In such a situation, tidal corrections are approximately the same as those described by Newton  This argument can serve as a heuristic justification of (\ref{EinsteinVacuum}) 

In 2017, Kassner made use of the Baez-Bunn form of Einstein's vacuum equation to derive the Schwarzschild solution, starting from what we have encountered as the static form of the metric (\ref{StaticForm}) \cite{Kassner2017} We follow the same general recipe, but using the infalling coordinates introduced in section \ref{Sec:InfallingObservers}, which makes our derivation even simpler 

Consider five test particles in a small region of space  Let the motion of each be the same as for the local representative from our coordinate-defining family of infalling observers  We take the central particle $C$ to be at radial coordinate value $r=R$ at the time of the snapshot shown in Fig ~\ref{TestParticlesOutside}  The other four are offset relative to the central particle: As described in the local inertial system that is co-moving with the central particle, one of the particles is shifted by $\Delta l$ upwards in the radial direction, another downward, while two of the particles are offset orthogonally by the same distance 
\begin{figure}[htbp]
\begin{center}
\includegraphics[width=0 5\linewidth]{01-free-fall-particles pdf}
\caption{Five test particles in our spherically-symmetric spacetime}
\label{TestParticlesOutside}
\end{center}
\end{figure}
The $\Delta l$ is meant to be infinitesimally small, so while Fig ~\ref{TestParticlesOutside} is of course showing a rather large $\Delta l$ so as to display the geometry of the situation more clearly, we will in the following only keep terms linear in $\Delta l$  

Consider a generic particle, which moves as if it were part of our coordinate-defining family of infalling observers, and which at the time $T_0$ is at $r=r_0$  By a Taylor expansion, that particle's subsequent movement is given by
\begin{equation}
r(T) = r_0 + \frac{\mathrm{d} r}{\mathrm{d} T}(T_0) \cdot \Delta T +\frac12 \frac{\mathrm{d}^2 r}{\mathrm{d} T^2}(T_0) \cdot \Delta T^2
\label{TaylorREvo}
\end{equation}
where $\Delta T\equiv T-T_0$  We know from (\ref{betaDefinition}) that the derivative in the linear term can be expressed in terms of $\beta(r)$; by the same token,
\begin{equation}
\frac{\mathrm{d}^2 r}{\mathrm{d} T^2} = -c\frac{\mathrm{d}\beta}{\mathrm{d} T}=-c\beta' \frac{\mathrm{d} r}{\mathrm{d} T} = c^2\beta\cdot\beta',
\end{equation}
where the prime denotes differentiation of $\beta$ with respect to its argument  Since, in the following, the product of $\beta$ and its first derivative will occur quite often, let us introduce the abbreviation
\begin{equation}
B(r) \equiv \beta(r)\cdot\beta'(r) 
\label{BigBDefinition}
\end{equation}
With these results, can rewrite the Taylor expansion (\ref{TaylorREvo}) as 
\begin{equation}
r(T) = r_0 -c\beta(r_0)\cdot\Delta T + \frac12 c^2B(r_0)\cdot\Delta T^2 
\label{RadialOrbitTime}
\end{equation}
In order to find $r_C(T)$ for our central particle, we simply insert $r_0=R$ into that expression  If, on the other hand, we want to write down the time evolution for particles $U$ and $D$, let us denote it by $r_{U,D}(T)$, we need to evaluate the expression (\ref{RadialOrbitTime}) at the initial location $r_0=R\pm\Delta l$  Since $\Delta l$ is small, we can make a Taylor expansion of $\beta(r)$ and its derivative around $r=R$, and neglect everything beyond the terms linear in $\Delta l$  The result is
\begin{multline}
r_{U,D}(T)=R \pm\Delta l-c\left[
\beta(R)\pm\beta'(R)\Delta l
\right]\Delta T \\[0 2em]
+\frac{c^2}{2}\big[
B(R)\pm B'(R)\Delta l
\big]\Delta T^2
\end{multline}
In consequence, the distance between the upper and lower particle, $d_{\parallel}(T)\equiv r_U(T)-r_D(T),$ changes over time as
\begin{equation}
d_{\parallel}(T) =  2\Delta l\left[
1-c\beta'(R)\Delta T+\frac12c^2 B'(R)\Delta T^2
\right] 
\label{dParallel}
\end{equation}
Next, let us look at how the distance between the particles $L$ and $R$ changes over time  The initial radial coordinate value for each of the particles is
\begin{equation}
r(T_0) = \sqrt{R^2+\Delta l^2}=R\left[1+\frac12\left(\frac{\Delta l}{R}\right)^2\right]\approx R,
\end{equation}
that is, equal to $R,$ as long as we neglect any terms that are higher than linear in $\Delta l$  In consequence, $r_{L,R}(t)$ is the same function as for our central particle, given by eq ~(\ref{RadialOrbitTime}) with $r_0=R$  The transversal (in Fig ~\ref{TestParticlesOutside}: horizontal) distance $d_{\perp}(T)$ between the particles $L$ and $R$ changes in proportion to the radius value,
\begin{align}
d_{\perp}(T) &= 2\Delta l\cdot\frac{r_{L}(T)}{R} \nonumber \\
                 &=2\Delta \left[1-\frac{c\beta(R)}{R}\Delta T+\frac{c^2}{2}\frac{B(R)}{R}\Delta T^2\right] 
                \label{dPerp}
\end{align}
With these preparations, consider the vacuum Einstein equation (\ref{EinsteinVacuum}) for the volume of a test ball  Initially, our particles $C, U, D, L, R$ define a circle, which is deformed to an ellipse  By demanding rotational symmetry around the radial direction, we can construct the associated ellipsoid, which is initially a spherical surface  That ellipsoid has one axis in radial direction, whose length is $d_{\parallel}(T)$, and two axes that are transversal and each have the length  $d_{\perp}(t)$  But that ellipsoid is not quite yet the test ball we need  After all, the particles of the test ball need to be at rest initially, at time $T_0$, in the co-moving system defined by the central particle $C$  Our defining particles are not, as the terms linear in $\Delta T$ in both (\ref{dParallel}) and (\ref{dPerp}) show, where the coefficients of $\Delta T$ correspond to the particles' initial velocities  

In order to define our test ball, we need to consider particles at the same location, undergoing the same acceleration, but which are initially at rest relative to the central particle $C$  

We could go back to the drawing board, back to Fig ~\ref{TestParticlesOutside}, make a more general Ansatz that includes initial velocities which measure the divergence of the motion of our test ball particles from that of the infalling-observer particles, and repeat our calculation while including those additional velocity terms  But there is a short-cut  The only consequence of those additional velocity terms will be to change the terms linear in $\Delta T$ in equations (\ref{dParallel}) and (\ref{dPerp})  And we already know the end result: We will choose the additional terms so as to cancel the terms linear in $\Delta T$ in the current versions of (\ref{dParallel}) and (\ref{dPerp})  But by that reasoning, we can skip the explicit steps in between, and write down the final result right away  The time evolution of the radial-direction diameter of our test ball, let us call it $L_{\parallel}(T)$, must be the same as $d_{\parallel}(T)$, but without the term linear in $\Delta T$  Likewise, the time evolution $L_{\perp}(T)$ of the two transversal diameters must be equal to $d_{\perp}(T)$, but again without the term linear in $\Delta T$  The result is
\begin{align}
L_{\parallel}(T)  &=  2\Delta l \left[1+\frac12c^2B'(R)\Delta T^2\right] \\
L_{\perp}(T) &= 2\Delta l \left[1+\frac{c^2}{2}\frac{B(R)}{R}\Delta T^2\right] 
\end{align}
Thus, our test ball volume is
\begin{align}
V(T) &= \frac{\pi}{6}L_{\parallel}(T) L_{\perp}^2(T) \\
       &= \left \frac{4\pi}{3}\Delta l^3\left[1+{c^2}\left( \frac{B(r)}{r} + \frac{B'(r)}{2}\right)\Delta T^2\right]\right|_{r=R}
\end{align}
For the second time derivative of $V(T)$ to vanish at the time $T=T_0$, we must have
\begin{equation}
\frac{B(r)}{r} + \frac{B'(r)}{2}= 0
\label{VolumeConditionR}
\end{equation}
for all values of $r$  This is readily solved by the standard method of separation of variables: We can rewrite (\ref{VolumeConditionR}) as
\begin{equation}
\frac{\mathrm{d} B}{B} = -2\frac{\mathrm{d} r}{r},
\end{equation}
which is readily integrated to give
\begin{equation}
\ln(B) = -\ln(r^{2}) + const   \;\; \Rightarrow \;\; \ln(Br^2) = C',
\end{equation}
with a constant $C'$, which upon taking the exponential gives us
\begin{equation}
Br^2= C,
\label{BSolution}
\end{equation}
with a constant $C$  Note that the constant $C$ can be negative --- there is no reason the constant $C'$ needs to be real; only our eventual function $B(r)$ needs to be that, and it is clear that (\ref{BSolution}) satisfies the differential equation
(\ref{VolumeConditionR}) for any constant $C$, positive, zero, or negative  By (\ref{BigBDefinition}), the solution (\ref{BSolution}) corresponds to the differential equation
\begin{equation}
\beta(r)\beta'(r) = \frac{C}{r^2}
\end{equation}
for our function $\beta$; with another separation of variables, we can re-write this as 
\begin{equation}
\beta\cdot\mathrm{d}\beta=C\frac{\mathrm{d} r}{r^2} 
\end{equation}
Both sides are readily integrated up; we can solve the result for $\beta(r)$ and obtain
\begin{equation}
\beta(r) = \sqrt{
-\frac{2C}{r} +2D
},
\end{equation}
where $D$ is the second integration constant, and where we have chosen the proper sign, since we know that $\beta(r)>0$  That brings us to the last step: The requirement that, for large values of $r$, the description provided by our solution should correspond to the results from Newtonian gravity  First of all, we note that our initial condition for the infalling observers, which had those observers start out at zero speed at infinity, means that we must choose $D=0$  Then, as we would expect, $\beta(r)$ for large values of $r$ becomes very small, corresponding to small speeds  But at slow speeds, time and length intervals as measured by the infalling observer will become arbitrarily close to time and length intervals as measured by an observer at rest in our static coordinate system at constant $r$, using the static time coordinate ${t}$  As is usual, we identify these coordinates with those of an approximately Newtonian description  In that description, the radial velocity is
\begin{equation}
v(r) = \sqrt{\frac{2GM}{r}},
\end{equation}
which follows directly from energy conservation for the sum of each observer's kinetic and Newtonian-gravitational potential energy  This fixes the remaining integration constant as
\begin{equation}
C = -\frac{GM}{c^2},
\end{equation}
and the final form of our function $\beta(r)$ becomes
\begin{equation}
\beta(r) = \sqrt{\frac{2GM}{rc^2}} 
\end{equation}
Inserting this result in (\ref{preMetric}), we obtain the metric
\begin{equation}
\mathrm{d} s^2 = -c^2\left[
1-\frac{2GM}{rc^2}
\right]\mathrm{d} T^2+2\sqrt{\frac{2GM}{r}}\mathrm{d} r\:\mathrm{d} T+\mathrm{d} r^2+r^2\mathrm{d}\Omega^2 
\label{GPMetric}
\end{equation}
This is known as the Gullstrand-Painlev\'e version of the Schwarzschild metric \cite{Martel2001,Visser2005,HamiltonLisle2008} A  last transformation step brings us back to the traditional Schwarzschild form  Recall our discussion in sec ~\ref{SymmetriesCoordinates}, leading up to the explicitly static form (\ref{StaticForm}) of the metric? The main difference between our current form and the static version is the mixed term containing $\mathrm{d} r\:\mathrm{d} T$ in (\ref{GPMetric})  Everything else already has the required shape  Inserting the Ansatz
\begin{equation}
\mathrm{d} T = \mathrm{d} t + \xi(r) \mathrm{d} r
\end{equation}
into the metric (\ref{GPMetric}), it is straightforward to see that the mixed term vanishes iff our transformation is
\begin{equation}
\mathrm{d} T = \mathrm{d} t +\frac{\sqrt{2GM/r}}{c^2\left(1-\frac{2GM}{rc^2}\right)}\mathrm{d} r 
\label{TtTrafo}
\end{equation}
Substitute this into (\ref{GPMetric}), and the result is the familiar form of the Schwarzschild metric in Schwarzschild's original coordinates $t,r,\vartheta,\varphi$, 
\begin{equation}
\mathrm{d} s^2 = -c^2\left(1-\frac{2GM}{c^2 r}
\right)\mathrm{d} t^2 + \frac{\mathrm{d} r^2}{\left(1-\frac{2GM}{c^2 r}
\right)} + r^2\mathrm{d}\Omega^2 
\end{equation}

\section{Conclusion}
Using coordinates adapted to the symmetries, we were able to write down the spherically symmetric, static spacetime metric  On this basis, and using the family of infalling observers that is characteristic for the Gullstrand-Painlev\'e solution, we wrote down the metric in the form (\ref{preMetric}), with a single unknown function $\beta(r)$  From the simplified form (\ref{EinsteinVacuum}) of the vacuum Einstein equations, as applied to a test ball in free fall alongside one of our family of observers, we were able to determine $\beta(r)$, up to two integration constants  By using the Einstein equation, we escape the restrictions imposed on simplified derivations by Gruber et al \cite{Gruber1988} 

From the initial condition for our infalling observers, as well as from the Newtonian limit at large distances from our center of symmetry, we were able to fix the values of the two intergration constants  Our derivation does not require knowledge of advanced mathematical concepts beyond the ability to properly interpret a given metric line element $\mathrm{d} s^2$  Even our analysis of tidal effects proceeds via a simple second-order Taylor expansion, leading to differential equations for $\beta(r)$ that are readily solved using two applications of the method of separation of variables  

What is new about the derivation presented here is the combination of the Baez-Bunn equations with the infalling coordinates typical for the Gullstrand-Painlev\'e form of the metric --- this combination is what, in the end, makes our derivation particularly simple  In turn, this simplicity is what should make the derivation particularly useful in the context of teaching general relativity in an undergraduate setting 

The derivation proceeds close to the physics, and gives ample opportunity to discuss interesting properties of Einstein's theory of gravity  Students who are presented with this derivation, either as a demonstration or as a (guided) exercise, will come to understand the way that symmetries determine the form of a metric, the deductions that can be made from Einstein's equivalence principle, and last but not least that we need to go beyond the equivalence principle, and consider tidal forces, to completely define our solution 

\section*{Acknowledgements}

I would like to thank Thomas M\"uller for helpful comments on an earlier version of this text 


Context 3: 

AN OPTIMAL SLR TEST, TWO CUSUM-OAL TESTS AND THEIR LIMITING RELATIONSHIPS

Let P 0 and E 0 denote the probability and the expectation respectively with the probability density p v 0 when there is no change for all the time  It is known that It follows from Proposition 2 38 in and (5 8)-(5 9) in Chow et al, P 108) that the following sequence test of sum of logarithmic likelihood ratio (SLR)
for B > 1, is optimal in the following sense min for P 0 (T SLR < ∞) = α, where c = log B and 0 < α < 1  In particular, if P 0 is the standard normal distribution with mean shift µ > 0 after changepoint, we have Z j − µ 0 = µX j , where µ 0 = −µ 2 /2  It follows from proposition 4 in that the SLR test T SLR in (4) is also optimal (minimal ARL 1 ) with the same false alarm probability P 0 (T < τ ) 
It can be seen that the in-control average run length of T SLR is infinite, that is, ARL 0 = E 0 (T SLR ) = ∞  However, the minimal ARL 1 with finite ARL 0 is a widely used optimality criterion in statistical quality control (see ) and detection of abrupt changes (see   In order to get finite ARL 0 for T SLR , we replace the constant control limit c of T SLR in (3) or (4) with the dynamic control limit n(µ 0 − r) and obtain a modified SLR test T SLR (r) in the following
for r ≥ 0  For comparison, the in-control ARL 0 of all candidate sequential tests are constrained to be equal to the same desired level of type I error, the test with the lowest out-of-control ARL v has the highest power or the fastest monitoring (detection) speed  In the following example 1, the numerical simulations of the out-of-control ARLs of the CUSUM-OAL tests T C (cg u,0 ) in detecting the mean shifts of observations with normal distribution will be compared with that of the SLR tests T * (r) and T * (0), and that of the CUSUM-SLR test T C (c) ∧ T * (0) := min{T C (c), T * (0)} in the following Table  
These comparisons lead us to guess that there are some limiting relationships between T C (cg u,r ) and T * (r), and T C (c g u ) and T C (c) ∧ T * (0), respectively  Example 1  Let X 1 , X 2 ,      be mutually independent following the normal distribution N(0, 1) if there is no change  After the change-point τ = 1, the mean E µ (X k ) ( k ≥ 1 ) will change from v 0 = 0 to v = 0 1, 0 25, 0 5, 0 75, 1, 1 25, 1 5, 3  Here, we let
, where v 1 = 1 is a given reference value which for the CUSUM test is the magnitude of a shift in the process mean to be detected quickly  We conducted the numerical simulation based on 1,000,000 repetitions  The following Table lists the simulation results of the ARLs of the tests T C (c), T C (c g u ) for u = 1, 10, 10 2 , 10 3 , 10 4 , T * (0 0007), T C (c) ∧ T * (0) and T * (0) for detecting the mean shifts, where the mean shift 0 0 means that there is no change which corresponds to the in-control ARL 0 and all tests have the common ARL 0 ≈ 1000 except the test T * (0) which has ARL 0 = ∞ 
The values in the parameters are the standard deviations of the tests  From the last row in Table , it's a little surprising that though the ARL 0 of T * (0) is infinite, that is, E 0 (T * (0)) = ∞, the detection speed of T * (0) is faster than that of the CUSUM chart T C for all mean shifts, in particular, for detecting the small mean shift 0 1, the speed of T * (0) is only 7 47 which is very faster than the speed, 439, of the CUSUM test 
Moreover, both control charts T * (0 0007) and T C (11 9271) ∧ T * (0) not only have the nearly same detection performance as T * (0) but also can have the finite in-control ARL 0   Note particularly that when the number u in g u is taken from 0 to 1, 10, 10 2 , 10 3 , 10 4 , the detection speed of T C (c g u ) is getting faster and faster, approaching to that of T C (c) ∧ T * (0) 
This inspires us to prove the following theoretic results  Let τ = 1 and {X k , k ≥ 1} be an i i d  observations sequence with Theorem 2 shows that when the constant control limit c of the CUSUM test T C (c) is replaced with the observation-adjusted control limits {cg u,r ( Ẑn )} and {c g u ( Ẑn )} respectively, the corresponding two CUSUM-OAL tests {T C (cg u,r )} and {T C (c g u )} will converge to the optimal SLR test T * (r) and the CUSUM-SLR test T C (c) ∧ T * (0) as u → ∞, respectively 
In other words, the fastest alarm times that {T C (cg u,r )} and {T C (c g u )} can be reached are T * (r) and T C (c) ∧ T * (0), respectively  u ≥ 0} can be seen as two "long bridges" connecting T C (c) and T * (r), and T C (c) and T C (c) ∧ T * (0), respectively 

ESTIMATION AND COMPARISON OF ARL OF THE CUSUM-OAL TEST

In this section we will give an estimation of the ARLs of the following CUSUM-OAL test that can be written as where g( ) is a decreasing function, Ẑn (ac x] denotes the smallest integer greater than or equal to x  Here Ẑn (ac) is a sliding average of the statistics, Next we discuss on the the post-change probability distribution in order to estimate the ARLs of T C (cg) 
Usually we rarely know the post-change probability distribution P v of the observation process before it is detected  But the possible change domain and its boundary (including the size and form of the boundary) about v may be determined by engineering knowledge, practical experience or statistical data 
So we may assume that the region of parameter space V and a probability distribution Q on V are known  If we have no prior knowledge of the possible value of v after the change time τ , we may assume that v occurs equally on V , that is, the probability distribution Q is an equal probability distribution (or uniform distribution ) on V 



ground_truth: Using the vacuum Einstein equation and the Baez-Bunn form.

prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: What are the three subsets into which the parameter space V is divided?

Read the following text and answer briefly.

Context 3: 
For example, let P v be the normal distribution and v = (µ, σ), where µ and σ denote the mean and standard deviation respectively, we can take the set V = {(µ, σ) : and Q is subject to the uniform distribution U(V ) on V if v occurs equally on V , where the numbers µ 1 , µ 2 , σ 1 and σ 2 are known  It means that we know the domain of the possible post-change distributions, P v , v ∈ V , i e , the boundary ∂V of the parameter space V is known 
Next we shall divide the parameter space V into three subsets V + , V 0 and V − by the Kullback-Leibler information distance  Let and are two Kullblak-Leibler information distances between P v , P v 0 and P v , P v 1   Since I(p|q) = 0 if and only if p = q, where p and q are two probability measures, it follows that
, it means that P v is closer to P v 0 than to P v 1 according to the Kullblak-Leibler information distance  There is a similar explanation for v ∈ V + or ∈ V 0   Suppose the post-change distribution P v and the function g(x) satisfy the following conditions: (I) The probability P v is not a point mass at E v (Z 1 ) and P v (Z 1 > 0) > 0 
(II) The moment-generating function h v (θ) = E v (e θZ 1 ) satisfies h v (θ) < ∞ for some θ > 0  (III) The function g(x) is decreasing, its second order derivative function g ′′ (x) is continuous and bounded, and there is a positive number x * such that g(x * ) = 0  ) and and therefore, Θ ′ (θ(u)) = −H(θ(u)) = −H(θ * v ) = 0, Θ ′ (θ(1/x)) > 0 for x > 1/u and Θ ′ (θ(1/x)) < 0 for x > 1/u 
Hence, there exists a positive number b defined in (??)  It can be seen, the main part of ARL v (T c (g)) will be an exponential function, square function, and linear function of c when the process {Z k : k ≥ 0} has no change or a "small change", a "medium change" and a "large change" from P v 0 to P v , respectively 
Here, the "small change" (v ∈ V − ) means that P v is closer to P v 0 than to P v 1 , i e , I(P v |P v 0 ) < I(P v |P v 1 ), and the "large change" is just the opposite  The "medium change" (v ∈ V 0 ) corresponds to In this paper, we will use another method to prove Theorem 3 since Wald's identity and the martingale method do not hold or can not work for showing the ARLs estimation of the test T c (g) when g is not constant 
Next we compare the detection performance of the CUSUM-OAL test (ARL v (T c ′ (g))) with that of the CUSUM test (ARL v (T C (c))) by using (??) in Theorem 4 1  ) when µ 0 < µ < 0 and for θ * v 0 > g(µ)/g(µ 0 ) when µ ≥ 0  This means that ARL v (T c (g)) can be smaller than ARL v (T C (c)) as long as g(µ)/g(µ 0 ) is small for all µ > µ 0  

NUMERICAL SIMULATION AND A REAL EX-AMPLE ILLUSTRATION

4 1 Numerical Simulation of ARLs for τ ≥ 1 By the simulation results of ARLs in Table , we see that the detection performance of T * (r), T C (c)∧T * (0), T * (0) and T C (c g u ) for large u is much better than that of the conventional CUSUM test T C for τ = 1  The following Table illustrates the simulation values of E τ i ,v and J ACE of nine tests in detecting two mean shifts v = 0 1 and v = 1 after six change-points, τ i , 1 ≤ i ≤ 6 with ARL 0 (T ) = E 0 (T ) ≈ 500 
Note that H v (θ) is a convex function and H ′ v (0) = µ < 0  This means that there is a unique positive number   It follows from (A 9) that for a large c  Taking θ ց θ * v and u ′ ց u, we have for a large c  Thus, by (A 11) we have as c → ∞  By the properties of exponential distribution, we have for a large c 
To prove the downward inequality of (A 10), let where b is defined in (??) and without loss of generality, we assume that b > a  Obviously, Let k = xcg(µ)  By Chebyshev's inequality, we have Since Hv (θ) and H v (θ) are two convex functions and Let m = tcg(µ)θ * v /bc for t > 0  By (A 13), (A 14), (A 15) and Theorem 5 1 in Esary, Proschan and Walkup (1967) we have
Finally, as c → +∞, where θ 0 > 0 satisfies h v (θ 0 ) = 1  Thus as c → ∞  This implies that for a large c  This completes the proof of (A 10)  Let v ∈ V 0   Let m 1 = (cg(0)) 2 /σ 2   It follows that Note that for a large c, where A = |g ′ (0)|/a, and , where Φ( ) is the standard normal distribution  Let m 2 = (cg(0)) 2 /(8σ 2 ln c) 
Note that as c → ∞, where the third inequality comes from Theorem 5 1 in Esary, Proschan and Walkup (1967)  Thus, we have Let v ∈ V + and let The uniform integrability of {T c (g)/c} for c ≥ 1, follows from the well-known uniform integrability of {T 0 /c} (see Gut (1988)) 



ground_truth: The three subsets are V+, V0, and V-, determined by the Kullback-Leibler information distance.